Theoretical Aspects of TDM in Psychiatry
Pharmacokinetics, metabolism and pharmacogenetics of neuropsychiatric drugs
Most psychotropic drugs share a number of pharmacokinetic characteristics
-
good absorption from the gastrointestinal tract within plasma concentrations reaching
a maximum within 1–6 h
-
highly variable first-pass metabolism (systemic bioavailability ranging 5–90%)
-
fast distribution from plasma to the central nervous system with 2- to 40-fold higher
levels in brain than in blood
-
high apparent volume of distribution (about 10–50 L/kg)
-
low trough plasma concentrations under steady-state (about 0.1–500 ng/mL for psychoactive
drugs and up to 20 µg/mL for neurological drugs)
-
slow elimination from plasma (half-life 12–36 h) mainly by hepatic metabolism
-
linear pharmacokinetics at therapeutic doses which has the consequence that doubling
the daily dose will result in a doubling of the plasma level
-
low renal excretion with small effect of renal insufficiency on the plasma concentrations
of parent drug and active metabolites
-
cytochrome P450 (CYP) and UDP-glucuronosyltranferases as major metabolic enzyme systems
There are, however, numerous exceptions. For example, venlafaxine, nefazodone, trazodone,
tranylcypromine, moclobemide, quetiapine, rivastigmine and ziprasidone display short
(about 2–10 h) elimination half-lives, whereas aripiprazole and fluoxetine have long
elimination half-lives (72 h for aripiprazole and 3–15 days for fluoxetine, taking
into account its active metabolite norfluoxetine). Amisulpride, milnacipran, memantine,
gabapentin, or sulpiride are not or only poorly metabolised in the liver but also
mainly excreted renally. Paroxetine exhibits non-linear pharmacokinetics, due to the
inhibition of its own metabolism by a metabolite which is irreversibly bound to the
enzyme (mechanism based inhibition) resulting in its inactivation [69].
Many psychotropic drugs are used as racemic compounds, and their enantiomers differ
markedly in their pharmacology, metabolism and pharmacokinetics [53]
[605]. So far however, methadone, methylphenidate and flupentixol are at present the only
racemic psychotropic compounds for which TDM of the enantiomers has been introduced
[39]
[189]. The active principles of racemic methadone and fluoxetine are (R)-methadone and
cis-(Z)-flupentixol, respectively. For research projects and other special situations,
stereoselective analysis should be considered, e. g., for citalopram, fluoxetine,
reboxetine, venlafaxine, paliperidone or amitriptyline metabolites.
Most psychotropic drugs undergo phase-I metabolism by oxidative (e. g., hydroxylation,
dealkylation, oxidation to N-oxides, S-oxidation to sulfoxides or sulfones), reductive
(e. g., carbonyl reduction to secondary alcohols) or hydrolytic reactions, dealkylation,
oxidation to N-oxides, carbonyl reduction to secondary alcohols or S-oxidation to
sulfoxides or sulfones. The phase-I reactions are predominantly catalysed by cytochrome
P450 (CYP) enzymes which comprise more than 200 isoenzymes. The most important isoenzymes
for psychotropic medications are CYP1A2, CYP2B6, CYP2D6, CYP2C9, CYP2C19 and CYP3A4/5
([Table 1]) [745]
[746]
[747]. In general, phase-I reactions introduce a polar functional group that enables a
phase-II conjugation reaction with highly polar molecules such as glucuronic or sulphuric
acid. For psychotropic compounds possessing functional groups in the parent compound,
glucuronidation of a hydroxyl group (for example oxazepam or lorazepam) or an N-H
group (for example olanzapine) may represent the essential metabolic pathway. In addition,
tertiary amine groups can be conjugated with the formation of quaternary ammonium
glucuronides. Actually, phase II enzymes are poorly characterised with regard to substrate
specificity, and there is much overlap between the isozymes regarding affinity for
substrates [143].
Table 1 Psychopharmacologic medications and enzymes involved in their metabolism.
Drug (active metabolite)
|
Enzymes
|
Reference
|
Inhibition of enzymes indicated in bold will significantly increase the plasma concentrations
of the drug, induction (CYP1A2, CYP3A4) will lead to decreased plasma concentrations
(See [Table 2]). Prepared by CH, reviewed and supplemented by EJS
|
Acamprosate
|
not involved (not metabolized)
|
[578]
|
Agomelatine
|
CYP1A2, CYP2C19
|
[78]
|
Amantadine
|
merely involved (90% excreted unmetabolized)
|
[24]
|
Alprazolam
|
CYP3A4/5
|
[17]
[496]
|
Amisulpride
|
merely involved (more than 90% is excreted unmetabolized via the kidney)
|
[566]
|
Amitriptyline and amitriptyline oxide (amitriptyline, nortriptyline)
|
CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4
|
[90]
[650]
[713]
|
Aripiprazole (dehydroaripiprazole)
|
CYP2D6, CYP3A4
|
[306]
[701]
|
Asenapine
|
Glucuronosyltransferase and CYP1A2
|
[707]
|
Atomoxetine
|
CYP2D6
|
[446]
|
Benperidol
|
unclear
|
[589]
|
Benserazide
|
hydroxylation, COMT
|
[347]
|
Biperiden
|
hydroxylation
|
[628]
|
Bromocriptine
|
CYP3A4
|
[513]
|
Bromperidol
|
CYP3A4
|
[230]
[633]
[645]
[736]
|
Brotizolam
|
CYP3A4
|
[655]
|
Buprenorphine (norbuprenorphine)
|
CYP2C8, CYP3A4
|
[79]
[454]
|
Bupropion (hydroxybupropion)
|
CYP2B6
|
[309]
|
Buspirone
|
CYP3A4
|
[416]
|
Cabergoline
|
hydrolysis, CYP3A4
|
[167]
|
Carbidopa
|
unknown metabolic pathways 1/3 unmetabolized
|
[575]
|
Carbamazepine, CBZ (CBZ-10,11-epoxide)*
|
CYP1A2, CYP2B6, CYP2C8, CYP3A4/5
|
[360]
[497]
|
Chlorpromazine
|
CYP1A2, CYP2D6
|
[724]
|
Citalopram
|
CYP2C19, CYP2D6, CYP3A4
|
[97]
[227]
[645]
|
Clomipramine (norclomipramine)
|
CYP1A2, CYP2C19, CYP2D6, CYP3A4
|
[244]
|
Clomethiazol
|
CYP2A6, CYP2B6, CYP3A4
|
[116]
|
Clozapine
|
CYP1A2, CYP2C19, CYP3A4
|
[334]
[487]
|
Desipramine
|
CYP2D6
|
[244]
|
Diazepam (nordazepam, oxazepam, temazepam)
|
CYP2B6, CYP2C19, CYP3A4
|
[228]
[704]
|
Dihydroergocryptine
|
CYP3A4
|
[19]
[162]
|
Diphenhydramine
|
CYP2D6
|
[13]
|
Disulfiram
|
CYP1A2, CYP2B6, CYP2E1, CYP3A4
|
[412]
|
Donepezil
|
CYP2D6, CYP3A4
|
[681]
|
Dothiepin=Dosulepin
|
CYP2C19, CYP2D6
|
[740]
|
Doxepin (nordoxepin)
|
CYP2C9, CYP2C19, CYP2D6
|
[295]
[365]
|
Duloxetine
|
CYP1A2, CYP2D6
|
[405]
|
Entacapone
|
Glucuronosyltransferase
|
[387]
|
Escitalopram
|
CYP2C19, CYP2D6, CYP3A4
|
[662]
[697]
|
Fluoxetine (norfluoxetine)
|
CYP2B6, CYP2C9, CYP2C19, CYP2D6
|
[404]
[588]
|
Flupenthixol
|
CYP2D6
|
[148]
[365]
|
Fluphenazine
|
CYP2D6
|
[746]
|
Fluvoxamine
|
CYP2D6, CYP1A2
|
[354]
[450]
|
Galantamine
|
CYP2D6, CYP3A4
|
[34]
|
Gabapentin
|
unmetabolized renal excretion
|
[77]
|
Haloperidol
|
CYP2D6, CYP3A4
|
[93]
[645]
|
Iloperidone
|
CYP2D6, CYP3A4
|
[106]
|
Imipramine (desipramine)
|
CYP1A2, CYP2C19, CYP2D6, CYP3A4
|
[244]
[413]
|
Lamotrigine
|
Glucuronosyltransferase, CYP2A6
|
[121]
|
Levodopa
|
Dopadecarboxylase, COMT, MAO
|
[575]
|
Levomepromazine
|
CYP1A2, CYP2D6
|
[36]
|
Levomethadon
|
CYPC19, CYP2B6, CYP3A4, CYP2D6
|
[145]
|
Lisuride
|
CYP3A4, CYP2D6
|
[539]
|
Lithium
|
no metabolism, renal clearance
|
[256]
[619]
|
Lorazepam
|
Glucuronosyltransferase
|
[164]
[196]
|
Maprotiline
|
CYP2D6, CYP1A2
|
[86]
|
Melatonin
|
CYP1A2
|
[296]
|
Memantine
|
merely metabolized
|
[251]
|
Methadone
|
CYP2B6, CYP2C19, CYP3A4, CYP2D6
|
[145]
|
Methylphenidate
|
Carboxylesterase 1
|
[468]
|
Mianserine
|
CYP2D6, CYP1A2, CYP3A4
|
[379]
|
Midazolam
|
CYP3A4
|
[220]
|
Milnacipran
|
no CYP related metabolism
|
[495]
[533]
|
Mirtazapine
|
CYP3A4, CYP1A2, CYP2B6, CYP2D6
|
[397]
[630]
|
Moclobemide
|
CYP2C19, CYP2D6
|
[255]
|
Modafinil
|
Amide hydrolysis, CYP3A4
|
[561]
|
Naltrexone
|
Aldoketoreductase AKR1C4
|
[92]
|
Nortriptyline
|
CYP2D6
|
[385]
[485]
[687]
|
Olanzapine
|
N-Glucuronosyltransferase, Flavin monoxigenase, CYP1A2, CYP2D6
|
[107]
|
Opipramol
|
unclear
|
|
Paliperidone (=9-Hydroxyrisperidone)
|
60% excreted unmetabolized, different pathways
|
[161]
|
Paroxetine
|
CYP1A2, CYP2D6, CYP3A4
|
[209]
[349]
[691]
|
Perazine
|
CYP1A2, CYP2C19, CYP3A4, Flavin monoxigenase
|
[629]
[725]
|
Pergolide
|
CYP3A4
|
[731]
|
Perphenazine
|
CYP1A2, CYP2C19, CYP2D6, CYP3A4
|
[12]
[77]
[168]
[486]
|
Pregabalin
|
unmetabolized renal excretion
|
[77]
|
Piripedil
|
demethylation, p-hydroxylation, and N-oxidation
|
[168]
|
Pimozide
|
CYP1A2, CYP3A4
|
[171]
|
Pramipexole
|
not metabolized
|
[62]
|
Promazine
|
CYP1A2, CYP2C19, CYP3A4
|
[726]
|
Promethazine
|
CYP2D6
|
[465]
|
Quetiapine
|
CYP3A4, CYP2D6
|
[38]
|
Rasagiline
|
CYP1A2
|
[277]
|
Reboxetine
|
CYP3A4
|
[307]
[716]
|
Risperidone (9-Hydroxyrisperidone)
|
CYP2D6, CYP3A4
|
[732]
|
Ropinirole
|
CYP1A2
|
[357]
|
Rotigotine
|
Glucuronosyltransferase, several other unknown pathways
|
[115]
|
Selegiline
|
CYP2B6
|
[60]
|
Sertindole
|
CYP3A4, CYP2D6
|
[729]
|
Sertraline
|
CYP2B6, CYP2C19, CYP2C9, CYP2D6
|
[482]
[705]
|
Thioridazine
|
CYP1A2, CYP2C19, CYP2D6, CYP3A4
|
[648]
[714]
|
Tiapride
|
mainly not metabolized
|
[477]
|
Tolcapone
|
Glucuronosyltransferase
|
[387]
|
Trimipramine (nortrimipramine)
|
CYP2C19, CYP2D6, CYP2C9
|
[187]
|
Tranylcypromine
|
monoamine oxidase, unclear
|
[37]
|
Trazodone
|
CYP3A4, CYP2D6
|
[268]
[567]
|
Valproic acid
|
Glucuronosyltransferase, CYP2A6, CYP2B6, CYP2C9, beta-oxidation
|
[641]
|
Venlafaxine (O-desmethylvenlafaxine)
|
CYP2C19, CYP2D6, CYP3A4
|
[217]
[434]
|
Zaleplone
|
Aldehyde oxidase, CYP3A4
|
[554]
|
Ziprasidone
|
CYP3A4, Aldehyde oxidase
|
[58]
[519]
|
Zolpidem
|
CYP1A2, CYP2C9, CYP3A4
|
[698]
|
Zopiclone
|
CYP2C8, CYP3A4
|
[57]
[659]
|
Zotepine
|
CYP1A2, CYP2D6, CYP3A4
|
[596]
|
Zuclopenthixol
|
CYP2D6
|
[330]
|
Other enzymatic systems may also be involved, such as keto-aldehyde oxidases [43], which have been shown to reduce ziprasidone to its dihydro-derivative [58] or naltrexone to naltrexol [92], or MAO-A and MAO-B, which deaminate citalopram stereoselectively to an apparently
inactive acidic metabolite [562].
Drugs are metabolised mainly in the liver and, to a minor degree, in extrahepatic
tissues such as the intestinal mucosa or the brain [59]
[238]
[444]. Inter- and intra-individual differences in plasma concentrations of psychotropic
drugs (i. e., the pharmacokinetic variability) are caused by different activities
of drug-metabolising enzymes. The enzyme activity may decrease with age [374] and can be modified by renal and hepatic diseases. Gender differences have been
reported for psychotropic drugs, but the findings are inconsistent and the clinical
relevance is not clear [7]
[8]
[9]
[608].
For a number of psychoactive drugs, metabolites actively contribute to the overall
clinical effect of the parent compound. For this reason, TDM must include the quantification
of active metabolites, e. g., in the case of clomipramine (norclomipramine), doxepin
(nordoxepin), fluoxetine (norfluoxetine) or risperidone (9-hydroxyrisperidone). For
drugs like sertraline or clozapine, the clinical relevance of their metabolites norsertraline
and norclozapine, respectively, is still a matter of debate. The analysis of pharmacologically
inactive metabolites, however, may give useful information on the metabolic state
of the patient or on his/her compliance [105]
[569]. [Table 2] shows the “normal” ratios of concentrations of metabolites to parent drugs. Calculated
ranges contain 68% of the ratios expected under standard dosages, i. e., ratios within
the range of the mean±1 SD assuming normal distribution. A ratio above or below the
“normal ratio” ([Table 2]) can indicate problems of drug adherence [546] or metabolic abnormalities due to a genetic variation [157]
[159]
[350]
[592] or a drug-drug interaction. Spina and co-workers [618] have shown this for the conversion of 2-hydroxy-desipramine to desipramine. With
regard to drug-drug interactions, ratios increase if the enzymatic conversion of the
parent medication is induced by concurrent psychotropic or non-psychotropic medications
or pharmacokinetically relevant activities such as smoking ([Table 3]). Other co-medications and food which inhibit metabolic enzymes may decrease the
ratio. [Table 3] summarizes drugs that are inhibitors or inducers of CYP enzymes and thus may lead
to clinically relevant pharmacokinetic drug-drug interactions.
Table 2 Ranges of metabolite-to-parent concentration ratios for psychopharmacologic medications.
Reported ranges contain 68% of ratios determined under “normal” conditions in the
blood of patients or healthy subjects.
Drug
|
Metabolite
|
Ratios of concentrations metabolite: parent drug (Mean̶ SD – Mean + SD)
|
Reference
|
*pharmacologically active metabolite, (*) active metabolite in vitro but unclear under
in vivo conditions
|
When SD values of ranges of ratios (SD ratio) were not reported in the literature,
SD ratios were calculated in accordance with Gaussian’s law for the propagation of
errors: SD ratio=[(SD parent drug x mean metabolite)+(SD metabolite x mean parent
drug)]/(mean metabolite)2
|
Prepared by CH, reviewed by Sonja Brünen, Christiane Knoth, Elnaz Ostad Haji and Viktoria
Stieffenhofer
|
Amitriptyline
|
Nortriptyline*
|
0.2–1.8 (n=83)
|
[545]
|
Aripiprazole
|
Dehydroaripirazole(*)
|
0.3–0.5 PM of CYP2D6: 0.2
|
[306]
[368]
[452]
|
Bromperidol
|
Reduced bromperidol
|
0.11–0.51 (n=31)
|
[609]
[633]
|
Buprenorphine
|
Norbuprenorphine
|
0.8–2.0 (n=5)
|
[383]
|
Bupropion
|
Hydroxybupropion
|
5–47 (24 h, n=9) 6–30 (12 h, n=9)
|
[152]
[253]
[336]
|
Buspirone
|
6-Hydroxybuspirone
|
25–53 (n=20)
|
[178]
|
Carbamazepine
|
Carbamazepine-10,11-epoxide
|
0.07–0.25 (n=14)
|
[338]
|
Citalopram
|
N-Desmethylcitalopram
|
0.31–0.60 (n=2330)
|
[549]
|
Clomipramine
|
Norclomipramine*
|
0.8–2.6 (n=115)
|
[545]
|
Clozapine
|
Norclozapine(*)
|
nonsmokers (n=98) 0.5–0.6 smokers (n=198) 0.4–0.7
|
[140]
[308]
[500]
|
Dothiepin
|
Nordothiepin
|
0–1.4 (n=50)
|
[325]
|
Doxepin
|
Nordoxepin
|
0.6–1.6 (n=12) PM CYP2C19: 1.8 (n=4) PM CYP2D6: 0.8 (n=6)
|
[172]
[363]
|
Escitalopram
|
N-Demethylescitalopram
|
0.3–1.0 (n=243)
|
[548]
|
Fluoxetine
|
Norfluoxetine*
|
0.7–1.9 (n=334)
|
[545]
|
Fluvoxamine
|
Fluvoxamino acid
|
0–1.2 (n=49)
|
[237]
|
Haloperidol
|
Reduced haloperidol
|
mean 0.6
|
[673]
|
Imipramine
|
Desipramine
|
0.6–3.2 (n=14) PM CYP2D6 4.1 (n=2)
|
[95]
[96]
[632]
|
Maprotiline
|
Desmethylmaprotiline
|
1.1–3.7 (n=76) PM CYP2D6 4.9
|
[699]
|
Mianserin
|
N-Desmethylmianserin
|
0.5–0.8 (n=182)
|
[545]
|
Mirtazapine
|
N-Desmethylmirtazapine
|
0.2–1.2 (n=100)
|
[591]
|
Moclobemide
|
Moclobemide N-oxide
|
0.8–2.5 (n=6)
|
[291]
|
Olanzapine
|
N-Demethylolanzapine
|
non smokers: 0.1–0.3 (n=76) smokers: 0.2–0.4 (n=69)
|
[602]
|
Perazine
|
Desmethylperazine
|
1.1–3.3 (n=27)
|
[91]
|
Perphenazine
|
N-Dealkylperphenazine
|
0.6–2.8 (n=54)
|
[637]
|
Quetiapine
|
Norquetiapine
|
0.1–3.8 (n=25) (calculated for 400 mg)
|
[723]
|
Reboxetine
|
O-Desethylreboxetine
|
<0.1
|
[484]
|
Risperidone
|
9-Hydroxyrisperidone*
|
EM or IM CYP2D6: 1.5–10.0 PM CYP2D6:≤1
|
[159]
[677]
|
Risperidone depot
|
9-Hydroxyrisperidone*
|
EM: 1.2–4.3
|
[469]
|
Sertindole
|
Dehydrosertindole
|
1.1–2.7 (n=6) 1.0 in PM of CYP2D6
|
[729]
|
Sertraline
|
Norsertraline
|
1.7–3.4 (n=348)
|
[546]
|
Trazodone
|
m-Chlorophenylpiperazine (mCPP)
|
0.04–0.22 (total range)
|
[328]
|
Trimipramine
|
Nortrimipramine*
|
0–12.0 (n=17)
|
[142]
|
Venlafaxine
|
O-Desmethylvenlafaxine* N-Desmethylvenlafaxine
|
EM or IM CYPD26: 0.3–5.2 PM CYP2D6:≤0.3 UM CYP2D6:>5.2 0.46–1.48
|
[592]
|
Table 3 Inhibitors and inducers of enzymes involved in the metabolism of drug.
Inhibiting drugs
|
Inhibited enzymes
|
Inducing drugs
|
Induced enzymes
|
Combination of psychoactive drugs with these inhibitors or inducers can lead to clinically
relevant drug-drug interactions (http://www.mediq.ch%20or%20www.psiac.de http://www.mediq.ch or http://www.psiac.de)
|
Prepared by CH, reviewed by EJS
|
Amiodarone
|
CYP2C9, CYP2D6, CYP3A4
|
Carbamazepine
|
CYP1A2, CYP2B6, CYP2C9, CYP3A4
|
Bupropion
|
CYP2D6
|
Dexamethason
|
CYP2C9, CYP3A4
|
Bromocriptine
|
CYP3A4
|
Efavirenz
|
CYP2B6, CYP3A4
|
Chinidine
|
CYP2D6
|
Ethanol
|
CYP2E1
|
Cimetidin
|
CYP1A2, CYP2D6, CYP3A4
|
Ginkgo biloba
|
CYP2C19
|
Ciprofloxacin
|
CYP1A2
|
Isoniazide
|
CYP2E1
|
Clarithromycin
|
CYP3A4
|
St. John’s wort
|
CYP2C19, CYP3A4
|
Clopidogrel
|
CYP2B6
|
Oxybutynin
|
CYP3A4
|
Disulfiram
|
CYP2E1
|
Phenobarbital
|
CYP2C9, CYP2C19, CYP3A4
|
Duloxetine
|
CYP2D6
|
Phenytoin
|
CYP2B6, CYP2C9, CYP2C19, CYP3A4
|
Enoxacin
|
CYP1A2
|
Primidon
|
CYP2C9, CYP2C19, CYP3A4
|
Erythromycin
|
CYP3A4
|
Smoke
|
CYP1A2
|
Esomeprazole
|
CYP2C19
|
Rifabutin
|
CYP3A4
|
Felbamate
|
CYP2C19
|
Rifampicin
|
CYP1A2, CYP2B6, CYP2C9, CYP2C19
|
Fluconazole
|
CYP2C19, CYP2C9, CYP3A4
|
Ritonavir
|
CYP3A4, CYP2C9, CYP3A4 (high dose)
|
Fluoxetine and norfluoxetine
|
CYP2D6, CYP2C19
|
|
|
Fluvoxamine
|
CYP1A2, CYP2C9, CYP2C19, CYP3A4
|
|
|
Indinavir
|
CYP3A4
|
|
|
Isoniazid
|
CYP1A2, CYP2A6, CYP2C19, CYP3A4
|
|
|
Itraconazol
|
CYP2B6, CYP3A4
|
|
|
Ketoconazol
|
CYP3A4
|
|
|
Levomepromazine
|
CYP2D6
|
|
|
Melperone
|
CYP2D6
|
|
|
Metoclopramide
|
CYP2D6
|
|
|
Metoprolol
|
CYP2D6
|
|
|
Miconazol
|
CYP2C9, CYP2C19
|
|
|
Mifepriston
|
CYP3A4
|
|
|
Moclobemide
|
CYP2C19, CYP2D6
|
|
|
Nelfinavir
|
CYP3A4
|
|
|
Norfloxacine
|
CYP1A2
|
|
|
Omeprazole
|
CYP2C19
|
|
|
Paroxetine
|
CYP2D6
|
|
|
Perazine
|
CYP1A2
|
|
|
Pergolide
|
CYP2D6
|
|
|
Perphenazin
|
CYP2D6
|
|
|
Propafenon
|
CYP1A2, CYP2D6
|
|
|
Propranolol
|
CYP2D6
|
|
|
Ritonavir
|
CYP2D6, CYP3A4
|
|
|
Saquinavir
|
CYP3A4, CYP2C9
|
|
|
Troleandomycin
|
CYP3A4
|
|
|
Valproate
|
CYP2C9
|
|
|
Verapamil
|
CYP3A4
|
|
|
Voriconazol
|
CYP2C9, CYP3A4
|
|
|
Pharmacogenetic aspects
The clinical importance of pharmacogenetic factors in the pharmacokinetics and pharmacodynamics
of psychoptropic drugs is increasingly recognised [156]
[199]
[457]. Drug-metabolising enzymes, especially CYP isoenzymes, exhibit genetic variability
[745]
[746]
[747]. When the frequency of a deviation in the alleles is at least 1% of the population,
it is considered a genetic polymorphism. The number of active alleles in a gene determines
how much of the enzyme is expressed (phenotype). Poor metabolisers (PM) lack functional
alleles. Intermediate metabolisers (IM) are either genetically heterozygous, carrying
an active and an inactive allele (or an allele with reduced activity) or have 2 alleles
with reduced activity. Extensive metabolisers (EM) are wild-type with 2 active alleles,
and ultra-rapid metabolisers (UM) have an amplification of functional alleles [66]. Genetic polymorphisms of drug-metabolising enzymes may be clinically important,
because unexpected adverse reactions and toxicity may occur in PM due to increased
plasma concentrations and non-response may occur in UM due to subtherapeutic plasma
concentrations [160]. Prodrugs are activated by metabolism such as codeine by CYP2D6 to morphine or clopidogrel
by CYP2C19 to 2-oxoclopidogrel. PM patients will not be able to produce pharmacologically
active metabolites. Other enzyme systems such as UDP-glucuronosyltransferases also
display genetic polymorphism [155], but their clinical relevance in pharmacopsychiatry is unclear.
CYP genotyping methods are becoming more and more available, and guidelines have been
published for their use in clinical practice [675]. The functional significance of many genotypes, however, is unclear. For some enzymes,
a genetic polymorphism is not clearly demonstrated despite the fact that they display
a wide interindividual variability in their activity. Therefore it may be advantageous
to use phenotyping methods with probe drugs such as caffeine for CYP1A2, omeprazole
for CYP2C19, dextromethorphan for CYP2D6, or midazolam for CYP3A4/5 [403]
[643]. Phenotyping measures the metabolic situation of the patient at the moment of the
test, and allows to follow its evolution. The measurement, however, may be influenced
by environmental factors such as smoking or comedications [201]
[601]
[749]. The clear advantage of genotyping is that it represents a “trait marker” and that
its result is not influenced by environmental factors. It can be carried out in any
situation and its result has a lifetime value.
Recent investigations indicate that the drug efflux transporter P-glycoprotein (P-gp)
in the intestinal mucosa and blood-brain-barrier is also relevant for the pharmacokinetic
variability of psychotropic medications [1]. This protein, a member of the ATP-cassette binding (ABC) transporter protein family,
is encoded by the multidrug resistance gene (MDR1; ABCB1). It displays a genetic polymorphism, but as yet, mainly genotyping but not phenotyping
(e. g., with digoxin) is more commonly used [129]
[183]
[210]
[389]. Genetic polymorphism of P-gp may be of the same considerable clinical relevance
as has been demonstrated for drug-metabolizing enzymes. For antidepressant drugs that
are substrates of P-gp, a genotype dependent association of drug response was found
[668]
[669]. Both plasma concentrations of quetiapine and its clinical effectiveness have been
shown to depend on the P-gp genotype of patients suffering from schizophrenia [470]. With regard to the occurrence of wanted or unwanted clinical effects of psychoactive
drugs, some first reports suggest the influence of the genetic polymorphism of P-gp
[279]
[560]. However, further research is needed to evaluate the clinical relevance of the genetic
polymorphisms of drug transporters.
Dose and drug concentration in blood
In most situations that use TDM for dose optimization, drugs are administered in a
series of repeated doses to attain a steady-state concentration within a given therapeutic
reference range. Steady-state is attained when the rate of medication input equals
the rate of medication loss, i. e., approximately after 4 times the elimination half
life. With multiple dosing, 94% of the steady state are achieved after 4 and 97% after
5 elimination half-lives. For more than 90% of all psychoactive medications, such
a steady-state is reached within 1 week of maintenance dosing. The dose required to
attain a steady-state concentration of a drug in plasma can be calculated if the dosing
interval (τ), the clearance (Cl) and the bioavailability (F) for the drug in a particular
patient are known. The calculation is based on the direct correlation of the drug
dose De (constant dose per day at steady-state) to its blood concentration c, with the total
clearance of the drug (Clt) being the correlation coefficient:
De=DxF/τ=c x Clt
Based on this information it is possible to calculate the dose-related plasma concentration
of a drug that may be expected in blood specimens of patients under medication with
a given dose [285]:
c=De/Clt
For psychoactive medications, such data are available from studies in which drug concentrations
were measured in plasma of healthy volunteers or patients treated with fixed doses.
When the clearance is taken as arithmetic mean±standard deviation from clinical trials
of the drug, a dose related reference range can be calculated [285].
Definition
The “dose-related reference range” reported in the present guidelines is calculated as a concentration range within
that a drug concentration is expected according to pharmacokinetic studies in human
blood specimens from subjects under medication with a given dose of the drug. It contains
68% of all the drug concentrations determined under normal conditions in the blood
of a “normal” patient or subject, “normal” being defined by the population in the
respective clinical trial. It usually consists of individuals 18-65 years of age without
relevant comorbidity, comedication, and genetic abnormalities in drug metabolism.
[Table 4] lists factors for calculation of dose-related reference ranges for the most relevant
psychoactive drugs. Dose-related reference ranges are calculated by multiplying C/Dlow and C/Dhigh by the daily dose. One must be aware, however, that many patients encountered in
the clinical context do not fulfil all the abovementioned conditions.
Table 4 Total clearance (Clt), bioavailability (F), dosing intervals (τ) and factors (C/Dlow and C/Dhigh) for calculation of dose-related plasma concentrations (C/D) for psychotropic drugs.
Drug
|
n
|
Clt– SD – Clt + SD [mL/min]
|
F
|
τ [h]
|
C/Dlow [ng/mL/mg]
|
C/Dhigh [ng/mL/mg]
|
Reference
|
SPC: Summary of product characteristics; n.r.: not reported; active moiety: risperidone
plus 9-hydroxyrisperidone; n: number of individuals; SD: standard deviation
|
Dose related ranges are obtained by multiplying C/Dlow and C/Dhigh by the dose. Drugs listed in [Table 5] were not included in this table, when clearance data were not available from the
literature.
|
Prepared by EH and CG, reviewed and supplemented by CH
|
Antidepressant drugs
|
Amitriptyline
|
8
|
198–373
|
0.5
|
24
|
1.03
|
1.68
|
[165]
|
Amitriptyline oxide
|
12
|
331–539
|
0.8
|
24
|
0.93
|
1.75
|
[384]
|
Bupropion
|
17
|
2500–11300
|
1.0
|
24
|
0.06
|
0.28
|
[665]
|
Citalopram
|
8
|
367–545
|
0.8
|
24
|
1.02
|
1.51
|
[616]
|
Clomipramine
|
9
|
583–933
|
0.5
|
24
|
0.37
|
0.60
|
[198]
|
Desipramine
|
12
|
1633–2333
|
0.5
|
24
|
0.15
|
0.21
|
[2]
|
Desvenlafaxine
|
7
|
233–396
|
1.0
|
24
|
1.75
|
2.98
|
[520]
|
Dothiepin=Dosulepin
|
22
|
674–3960
|
0.3
|
24
|
0.05
|
0.31
|
[740]
|
Doxepin
|
85
|
769–2644
|
1.0
|
24
|
0.18
|
0.27
|
[100]
|
Duloxetine
|
12
|
610–1733
|
0.5
|
24
|
0.20
|
0.57
|
[600]
|
Escitalopram
|
24
|
360–960
|
0.8
|
24
|
0.58
|
1.54
|
[607]
|
Fluoxetine
|
n. r.
|
600–833
|
0.7
|
24
|
0.60
|
0.83
|
[18]
|
Fluvoxamine
|
6
|
807–1 960
|
1.0
|
24
|
0.35
|
0.86
|
[163]
|
Imipramine
|
n. r.
|
791–1029
|
0.4
|
24
|
0.28
|
0.37
|
[100]
|
Maprotiline
|
6
|
503–1747
|
0.8
|
24
|
0.32
|
1.10
|
[415]
|
Mianserin
|
n. r.
|
843–1948
|
0.3
|
24
|
0.11
|
0.25
|
[137]
|
Mirtazapine
|
10
|
455–945
|
0.5
|
24
|
0.37
|
0.85
|
[651]
|
Nordoxepin
|
85
|
504–2738
|
1.0
|
24
|
0.25
|
1.38
|
[445]
|
Nortriptyline
|
n. r.
|
300–1117
|
0.5
|
24
|
0.31
|
1.16
|
[664]
|
Paroxetine
|
30
|
1561–10856
|
1.0
|
24
|
0.06
|
0.44
|
[213]
|
Reboxetine
|
n. r.
|
22–51
|
1.0
|
24
|
12.55
|
31.10
|
[141]
|
Sertraline
|
11 (m) 11 (f)
|
1313–2213 (m) 793–2357 (f)
|
1.0 1.0
|
24 24
|
0.31 0.29
|
0.53 0.88
|
[565]
|
Trazodone
|
8
|
73–103
|
1.0
|
24
|
6.72
|
9.47
|
[473]
|
Trimipramine
|
12
|
898–1215
|
0.40
|
24
|
0.23
|
0.31
|
[165]
[364]
|
Venlafaxine O-Desmethylvenlafaxine
|
18
|
747–1540 315–618
|
1.0 1.0
|
24 24
|
0.45 1.12
|
0.93 2.2
|
[372]
|
Antipsychotic drugs
|
Amisulpride
|
78
|
520–693
|
0.5
|
24
|
0.50
|
0.67
|
[566]
|
Asenapine
|
n. r.
|
867
|
0.35
|
24
|
0.28
|
|
[707]
|
Aripiprazole
|
6
|
47–70
|
0.9
|
24
|
8.63
|
12.85
|
[417]
|
Benperidol
|
14
|
1073–2240
|
0.5
|
24
|
0.15
|
0.31
|
[589]
|
Bromperidol
|
14
|
3570–7938
|
1.0
|
24
|
0.09
|
0.19
|
[390]
|
Chlorpromazine
|
11
|
1043–1510
|
0.1
|
24
|
0.05
|
0.07
|
[738]
|
Chlorprothixene
|
3
|
918–1448
|
0.2
|
24
|
0.10
|
0.15
|
[534]
|
Clozapine
|
16
|
258–728
|
0.5
|
24
|
0.40
|
0.80
|
[128]
[176]
[332]
|
Flupentixol
|
3
|
440–490
|
0.6
|
24
|
0.78
|
0.87
|
[348]
|
Fluphenazine decanoate
|
12
|
2380–3940
|
1.0
|
24
|
0.18
|
0.29
|
[197]
|
Haloperidol
|
6
|
420–680
|
0.6
|
24
|
0.61
|
0.99
|
[123]
|
Haloperidol decanoate
|
|
420–680
|
1.0
|
336 672
|
0.073 0.036
|
0.118 0.059
|
[123]
|
Melperone
|
6
|
1484–2898
|
0.6
|
24
|
0.14
|
0.28
|
[83]
|
Levomepromazine
|
8
|
913–4737
|
0.5
|
24
|
0.07
|
0.38
|
[149]
|
Olanzapine
|
491
|
233–637
|
0.8
|
24
|
0.87
|
2.38
|
[67]
|
Paliperidone
|
n. r.
|
31–98
|
0.3
|
24
|
1.99
|
6.31
|
[161]
|
Perphenazine
|
8
|
1009–2566
|
0.4
|
24
|
0.11
|
0.28
|
[195]
|
Pimozide
|
7
|
21–553
|
0.5
|
24
|
0.64
|
16.53
|
[581]
|
Quetiapine
|
10
|
1146–2421
|
1.0
|
24
|
0.13
|
0.21
|
[7]
[435]
|
Risperidone, oral
|
8
|
91–171
|
0.7
|
24
|
3.50 active moiety
|
14.00 active moiety
|
[159]
|
Risperidone, depot
|
n. r.
|
91–171
|
1.0
|
336
|
0.29 active moiety
|
0.55 active moiety
|
[606]
|
Sertindole
|
6
|
133–600
|
1.0
|
24
|
1.16
|
5.22
|
[728]
|
Supiride
|
6
|
331–499
|
0.25
|
24
|
0.35
|
0.52
|
[717]
|
Thiordazine
|
11
|
404–982
|
0.60
|
24
|
0.42
|
1.03
|
[117]
|
Zotepine
|
14
|
467–10267
|
1.0
|
24
|
0.07
|
1.49
|
[642]
|
Ziprasidone
|
12
|
303–397
|
0.6
|
24
|
1.05
|
1.36
|
SPC
|
Zuclopenthixol
|
8
|
867–2300
|
0.4
|
24
|
0.13
|
0.35
|
[337]
|
Anticonvulsant drugs Mood stabilizers
|
Carbamazepine
|
n. r.
|
58–74
|
1.0
|
24
|
9.40
|
11.93
|
SPC
|
Felbamate
|
10
|
29.1–33.3
|
1.0
|
24
|
20.85
|
23.86
|
[556]
|
Lamotrigine
|
129
|
22–49
|
1.0
|
24
|
14.09
|
31.28
|
[118]
|
Levetiracetam
|
216
|
52–72
|
1.0
|
24
|
9.65
|
13.35
|
[535]
|
Lithium
|
n. r.
|
10–40
|
1.0
|
24
|
17.36
|
69.44
|
[706]
|
Oxcarbazepine
|
7
|
1703–5063
|
1.0
|
24
|
0.14
|
0.41
|
[319]
[694]
|
Primidone
|
8
|
30–47
|
1.0
|
24
|
14.78
|
23.15
|
[423]
|
Topiramate
|
6
|
21–31
|
1.0
|
24
|
22.47
|
33.55
|
[179]
|
Valproic acid
|
9
|
4.5–9.8
|
1.0
|
24
|
71.23
|
154.32
|
[682]
|
Anxiolytic and hypnotic drugs
|
Alprazolam
|
6
|
34–83
|
0.8
|
24
|
6.73
|
16.53
|
[496]
[604]
|
Bromazepam
|
10
|
50–91
|
1.0
|
24
|
7.67
|
13.95
|
[352]
|
Brotizolam
|
8
|
85–141
|
0.7
|
24
|
4.93
|
8.17
|
[341]
|
Buspirone
|
41
|
1260–2702
|
0.04
|
24
|
0.01
|
0.02
|
[41]
|
Clonazepam
|
9
|
63–90
|
0.8
|
24
|
5.43
|
7.69
|
[259]
|
Diazepam
|
48
|
10–43
|
0.9
|
24
|
13.01
|
52.91
|
[264]
|
Lorazepam
|
15
|
36–109
|
0.8
|
24
|
5.98
|
17.93
|
[266]
|
Oxazepam
|
18 (m) 20 (w)
|
36–167 29–109
|
0.8 0.8
|
24 24
|
3.33 5.12
|
15.22 18.90
|
[260]
|
Triazolam
|
13
|
326–584
|
0.9
|
24
|
1.01
|
1.81
|
[263]
|
Zaleplon
|
10
|
868–1330
|
0.3
|
24
|
0.16
|
0.25
|
[265]
|
Zolpidem
|
10
|
266–364
|
0.67
|
24
|
1.02
|
2.14
|
[265]
|
Zopiclone
|
10
|
250–883
|
1
|
24
|
0.79
|
2.78
|
[411]
|
Antidementia drugs
|
Donepezil
|
14
|
112–217
|
1.0
|
24
|
3.20
|
6.20
|
[463]
|
Galantamine
|
8
|
268–400
|
1.0
|
24
|
1.74
|
2.59
|
[744]
|
Rivastigmine
|
20
|
29–64 (patch)
|
0.5
|
24
|
0.18
|
0.74
|
[391]
|
Drugs for treatment of substance related disorders
|
Acamprosate
|
24
|
1741–4221
|
1.0
|
24
|
0.16
|
0.40
|
[287]
|
Buprenorphin
|
|
|
|
|
|
|
no data available
|
Bupropion
|
17
|
2500–11300
|
1.0
|
24
|
0.06
|
0.28
|
[665]
|
Methadone
|
12
|
75–148
|
0.95
|
24
|
4.46
|
8.80
|
[474]
[727]
|
Naltrexone 6β-naltrexol
|
453
|
2077–2590 928–1242
|
1.0
|
24
|
0.27
0.56
|
0.33 0.75
|
[182]
|
Varenicline
|
1878
|
170–176
|
1.0
|
24
|
3.95
|
4.08
|
[540]
|
Drug concentration in blood and brain
The pharmacological activity of a psychotropic drug depends on its availability in
the target organ, the brain. However, the latter is separated from the blood by 2
barriers, which have to be crossed by the drug, the blood-brain barrier (BBB) and
the blood-cerebrospinal fluid barrier [154]. Most psychoactive drugs enter the brain due to their high lipid solubility by passive
diffusion and thereby cross the barriers. The BBB is a physical barrier that separates
circulating blood and the central nervous system, and it consists of endothelial cells
around the capillaries joined together by tight junctions [154]. It efficiently restricts the exchange of solutes between the blood and the brain
extracellular fluid. Functionally, it protects the brain against potentially harmful
chemicals. As mentioned above, a number of psychoactive drugs, such as risperidone,
aripiprazole or venlafaxine are substrates of P-gp [180]
[370]
[668]. As a consequence, brain to plasma concentration ratios vary widely for psychotropic
drugs with similar physicochemical properties. Animal studies found ratios from 0.22
for risperidone [29] to 34 for fluphenazine [27]. In spite of highly variable ratios of brain to plasma concentrations of the different
psychotropic drugs, animal studies have shown that steady-state plasma concentrations
of psychoactive drugs correlate well with concentrations in brain, much better than
doses. This has been shown for tricyclic antidepressants [249], trazodone [173], or olanzapine [28]. Drug concentrations in plasma can therefore be considered as a valid surrogate
marker of concentrations in brain.
Drug concentration in blood and target structure occupancy in brain
Positron emission tomography (PET) enables analysis of central nervous receptor occupancy
in vivo [207]
[274]
[275]. Antipsychotic drugs exert most of their therapeutic actions by blockade of dopamine
D2-like receptors. Blockade of D2 receptors by antipsychotic drugs reduces the binding
of radioactive PET ligands [207]
[272]
[275]. Using this approach and quantification of the displacement of dopamine receptor
radioligands, it has been shown that plasma concentrations of antipsychotic drugs
correlate well with receptor occupancy. In accordance with the high variability of
drug concentrations in plasma under same doses it was found that receptor occupancy
correlates better with plasma concentrations than with daily doses [313]. Optimal response was seen at 70–80% receptor occupancy, and 80% receptor occupancy
was defined as the threshold for the occurrence of extrapyramidal side effects [207]
[480]. PET was also used to characterize in vivo serotonin transporter occupancy by SSRIs
[442]
[443]. Using a serotonin transporter radioligand, plasma concentrations of citalopram,
paroxetine, fluoxetine and sertraline were shown to correlate well with serotonin
transporter occupancy. It was found that at least 80% occupancy should be attained
for optimal clinical outcome [442]
[443]. PET studies have thus brought about highly relevant information for the determination
of optimal plasma concentrations of a considerable number of psychotropic drugs which
is reviewed in this special issue by Gründer and co-workers [274].
“Therapeutic window” – therapeutic reference range
TDM is based on the assumption that there is a relationship between plasma concentrations
and clinical effects (therapeutic improvement, side effects and adverse effects).
It also assumes that there is a plasma concentration range of the drug which is characterized
by maximal effectiveness and maximal safety, the so-called “therapeutic window”. Studies
on relations between plasma concentration and clinical improvement have supported
this concept since the sixties for lithium, tricyclic antidepressants and classical
antipsychotic drugs. Systematic reviews and meta-analyses that were based on adequately
designed studies led to convincing evidence of a significant relationship between
clinical outcomes and plasma concentrations for nortriptyline, imipramine and desipramine
which are associated with a high probability of response [51]. For amitriptyline as a model compound, a meta-analysis of 45 studies has shown
that various statistical approaches provided almost identical results [672]
[674]. For new antipsychotic drugs like aripiprazole [612], olanzapine [509] or risperidone [737] relationships between plasma concentration and clinical effectiveness have been
reported.
For the “therapeutic window” there are many synonymous terms like “therapeutic reference
range”, “therapeutic range”, “optimal plasma concentration”, “effective plasma concentration”,
“target range”, “target concentration”, or “orienting therapeutic range”, the term
used in the first consensus [51]. The present consensus uses the term “therapeutic reference range” in accordance
with the guidelines on TDM for antiepileptic drugs [499]. The “therapeutic reference range” was defined in this consensus guideline for neuropsychiatric
drugs as follows:
Definition
The “therapeutic reference ranges” reported in this guideline ([Table 5]) define ranges of medication concentrations which specify a lower limit below which a drug induced therapeutic response is relatively unlikely to occur and
an upper limit above which tolerability decreases or above which it is relatively unlikely that
therapeutic improvement may be still enhanced.
The therapeutic reference range is an orienting, population based range which may
not necessarily be applicable to all patients. Individual patients may show optimal
therapeutic response under a drug concentration that differs from the therapeutic
reference range. Ultimately, psychopharmacotherapy can be best guided by identification
of the patient’s “individual therapeutic concentration”.
The therapeutic reference ranges as recommended by the TDM group of the AGNP are given
in [Table 5]. They were evidence-based and derived from the literature by the structured review
process described above. For only 15 neuropsychiatric drugs therapeutic reference
ranges based on randomized clinical trials were found in the literature. For most
drugs, reference ranges were obtained from studies with therapeutically effective
doses. Therefore, there is a need for further studies to define therapeutic ranges.
Table 5 Recommended reference ranges, laboratory alert levels and levels of recommendation
for TDM.
Drugs and active metabolites
|
Therapeutic reference range/recommended drug concentration
|
t1/2
|
Laboratory alert level
|
Level of recommendation to use TDM (consensus)
|
Conversion factor (CF, see below)
|
Reference
|
Comments
|
Plasma concentrations given in mass units can be converted to molar units by multiplication
with the conversion factor (CF) nmol/L=ng/mL x CF
|
&Active metabolite contributes to wanted and unwanted effects. Indicated reference
ranges and laboratory alert levels refer to the mother compound only.
|
For bupropion, carbamazepine, lamotrigine and valproic acid recommended reference
ranges were listed twice in accordance with the 2 different indications.
|
Prepared by CH, PB, SU, BR and HK, reviewed by AC, OD, KE, MF, MG, CG, GG, EH, UH-R,
CH, EJS, HK, GL, UL, TM, BP, BS, MU, SU, GZ
|
Antidepressant drugs
|
Agomelatine
|
7–300 ng/mL 1–2 h after 50 mg
|
1–2 h
|
600 ng/mL
|
4
|
4.11
|
[78]
|
Because of rapid elimination, trough drug concentrations are not measurable under
chronic treatment. Determinations, preferentially of Cmax, should be restricted to
specific indications.
|
Amitriptyline plus nortriptyline
|
80–200 ng/mL
|
10–28 h 30 h
|
300 ng/mL
|
1
|
3.41 3.61
|
[282]
[502]
[672]
|
|
Bupropion plus hydroxybupropion
|
225–1500ng/mL
|
8–26 h 17–47 h
|
2000 ng/mL
|
3
|
4.17 3.91
|
[151]
[152]
[336]
[529]
[636]
|
Bupropion, and to a lesser degree its metabolite, are unstable, plasma or serum must
be stored frozen (−20oC)
|
Citalopram
|
50–110 ng/mL
|
33 h
|
220 ng/mL
|
2
|
3.08
|
[42]
[73]
[111]
[339]
[388]
[442]
[471]
[491]
[549]
[598]
|
N-Demethylated metabolites do not contribute to pharmacological actions
|
Clomipramine plus norclomipramine
|
230–450 ng/mL
|
16–60 h 36 h
|
450 ng/mL
|
1
|
3.18 3.32
|
[239]
|
|
Desipramine
|
100–300 ng/mL
|
15–18 h
|
300 ng/mL
|
2
|
3.75
|
[502]
|
Delayed elimination in PM of CYP2D6
|
Desvenlafaxine
|
100–400 ng/mL
|
11 h
|
600 ng/mL
|
2
|
3.80
|
[520]
|
|
Dosulepin=Dothiepin
|
45–100 ng/mL
|
18–21 h
|
200 ng/mL
|
2
|
3.39
|
[102]
[325]
[414]
[541]
|
|
Doxepin plus nordoxepin
|
50–150 ng/mL
|
15–20 h
|
300 ng/mL
|
2
|
3.58 3.77
|
[172]
[321]
[393]
[445]
|
|
Duloxetine
|
30–120 ng/mL
|
9–19 h
|
240 ng/mL
|
2
|
3.36
|
[21]
[640]
[703]
|
No active metabolites
|
Escitalopram
|
15–80 ng/mL
|
30 h
|
160 ng/mL
|
2
|
3.08
|
[409]
[679]
|
N-Demethylated metabolites do not contribute to pharmacological actions lower level of the reference range was calculated from a PET study (80% 5HTT occupancy)
[409], upper level from the SPC
|
Fluoxetine plus norfluoxetine
|
120–500 ng/mL
|
4–6 days 4–16 days
|
1000 ng/mL
|
2
|
3.23 3.39
|
[84]
[187]
[410]
[442]
[545]
|
Long elimination half life of norfluoxetine (mean 14 days) and long-lasting potent
inhibition of CYP2D6
|
Fluvoxamine
|
60–230 ng/mL
|
20 h
|
500 ng/mL
|
2
|
3.14
|
[353]
[587]
[631]
[634]
[639]
|
Inhibtion of CYP1A2, CYP2C19
|
Imipramine plus desipramine
|
175–300 ng/mL
|
11–25 h 15–18 h
|
300 ng/mL
|
1
|
3.57 3.75
|
[72]
[229]
[245]
[510]
[538]
|
Hydroxylated metabolites
|
Maprotiline
|
75–130 ng/mL
|
20–58 h
|
220 ng/mL
|
2
|
3.60
|
[231]
[321]
[384]
|
Active metabolite N-desmethylmaprotiline
|
Mianserine
|
15–70 ng/mL
|
14–33 h
|
140 ng/mL
|
3
|
3.78
|
[191]
[192]
[453]
|
|
Milnacipran
|
50–110 ng/mL
|
5–8 h
|
220 ng/mL
|
2
|
2.24
|
[206]
[315]
|
|
Mirtazapine
|
30–80 ng/mL
|
20–40 h
|
160 ng/mL
|
2
|
3.77
|
[257]
[367]
[397]
[440]
[552]
[591]
|
N-Demethylated metabolite does not contribute to pharmacological actions
|
Moclobemide
|
300–1000 ng/mL
|
2–7 h
|
2000 ng/mL
|
3
|
3.72
|
[225]
[291]
[327]
|
Metabolites are pharmacologically inactive
|
Nortriptyline
|
70–170 ng/mL
|
30 h
|
300 ng/mL
|
1
|
3.80
|
[30]
[31]
[504]
[506]
[510]
|
Hydroxylated metabolites
|
Paroxetine
|
30–120 ng/mL
|
12–44 h
|
240 ng/mL
|
3
|
3.04
|
[242]
[243]
[410]
[443]
|
|
Reboxetine
|
60–350 ng/mL
|
13–30 h
|
700 ng/mL
|
3
|
3.19
|
[483]
[484]
|
|
Sertraline
|
10–150 ng/mL
|
26 h
|
300 ng/mL
|
2
|
3.27
|
[15]
[49]
[258]
[281]
[410]
[443]
[545]
[696]
|
N-Demethylated metabolite has a 2-fold longer elimination half life than sertraline,
but only 1/20 of the activity of sertraline
|
Tranylcypromin
|
≤50 ng/mL
|
1–3 h
|
100 ng/mL
|
4
|
7.51
|
[103]
[329]
|
Due to irreversible inhibition of monoamine oxidase, plasma concentrations do not
correlate with drug actions
|
Trazodone
|
700–1000 ng/mL
|
4–11 h
|
1200 ng/mL
|
2
|
2.69
|
[250]
[262]
[268]
[447]
[590]
|
|
Trimipramine
|
150–300 ng/mL
|
23 h
|
600 ng/mL
|
2
|
3.40
|
[142]
[187]
[223]
[326]
|
Active metabolite N-desmethyltrimipramine
|
Venlafaxine plus O-desmethylvenlafaxine
|
100–400 ng/mL
|
5 h 11 h
|
800 ng/mL
|
2
|
3.61 3.80
|
[85]
[241]
[316]
[443]
[545]
[550]
[592]
[684]
[696]
|
In most patients O-desmethylvenlafaxine is the active principle in vivo, N-demethylated
venlafaxine does not contribute to pharmacological actions. At low concentrations,
the drug acts predominanty as an SSRI
|
Antipsychotic drugs
|
Amisulpride
|
100–320 ng/mL
|
12–20 h
|
640 ng/mL
|
1
|
2.71
|
[64]
[89]
[441]
[461]
[531]
[613]
[690]
|
No metabolites
|
Aripiprazole
|
150–500 ng/mL
|
60–80 h
|
1000 ng/mL
|
2
|
2.23
|
[33]
[273]
[306]
[368]
[452]
[612]
|
The metabolite dehydroaripiprazole is active in vitro, it remains unclear to which
extend it contributes to clinical effects
|
Asenapine
|
2–5 ng/mL
|
24 h
|
10 ng/mL
|
4
|
3.50
|
[707]
|
|
Benperidol
|
1–10 ng/mL
|
5 h
|
20 ng/mL
|
3
|
2.62
|
[472]
[589]
|
Higher levels may be tolerated in patients under long-term high-dose therapy due to
adaptive changes.
|
Bromperidol
|
12–15 ng/mL
|
20–36 h
|
30 ng/mL
|
2
|
4.38
|
[609]
[656]
[735]
|
|
Chlorpromazine
|
30–300 ng/mL
|
15–30 h
|
600 ng/mL
|
2
|
3.14
|
[127]
[559]
|
|
Chlorprothixene
|
20–300 ng/mL
|
8–12 h
|
400 ng/mL
|
3
|
3.17
|
[542]
|
|
Clozapine
|
350–600 ng/mL
|
12–16 h
|
1000 ng/mL
|
1
|
3.06
|
[175]
[507]
[493]
[507]
[678]
|
Major metabolite N-desmethylclozapine with unclear antipsychotic activity
|
Flupenthixol
|
1–10 ng/mL
|
20–40 h
|
15 ng/mL
|
2
|
2.30
|
[40]
[543]
[564]
|
|
Fluphenazine
|
1–10 ng/mL
|
16 h
|
15 ng/mL
|
1
|
2.29
|
[564]
[680]
|
|
Fluspirilen
|
0.1–2.2 ng/mL
|
7–14 days
|
4.4 ng/mL
|
2
|
2.10
|
[611]
|
|
Haloperidol
|
1–10 ng/mL
|
12–36 h
|
15 ng/mL
|
1
|
2.66
|
[74]
[214]
[480]
[494]
[508]
[674]
[680]
|
Higher levels can be tolerated in patients under long-term high-dose therapy due to
adaptive changes.
|
Iloperidone
|
5–10 ng/ml
|
18–33 h
|
20 ng/ml
|
3
|
2.34
|
[476]
[576]
|
|
Levomepromazine
|
30–160 ng/mL
|
16–78 h
|
320 ng/mL
|
3
|
3.04
|
[656]
|
|
Melperone
|
30–100 ng/mL
|
4–6 h
|
200 ng/mL
|
3
|
3.80
|
[83]
[324]
|
Inhibitor of CYP2D6
|
Olanzapine
|
20–80 ng/mL
|
30–60 h
|
150 ng/mL
|
1
|
3.20
|
[32]
[56]
[63]
[132]
[208]
[240]
[418]
[478]
[509]
[602]
[711]
|
Under olanzapine pamoate, patients exhibited a post injection syndrome when drug concentrations
exceeded 150 ng/mL
|
Paliperidone
|
20–60 ng/mL
|
23 h
|
120 ng/mL
|
2
|
2.35
|
[26]
[70]
[131]
[466]
|
Paliperidone=9-hydroxyrisperidone
|
Perazine
|
100–230 ng/mL
|
8–16 h
|
460 ng/mL
|
1
|
2.95
|
[91]
|
|
Perphenazine
|
0.6–2.4 ng/mL
|
8–12 h
|
5 ng/mL
|
1
|
2.48
|
[564]
[637]
[680]
|
|
Pimozide
|
15–20 ng/mL
|
23–43 h
|
20 ng/mL
|
3
|
2.17
|
[649]
|
|
Pipamperone
|
100–400 ng/mL
|
17–22 h
|
500 ng/mL
|
3
|
2.66
|
[82]
[517]
|
|
Prothipendyl
|
5–10 ng/mL
|
2–3 h
|
20 ng/mL
|
4
|
3.35
|
[436] SPC
|
|
Quetiapine
|
100–500 ng/mL
|
7 h
|
1000 ng/mL
|
2
|
2.61
|
[112]
[212]
[236]
[299]
[498]
[603]
[627]
[689]
[723]
|
When the patient has taken the extended release (XR) formulation in the evening and
blood was withdrawn in the morning, expected plasma concentrations are 2-fold higher
than trough levels
|
Risperidone plus 9-hydroxyrisperidone
|
20–60 ng/mL
|
3 h 24 h
|
120 ng/mL
|
2
|
2.44 2.35
|
[150]
[406]
[426]
[437]
[469]
[475]
[553]
[557]
[617]
[729]
[737]
|
|
Sertindole
|
50–100 ng/mL
|
55–90 h
|
200 ng/mL
|
2
|
2.27
|
[71]
[109]
[110]
[653]
[728]
[729]
|
Active metabolite dehydrosertindole (concentration at therapeutic doses 40–60 ng/mL),
concentration dependent increase of QT interval by blockade of potassium chanels
|
Sulpiride
|
200–1000 ng/mL
|
8–14 h
|
1000 ng/mL
|
2
|
2.93
|
[460]
[656]
|
No metabolites, renal eliminiation
|
Thioridazine
|
100–200 ng/mL
|
30 h
|
400 ng/mL
|
1
|
2.70
|
[190]
[656]
|
Contraindicated in poor metabolizers of CYP2D6
|
Ziprasidone
|
50–200 ng/mL
|
6 h
|
400 ng/mL
|
2
|
2.55
|
[126]
[419]
[427]
[688]
[695]
|
The drug should be taken with a meal, otherwise absorption is reduced and plasma concentrations
will be lower than expected
|
Zotepine
|
10–150 ng/mL
|
13–16 h
|
300 ng/mL
|
3
|
3.01
|
[376]
[642]
|
|
Zuclopentixol
|
4–50 ng/mL
|
15–25 h
|
100 ng/mL
|
3
|
2.49
|
[330]
[371]
[692]
|
|
Mood stabilizing drugs
|
Carbamazepine
|
4–10 µg/mL
|
10–20 h
|
20 µg/mL
|
2
|
4.23
|
[512]
|
Active 10,11-epoxide metabolite contributes to clinical effects
|
Lamotrigine
|
3–14 µg/mL
|
7–23 h
|
30 µg/mL
|
2
|
3.90
|
[455]
[558]
|
So far no specific reference rang for mood stabilizing effect, valproate increases
elimination half life to 48–70 h
|
Lithium
|
0.5–1.2 mmol/l (4–8 µg/mL)
|
24 h
|
1.2 mmol/l (8 µg/mL)
|
1
|
125.8
|
[593]
[721]
|
Age dependent increase of elimination half life
|
Valproic acid
|
50–100 µg/mL
|
18 h
|
120 µg/mL
|
2
|
6.93
|
[16]
[216]
[301]
[683]
|
In individual cases 120µg/mL are also tolerated in acute mania.
|
Anticonvulsant drugs
|
Carbamazepine
|
4–12 µg/mL
|
10–20 h
|
20 µg/mL
|
2
|
4.25
|
[87]
[338]
[499]
|
Active 10,11-epoxide metabolite contributes to clinical effects
|
Clobazam and N-desmethylclobazam
|
30–300 ng/mL 300–3000 ng/mL
|
18–42 h
|
500 ng/mL 5000 ng/mL
|
2
|
3.33 3.49
|
[278]
[499]
|
Active N-demethylated metabolite contributes to clinical effects
|
Clonazepam
|
20–70 ng/mL
|
40 h
|
80 ng/mL
|
2
|
3.17
|
[44]
[464]
[499]
|
7-Amino metabolite retains some activity
|
Ethosuximide
|
40–100 µg/mL
|
33–55 h
|
120 µg/mL
|
2
|
7.08
|
[88]
[499]
|
|
Felbamate
|
30–60 µg/mL
|
15–23 h
|
100 µg/mL
|
2
|
4.20
|
[290]
[343]
[499]
|
|
Gabapentin
|
2–20 µg/mL
|
6 h
|
25 µg/mL
|
3
|
5.84
|
[75]
[76]
[77]
[343]
[398]
[499]
|
|
Lacosamide
|
1–10 µg/mL
|
13 h
|
20 µg/mL
|
|
2.66
|
[47]
|
|
Lamotrigine
|
3–14 µg/mL
|
7–23 h
|
20 µg/mL
|
2
|
3.90
|
[88]
[343]
[455]
[456]
[499]
[610]
|
Valproate increases elimination half life to 48–70 h
|
Levetiracetam
|
10–40 µg/mL
|
6–8 h
|
100 µg/mL (morning levels)
|
2
|
3.87
|
[88]
[343]
[430]
[499]
|
|
Methsuximide plus methsuximide
|
10–40 µg/mL
|
1–3 h 36–45 h
|
45 µg/mL
|
2
|
4.92 and 5.29
|
[88]
|
The metabolite is the active principle in vivo
|
Oxcarbazepine plus 10-hydroxycarbazepine
|
10–35 µg/mL
|
5 h 10–20 h
|
40 µg/mL
|
2
|
3.96 and 3.73
|
[88]
[343]
[428]
[499]
|
|
Phenobarbital
|
10–40 µg/mL
|
80–120 h
|
50 µg/mL
|
1
|
4.31
|
[88]
[499]
|
|
Phenytoin
|
10–20 µg/mL
|
20–60 h
|
25 µg/mL
|
1
|
3.96
|
[88]
[380]
[499]
|
|
Pregabalin
|
2–5 µg/mL
|
6 h
|
10 µg/mL
|
3
|
6.28
|
[68]
[77]
[88]
[343]
[432]
[499]
|
|
Primidone (active metabolite phenobarbital)
|
5–10 µg/mL
|
14–15 h
|
25 µg/mL
|
2
|
4.58
|
[88]
[499]
|
Data given are restricted to primidone, for the active metabolite phenobarbital recommended
plasma concentrations are 10–40 µg/mL
|
Rufinamid
|
5–30 µg/mL
|
7 h
|
40 µg/mL
|
2
|
4.20
|
[511]
|
|
Stiripentol
|
1–10 µg/mL
|
4–13 h
|
15 µg/mL
|
2
|
4.27
|
[503]
|
|
Sulthiame
|
2–8 µg/mL
|
3–30 h
|
12 µg/mL
|
2
|
3.46
|
[88]
[375]
[429]
|
|
Tiagabine
|
20–200 ng/mL
|
7–9 h
|
300 ng/mL
|
2
|
2.66
|
[88]
[235]
[343]
[499]
|
|
Topiramate
|
2–8 µg/mL (morning levels)
|
21 h
|
16 µg/mL
|
3
|
2.95
|
[88]
[226]
[343]
[431]
[499]
|
|
Valproic acid
|
50–100 µg/mL
|
18 h
|
120 µg/mL
|
2
|
6.93
|
[16]
[88]
[216]
[301]
[499]
[682]
[683]
|
|
Vigabatrin
|
2–10 µg/mL
|
5–8 h
|
20 µg/mL
|
4
|
7.74
|
[88]
[342]
[398]
[499]
[719]
|
|
Zonisamide
|
10–40 µg/mL
|
60 h
|
40 µg/mL
|
2
|
4.71
|
[247]
[448]
[449]
|
|
Anxiolytic/hypnotic drugs
|
Alprazolam
|
5–50 ng/mL
|
12–15 h
|
100 ng/mL§
|
4
|
3.22
|
[586]
[686]
|
In chronic users of benzodiazepines, effective plasma concentrations can be markedly
higher than in non users.
|
Bromazepam
|
50–200 ng/mL
|
15–35 h
|
300 ng/mL§
|
4
|
3.16
|
[218]
[286]
[586]
|
Brotizolam
|
4–10 ng/mL (Cmax)
|
3–6 h
|
20 ng/mL
|
4
|
2.53
|
[341]
[669]
|
Buspirone (active metabolite 6-hydroxybuspirone)
|
1–4 ng/mL
|
2–3 h
|
8 ng/mL&
|
3
|
2.59 2.49
|
[178]
[580]
[586]
|
|
Chlordiazepoxide
|
400–3000 ng/mL
|
5–30 h
|
3500 ng/mL
|
4
|
3.48
|
[408]
[586]
|
|
Clonazepam
|
4–80 ng/mL
|
19–30 h
|
100 ng/mL
|
4
|
3.17
|
[181]
[467]
[586]
|
|
Diazepam and metabolites
|
200–2500 ng/mL
|
24–48 h
|
3000 ng/mL
|
4
|
3.51
|
[224]
[261]
[264]
[586]
|
Active metabolites are nordazepam, oxazepam and temazepam
|
Flunitrazepam
|
5–15 ng/mL
|
10–30 h
|
50 ng/mL
|
4
|
3.20
|
[80]
[425]
|
|
Lorazepam
|
10–15 ng/mL
|
12–16 h
|
30 ng/mL
|
4
|
3.20
|
[164]
[196]
[218]
[267]
|
|
Lormetazepam
|
2–10 ng/mL
|
8–14 h
|
100 ng/mL
|
4
|
2.98
|
[3]
[515]
|
|
Midazolam
|
6–15 ng/mL Cmax: 60–80 ng/mL
|
1–3 h
|
1000 ng/mL
|
4
|
3.06
|
[35]
[261]
[323]
|
|
Nitrazepam
|
30–100 ng/mL
|
18–30 h
|
200 ng/mL
|
4
|
3.56
|
[467]
[586]
|
|
Nordazepam
|
20–800 ng/mL
|
50–90 h
|
1500 ng/mL
|
4
|
3.69
|
[586]
|
|
Opipramol
|
50–500 ng/mL
|
11 h
|
1000 ng/mL
|
3
|
2.87
|
[386]
|
|
Oxazepam
|
200–1500 ng/mL
|
4–15 h
|
2000 ng/mL
|
4
|
3.49
|
[586]
|
|
Pregabalin
|
2–5 µg/mL
|
6 h
|
10µg/mL
|
3
|
6.28
|
[76]
[77]
|
|
Temazepam
|
20–900 ng/mL
|
5–13 h
|
1000 ng/mL
|
4
|
3.51
|
[586]
|
|
Triazolam
|
2–20 ng/mL
|
1–5 h
|
40 ng/mL§
|
4
|
4.12
|
[586]
|
|
Zolpidem
|
80–150 ng/mL
|
1–4 h
|
300 ng/mL
|
4
|
3.23
|
[586]
|
|
Zopiclone
|
10–50 ng/mL
|
5 h
|
150 ng/mL
|
4
|
3.48
|
[586]
|
Unstable at room temperature
|
Antidementia Drugs
|
Donepezil
|
30–75 ng/mL
|
70–80 h
|
75 ng/mL
|
2
|
2.64
|
[492]
[563]
[652]
|
|
Galantamine
|
30–60 ng/mL
|
8 h
|
90 ng/mL
|
3
|
3.48
|
[322]
[333]
[734]
|
|
Memantine
|
90–150 ng/mL
|
60–100 h
|
300 ng/mL
|
3
|
5.58
|
[251]
[378]
|
|
Rivastigmine
|
oral 8–20 ng/mL (1–2 h after dose) Patch 5–13 ng/mL (1 h before application of a new patch)
|
1–2 h
|
40 ng/mL
|
3
|
4.00
|
[597]
[147]
[391]
|
|
Drugs for treatment of substance related disorders
|
Acamprosate
|
250–700 ng/mL
|
13 h
|
1000 ng/mL
|
3
|
8.68
|
[287]
[288]
[424]
|
|
Buprenorphine
|
0.7–1.6 ng/mL Cmax: < 9 ng/mL after 24 mg
|
2–5 h
|
10 ng/mL (Cmax)
|
2
|
2.38
|
[120]
[130]
[383]
|
|
Bupropion plus Hydroxybupropion
|
550–1500 ng/mL
|
20 h 20 h
|
2000 ng/mL
|
2
|
4.17 3.91
|
[345]
|
Bupropion is unstable, plasma or serum must be stored frozen (−20oC) after blood withdrawal In a clinical trial 300 mg was the most effective dose with resulting plasma concentrations
as indicated
|
Clomethiazol
|
100–5000 ng/mL
|
2–5 h
|
|
4
|
6.19
|
[672]
|
In alcohol dependent patients much higher plasma concentrations may be tolerated than
in healthy subjects
|
Disulfiram
|
50–400 ng/mL
|
7 h
|
500 ng/mL
|
3
|
3.37
|
[203]
[344]
[586]
|
Disulfiram (DSF) is a prodrug, its active metabolite diethylthiomethylcarbamate (DDTC-Me)
has been suggested as a possible marker for proper dose titration of disulfiram [344].
In a pharmacokinetic study under 300 DSF mean±SD steady state concentrations of DSF
amounted to 170±10 ng/mL those of DDTC-Me to 290±20 ng/mL.
|
Levomethadone
|
250–400 ng/mL
|
14–55 h
|
400 ng/mL 100 ng/mL§
|
2
|
3.23
|
[146]
|
§In non users of opiates, effective or toxic plasma concentrations are markedly lower
than in users. Chronic users may even need “toxic” concentrations in blood to avoid
the occurrence of withdrawal symptoms.
|
Methadone
|
400–600 ng/mL
|
24–48 h
|
600 ng/mL 300 ng/mL§
|
2
|
3.23
|
[146]
[188]
[595]
|
Naltrexone plus 6β-naltrexol
|
25–100 ng/mL
|
4 h 13 h
|
200 ng/mL
|
2
|
3.06 3.04
|
[99]
[211]
[252]
[424]
|
|
Varenicline
|
4–5 ng/mL
|
24 h
|
10 ng/mL
|
3
|
4.73
|
[202]
[532]
|
|
Antiparkinson drugs
|
Amantadine
|
0.3–0.6 µg/mL
|
10–14 h
|
1.2 µg/mL
|
3
|
5.98
|
[320]
|
|
Biperiden
|
Cmax. 1–6.5 ng/mL0.5–2 h after 4 mg
|
18–24 h
|
13 ng/mL
|
3
|
3.21
|
[270]
|
|
Bornaprine
|
Cmax. 0.7–7.2 ng/mL 1–2 h after 4 mg
|
30 h
|
14 ng/mL
|
3
|
3.04
|
[433]
|
|
Bromocriptine
|
Low dose (2.5mg): 0.1–0.3 ng/mL Max. dose (25 mg): 1.0–4.0 ng/mL
|
38 h
|
8 ng/mL
|
3
|
1.53
|
[168]
|
|
Cabergoline
|
Cmax. 58–144 pg/mL at 0.5–4 h after drug intake for 4 weeks
|
63–68 h
|
390 pg/mL
|
3
|
2.21
|
[168]
|
Unstable at room temperature, plasma or serum should be stored frozen (<−20℃)
|
Carbidopa
|
Cmax. 20–200 ng/mL after 2 h
|
2 h
|
400 ng/mL
|
3
|
4.42
|
[574]
|
Unstable at room temperature, plasma or serum should be stored frozen (<−20℃)
|
Levodopa O-Methyldopa
|
Cmax.0.9–2.0µg/mL 0.6–0.9 h after 250 mg combined with 25 mg carbidopa 0.7–10.9µg/mL
|
1–3 h
|
5µg/mL
|
3
|
5.07
|
[4]
[135]
[394]
[479]
[574]
|
Unstable at room temperature, plasma or serum should be stored frozen (<−20℃) Elimination half-life and plasma concentrations increases under comedication with
carbidopa or benserazide
|
Entacapone
|
Cmax. 0.4–1.0µg/mL
|
0.5 h
|
2 µg/mL
|
3
|
3.28
|
[304]
[570]
|
Unstable at room temperature, plasma or serum should be stored frozen (< −20 ℃)
|
Pramipexole
|
0.39–7.17 ng/mL
|
8–12 h
|
15 ng/mL
|
3
|
4.73
|
[730]
|
|
Ropinirole
|
0.4–6.0 ng/mL
|
3–10 h
|
12 ng/mL
|
3
|
3.84
|
[657]
|
|
Tiapride
|
Cmax. 1–2 µg/mL
|
3–4 h
|
4 µg/mL
|
3
|
3.05
|
[108]
|
|
Tolcapone
|
Cmax. 3–6 µg/mL
|
2 h
|
12 µg/mL
|
3
|
3.66
|
[177]
[346]
|
|
Other Drugs
|
Atomoxetine
|
200–1000 ng/mL 60–90 min after intake of 1.2 mg/kg/day
|
4 h
|
2000 ng/mL
|
3
|
3.91
|
[233]
[302]
[446]
[583]
|
Recommended reference ranges indicate Cmax measured in remitters. Elimination half-life is 21 h in PM of CYP2D6
|
Dexmethylphenidate
|
13–23 ng/mL 4 h after 20 mg
|
2
|
44
|
2
|
4.29
|
[663]
|
5.2–5.5 ng/mL are associated with 50% dopamine transporter blockade [614]
|
Methylphenidate
|
13–22 ng/mL d-methyl-phenidate 2 h after 20 mg immediate release or 6–8 h after 40 mg extended release
|
2 h
|
44 ng/mL
|
2
|
4.29
|
[331]
[422]
[614]
[615]
|
Methylphenidate is unstable at room temperature, recommended reference range indicates
Cmax
|
Modafinil
|
1000–1700 ng/mL after 200 mg/day
|
10–12 h
|
3400 ng/mL
|
3
|
4.21
|
[733]
|
|
The reference ranges listed in [Table 5] are generally those for the primary indication. A number of drugs, however, are
recommended for several indications. For example, antidepressant drugs are also used
for the treatment of anxiety states, and antipsychotic drugs are increasingly used
to treat mania. Little information is available on optimum plasma concentrations in
these situations. Exceptions are carbamazepine, lamotrigine and valproic acid, which
are therefore listed twice in [Table 5]. Moreover, it should be mentioned that studies are on the way to evaluate therapeutic
reference ranges for children or adolescent patients and for elderly patients.
Estimation of the lower limit of the therapeutic reference range
Estimation of a therapeutic reference range (TRR) requires estimation of a lower and
an upper limit of drug concentration in plasma. A generally accepted method for calculation
of these limits does not exist. Whenever possible the lower limit of a drug’s therapeutic
range should be based on studies on the relationship between a drug’s plasma concentration
and clinical effectiveness. Below this limit, therapeutic effects are not significantly
different from placebo. The optimum study design for evaluation of the lower limit
of the therapeutic range is a prospective double-blind study where patients are treated
with drug doses which lead to a defined plasma concentration range of the drug. Such
a design was applied by Van der Zwaag and co-workers for patients treated with clozapine
[678]. Patients were titrated to 3 different plasma concentrations of the antipsychotic
drug. Significant superiority was found in patients with middle and high plasma concentration
compared with low concentrations of clozapine. A similar design was applied for a
blood-level study comparing imipramine and mirtazapine [98]. To conduct such studies, however, is a considerable logistic challenge. Fixed dose
studies are therefore preferred for evaluation of the lower limit of the therapeutic
reference range [672]
[674].
For the estimation of threshold values of the therapeutic reference range, receiver
operating characteristic (ROC) analysis has proven helpful [289]. A ROC plot allows the identification of a cut-off value that separates responders
from non-responders and estimates the sensitivity and specificity of the parameter
“medication plasma concentration”. The usefulness of the ROC analysis has been demonstrated
for a number antipsychotic and antidepressant drugs [461]
[505]
[510]
[703].
Estimation of the upper limit of the therapeutic reference range
In the first study on TDM in psychiatry [31] an U-shaped relationship between plasma concentration and clinical effect was reported
for nortriptyline. The lack of effect at high concentrations was attributed to the
mechanism of action of the tricyclic antidepressant drug on monoaminergic neurons.
According to actual knowledge, however, it seems more likely that reduced amelioration
at high concentrations is due to side effects. The upper limit of the therapeutic
range is therefore defined by the occurrence of side effects, also in this guideline.
For most side effects (type A adverse reactions), it is also assumed that they are
a function of dose and drug concentration in the body [335]. This assumption has been confirmed for motor side effects of antipsychotic drugs
[536] and for unwanted side effects of tricyclic antidepressant drugs [153]
[282]. For paroxetine, a positive correlation was found between drug concentration in
plasma and serotonin syndrome symptoms [303]. When such data are available, it is possible to apply ROC analysis for the calculation
of the upper limit of the therapeutic range [461]. For many psychotropic drugs listed in [Table 5], however, valid data on both plasma concentration and the incidence of side effects
are lacking. Case reports on tolerability problems or intoxications do often not include
drug concentration measurements in plasma. Sporadic reports on fatal cases and intoxications
are of limited value. Most blood concentrations reported to have caused death are
far above drug concentrations that are associated with maximum therapeutic effects
[544]
[622]. Post mortem redistribution of medications from or into the blood can lead to dramatic
changes in blood levels [382]
[518], and the direction of the change does not follow a general rule [359]. Estimation of an upper threshold level above which tolerability decreases or the
risk of intoxication increases is therefore more difficult than estimation of the
lower threshold level, especially for drugs with a broad therapeutic index like SSRIs.
Estimation and definition of a laboratory alert level
As explained above, plasma concentrations with an increased risk of toxicity are normally
much higher than the upper threshold levels of the therapeutic reference ranges for
most psychotropic drugs shown in [Table 5]. For the present guidelines, we therefore defined an upper plasma concentration
limit above which it seems unlikely that therapeutic effects may be enhanced and added
a “laboratory alert level” which was defined as follows:
Definition
The “laboratory alert levels” reported in this guideline ([Table 5]) indicate drug concentrations above the recommended reference range that causes
the laboratory to feedback immediately to the prescribing physician. The alert levels
are based on reports on intolerance or intoxications and plasma concentration measurements.
In most cases, however, it was arbitrarily defined as a plasma concentration that
is 2-fold higher than the upper limit of the therapeutic reference range. The laboratory
alert should lead to dose reduction when the patient exhibits signs of intolerance
or toxicity. When the high drug concentration is well tolerated by the patient and
if dose reduction bears the risk of symptom exacerbation, the dose should remain unchanged.
The clinical decision, especially in case of unchanged dose needs to be documented
in the medical file.
From population-based to subject-based reference values
All therapeutic reference ranges listed in [Table 5] are orienting, population-based ranges. The population-derived ranges constitute
descriptive statistical values which may not necessarily be applicable to all patients.
Individual patients may show the optimum therapeutic response under a drug concentration
that differs from the therapeutic reference range. Psychopharmacotherapy should therefore
try to identify a patient’s “individual therapeutic concentration” to guide the treatment
[61]
[523]. For lithium it has been shown that the recommended plasma concentration range depends
on whether the patient is in an acute manic episode or needs maintenance therapy [593]. For clozapine, Gaertner and colleagues [232] determined optimal plasma concentrations required for stable remission of individual
patients under maintenance therapy in a relapse prevention study.
Recommendations for measuring plasma concentrations of psychoactive drugs
The usefulness of TDM varies with the clinical situation and the particular drug involved.
In case of suspected non-adherence to medication or intoxications, quantifying plasma
concentrations is a generally accepted tool for all drugs and groups of patients.
However, it is still a matter of debate if TDM should be implemented in clinical routine.
Based on empirical evidence, 5 levels of recommendation to use TDM were defined in
the guidelines 2004 for 65 psychotropic drugs. These definitions were revised and
grading reduced to 4 levels of recommendation, now ranging from “strongly recommended”
to “potentially useful” as follows:
Definitions
Level 1: Strongly recommended
Evidence: Reported drug concentrations are established and evaluated therapeutic reference
ranges. Controlled clinical trials have shown beneficial effects of TDM, reports on
decreased tolerability or intoxications.
Recommendation: TDM is strongly recommended for dose titration and for special indications. For lithium,
TDM is a standard of care.
Clinical consequences: At therapeutic plasma concentrations highest probability of response or remission;
at “subtherapeutic” plasma concentrations: response rate similar to placebo under
acute treatment and risk of relapse under chronic treatment; at “supratherapeutic”
plasma concentrations: risk of intolerance or intoxication.
Level 2: Recommended
Evidence: Reported drug concentrations were obtained from plasma concentrations at therapeutically
effective doses and related to clinical effects; reports on decreased tolerability
or intoxications at “supratherapeutic” plasma concentrations.
Recommendation: TDM is recommended for dose titration and for special indications or problem solving.
Clinical consequences: TDM will increase the probability of response in non-responders. At “subtherapeutic”
plasma concentrations: risk of poor response; at “supratherapeutic” plasma concentrations:
risk of intolerance or intoxication.
Level 3: Useful
Evidence: Reported drug concentrations were calculated from plasma concentrations at effective
doses obtained from pharmacokinetic studies. Plasma concentrations related to pharmacodynamic
effects are either not yet available or based on retrospective analysis of TDM data,
single case reports or non-systematic clinical experience.
Recommendation: TDM is useful for special indications or problem solving.
Clinical consequences: TDM can be used to control whether plasma concentrations are plausible for a given
dose, or clinical improvement may be attained by dose increase in non-responders who
display too low plasma concentrations.
Level 4: Potentially useful
Evidence: Plasma concentrations do not correlate with clinical effects due to unique pharmacology
of the drug, e. g., irreversible blockade of an enzyme, or dosing can be easily guided
by clinical symptoms, e. g., sleep induction by a hypnotic drug.
Recommendation: TDM is not recommended for dose titration but may be potentially useful for special
indications or problem solving.
Clinical consequences: TDM should be restricted to special indications.
According to our literature-based evaluations, TDM was graded as “strongly recommended”
for 15 of the 128 surveyed neuropsychiatric compounds, “recommended” for 52 medications,
“useful” for 44 drugs and “potentially useful” for 19 drugs ([Table 5]).
TDM is highly recommended for most tricyclic antidepressants. It reduces the risk of intoxications [103]
[381]
[459]
[510]
[525]
[527]
[528]
[718], and for many tricyclic antidepressants, a plasma concentration – clinical effectiveness
relationship has been shown. For SSRIs, TDM is of little clinical importance in clinical
practice [6]
[537]
[644]. Toxicity of this type of antidepressants is low in comparison to most of the pre-SSRI
antidepressants [48]
[314]
[166]
[314]
[646]
[715]. Data from Sweden revealed that TDM of SSRIs is cost-effective in elderly patients
where it helped to use minimum effective doses [410]. For citalopram a recent observational study revealed that plasma concentrations
on day 7 of treatment are predictive for later non-response [491]. Patients exhibiting citalopram plasma concentrations below 50 ng/mL had a significantly
reduced improvement on the Hamilton rating scale for depression. Evidence for a statistically
significant relationship between drug concentration and therapeutic outcome is lacking
for the tetracyclic antidepressants maprotiline, mianserin and mirtazapine and also
for trazodone and reboxetine, the monoamine oxidase inhibitors moclobemide and tranylcypromine.
TDM is strongly recommended for the typical antipsychotic drugs haloperidol, perphenazine and fluphenazine, and for the atypical antipsychotics amisulpride,
clozapine, olanzapine, and risperidone ([Table 5]). Overdosing may lead to extrapyramidal side effects. In the case of clozapine,
there is a strong correlation between clozapine plasma levels and incidence of seizures.
Avoiding overdosing of typical antipsychotic drugs by TDM is for the majority of patients
a matter of quality of life rather than safety [136]. TDM of antipsychotics is also useful when medication is switched from the oral
to the depot form, or vice versa.
With regard to the mood stabilizing and/or antimanic drugs lithium, valproic acid and carbamazepine, therapeutic reference ranges and toxic
levels are well defined. Therefore TDM is strongly recommended for these drugs ([Table 5]). For lithium TDM is even the standard of care [133]
[170]
[185]
[280]
[395]
[593]
[706]
[721]. For its long-term use, plasma concentrations of 0.5–0.8 nmol/L are advised. For
an acute treatment with lithium, it may be justified to increase its concentrations
up to 1.2 mmol/L.
Compounds that have been shown to be effective as antidementia drugs are donepezil, rivastigmine, galantamine and memantine. TDM is rarely used for the
treatment of dementia, though there is evidence that it can be useful. For donepezil,
it has been shown that the patients’ improvement was significantly better if their
plasma concentrations were above 50 ng/mL as compared to patients that showed lower
drug concentrations [563].
Most anxiolytic and hypnotic drugs belong to the class of benzodiazepines. Anxiolytic and hypnotic effects are rapid.
Treatment can therefore be guided by immediate clinical impression rather than by
TDM. In case of lack of therapeutic effects under usual doses, however, TDM may clarify
if non-response was due to drug abuse that has led to tolerance or due to pharmacokinetic
abnormalities. For alprazolam, TDM may be useful to suppress panic attacks [722].
The opiate agonists methadone, R-methadone (levomethadone), buprenorphine, l-α-acetylmethadol (LAAM)
and slow-release formulations of morphine are used for the treatment of opioid addiction.
TDM is indicated for patients treated with methadone or R-methadone. The usefulness
of TDM for monitoring treatment with “anti-craving” medications such as acamprosate
or naltrexone, employed for the treatment of alcohol use disorders, has recently been
reviewed elsewhere [99]. TDM was recommended to enhance the moderate efficacy of these drugs.
For anticonvulsant drugs, TDM is well established, especially for old drugs which are more toxic than the
new ones [499].
For antiparkinson drugs, TDM has not been established so far. For the dopamine agonists, data on reference
ranges are scarce. For L-dopa, there is an imperfect correlation between plasma concentrations
and short-term clinical response [479]. Nevertheless, we considered the pharmacologic properties of these neurological
drugs ([Table 1]
[5]), since psychiatric patients may receive antiparkinson drugs that possibly interfere
with the action of psychotropic medication. For most of these drugs Cmax values are
given.
Indications for measuring plasma concentrations of psychoactive drugs
[Table 6] presents a list of indications for TDM in psychiatry. The validity of these indications
has to be examined on an individual basis and evaluated for each case individually.
Similar to any diagnostic test, TDM should only be requested when there is evidence
that the result will provide an answer to a well defined question.
Table 6 Typical indications for measuring plasma concentrations of medications in psychiatry.
– Dose optimization after initial prescription or after dose change
|
– Drugs, for which TDM is mandatory for safety reasons (e. g., lithium)
|
– Suspected complete or partial non-adherence (non-compliance) to medication
|
– Lack of clinical improvement under recommended doses
|
– Adverse effects and clinical improvement under recommended doses
|
– Combination treatment with a drug known for its interaction potential or suspected
drug interaction
|
– TDM in pharmacovigilance programs
|
– Relapse prevention under maintenance treatment
|
– Recurrence under adequate doses
|
– Presence of a genetic particularity concerning drug metabolism (genetic deficiency,
gene multiplication)
|
– Pregnant or breast feeding patient
|
– Children and adolescent patient
|
– Elderly patient (>65 y)
|
– Individuals with intellectual disabilities
|
– Patients with pharmacokinetically relevant comorbidities (hepatic or renal insufficiency,
cardiovascular disease)
|
– Forensic patient
|
– Problems occurring after switching from an original preparation to a generic form
(and vice versa)
|
For drugs with well defined therapeutic reference ranges or with a narrow therapeutic
index it makes sense to measure plasma levels for dose titration after initial prescription
or after dose change. Even without a specific problem, there is sufficient evidence
that TDM has beneficial effects for patients treated with these drugs. This holds
true for lithium, tricyclic antidepressants, several antipsychotics or anticonvulsants
([Table 5]). For lithium, TDM is even mandatory for safety reasons.
In case of suspected non-adherence or lack of clinical improvement under recommended doses: TDM is a valid tool for
treatment with all drugs considered in these guidelines. Loss of adherence is a major
problem of long-term medication [10]
[55]
[401]. In patients with schizophrenia [55]
[351] and in patients with unipolar or bipolar disorders non-adherence ranges from 10
to 69% [401]
[439]. Methods used to measure adherence include pill counting, examining case-note recordings,
interviewing patients or noting the attending physicians’ clinical judgement about
adherence [11]
[355]
[685]
[708]. Studies have shown that clinicians cannot reliably predict their patients’ adherence
[104]
[579]. TDM is advantageous, since it is an objective method and tells the prescribing
physician if the drug is in the body at a concentration that is potentially sufficient
for the expected clinical response. Deviations from the expected dose-related reference
range ([Table 4]) indicate if the patient has taken his/her medication, and concomitant determination
of metabolites is another approach to clarify if the drug was taken continuously as
recommended. For interpretation, however, possible interactions with co-medications
exhibiting enzyme inhibiting or inducing properties must be considered ([Table 3]). Reis and coworkers [546]
[547] analysed the compliance of patients who were treated with sertraline by repeated
determination of serum drug concentrations of the parent compound and of the metabolite.
Variations of the ratios of concentrations of norsertraline to sertraline were highly
indicative for hidden and partial non-adherence. To be able to use this approach,
these guidelines were supplemented with data on ratios of concentrations for 32 psychoactive
drugs ([Table 2]). By taking several blood samples per day and by calculation the observed and expected
time dependent plasma concentrations it can be differentiated if a low plasma concentration
is due to reduced bioavailability, enhanced degradation or poor adherence. Pharmacokinetic
modelling of the expected time dependent plasma concentration thereby considers a
drug’s basic pharmacokinetic properties [4]
[78]
[340]
[626]
[654].
When clinical improvement under recommended doses is insufficient and the drug is well tolerated, TDM will clarify if the drug concentration is too
low and if it makes sense to increase the dose.
When adverse effects are associated with clinical improvement under recommended doses, measurement of
the plasma concentration may clarify if side effects are related to excessively high
drug levels in the blood and if the dose should be decreased.
When combining medications that are inhibitors or inducers of drug metabolizing enzymes ([Table 1]), pharmacokinetic drug interactions will occur if the comedication is a substrate
of the inhibited or induced enzyme ([Table 3]). Dose adaptation should be guided by TDM in combination with an inducer or inhibitor
and avoid loss of action, poor tolerability or intoxication due to a pharmacokinetic
drug-drug interaction [215]
[244]
[594]. With regard to environmental factors smoking is of high clinical relevance for
drugs that are substrates of CYP1A2 ([Table 1]). The isoenzyme is dose dependently induced by constituents of cigarette smoke (polycyclic
aromatic hydrocarbons, not nicotine). Its activity increases by 1.2-fold, 1.5-fold
for 1.7-fold for 1–5, 6–10 and >10 cigarettes smoked per day [201]. On the other hand, CYP1A2 activity decreases until the fourth day immediately on
cessation of heavy smoking [200]. Smoking effects should therfore be considered when patients are under therapy with
a CYP1A2 substrate ([Table 1]) such as clozapine [81]
[676], duloxetine [222] or olanzapine [749]. It should also be mentioned that many pharmacokinetic drug-drug interactions have
been found by TDM either by chance or by retrospective analysis of TDM data bases
[112]
[537].
In pharmacovigilance programs, the safety of drug use is supervised under naturalistic conditions [271]
[285]. In case of observed adverse events, measurement of plasma concentrations is most
helpful for clarification [335].
Relapse prevention is a major goal of maintenance treatment. Reduction of relapse rates by TDM is highly
cost-effective, as relapses can lead to hospitalization [377]. In schizophrenic patients, it has been shown that fluctuations of clozapine plasma
concentrations are predictive for relapses [232]
[670] and rehospitalizations [627]. In these patients, TDM may help reduce the risk of relapse or recurrence by increasing
adherence to the medication. One day in the hospital is 4–16 times more expensive
than a single drug concentration measurement in the laboratory.
Recommendation
Though clinical evidence is still scarce, we recommend regular monitoring of plasma
concentrations under maintenance therapy, at least every 3–6 months, to prevent relapses
and rehospitalizations. The frequency of TDM requests may be increased if patients
are known to be non-adherent to the medication or in case of changes of co-medications
or of smoking that affect the pharmacokinetics of the drug.
In patients exhibiting genetic peculiarities of drug metabolizing enzymes, doses must be adapted. Kirchheiner and coworkers [362]
[365] calculated doses for PM or UM of CYP2D6 based on pharmacokinetic and pharmacodynamic
findings. However, even in the case of a confirmed abnormal CYP genotype, TDM is recommended,
because genotyping can only roughly predict to which extent the plasma concentration
may be changed in the individual patient [496]
[497]
[625].
For special groups of patients, such as pregnant or breastfeeding patients, children or adolescent patients [22]
[373]
[194], individuals with intellectual disabilities [158]
[300], or elderly patients, especially patients aged above 75 years [374], TDM is highly recommended.
Any psychopharmacologic therapy of pregnant or breastfeeding women should assure that
the plasma concentration of the drug is in the therapeutic reference range to minimize
the risk of relapse on the mother’s side and, at the same time, to minimize risks
associated with drug exposure of the fetus or the child [169]
[174]. Renal clearance and the activity of the CYP isoenzymes 3A4, 2D6 and 2C9, and uridine
5′-diphosphate glucuronosyltransferase are increased during pregnancy, whereas activities
of CYP1A2 and 2C19 decrease [21]. TDM in pregnant women and/or mothers should be carried out at least once per trimester
and within 24 h after delivery [65].
Many psychoactive drugs are not approved for use in children or adolescents [248]. Pharmacokinetics and pharmacodynamics change during development [194]
[438]
[514]
[516]. In adolescents suffering from psychotic disorders, comorbid drug abuse is very
common, and compliance with an antipsychotic treatment is generally marginal [318]. Therefore, TDM is recommended in these patients. To raise data on the effectiveness
and tolerability of psychoactive drugs under every day conditions, a TDM network was
established for child and adolescent patients [see http://www.tdm-kjp.de/eng/contact.html].
In elderly patients, who frequently are hypersensitive to medication, TDM is helpful to distinguish between
pharmacokinetic and pharmacodynamic factors when adverse effects occur [666]. Ageing involves progressive impairments of the functional reserve of multiple organs
[407], especially renal excretion, and body composition changes significantly [361]
[374]. Hepatic clearance can be reduced by up to 30%. Phase I reactions are more likely
to be impaired than phase II reactions. On the other hand, there are no age-dependent
changes in CYP isoenzyme activity [374]. Age-related changes in physiologic and pharmacokinetic functions as well as the
comorbidity and polypharmacy complicate pharmacotherapy in the elderly [125]. Therefore, TDM should be used for these patients to improve safety and tolerability
of psychopharmacotherapy.
In individuals with intellectual disabilities, new generation antipsychotic drugs are frequently used. Recently published guidelines
recommend TDM for these patients, at least when treated with risperidone or olanzapine
[158]. For ethical and legal reasons, patients with intellectual disabilities are excluded
from clinical trials. On the other hand, many of these patients need medication. In
these individuals, it may be difficult to differentiate between morbogenic and pharmacogenic
reasons for symptom aggravation. Though evidence is poor, TDM is recommended to guide
the pharmacotherapy of these patients [158].
In forensic psychiatry the primary aim of pharmacotherapy, consisting mostly antipsychotic drugs, is reduction
of dangerous behaviour [458]
[462]. To consistently reduce the risk of violence and aggression, adherence to the prescribed
medication is essential [658]. Therefore, TDM is recommended for this group of psychiatric patients. It is, however,
not clear if effective plasma concentrations are identical in forensic and general
psychiatry patients. Castberg and Spigset [113] analyzed data obtained by survey in a high security forensic unit and found higher
doses in forensic patients than in a control group. The dose related plasma concentrations
were significantly lower for olanzapine but higher for quetiapine in the forensic
patients than in the control group.
The indication ”problem occurring after switching from an original preparation to a generic form (and
vice versa)” is still under-investigated and data are scarce [124]
[139].
Another potential indication for TDM not listed in [Table 6] is the increasing availability of counterfeit drugs on the internet [599]. WHO launched a program in 2006 to combat this illegal industry. There are no data
published on this type of market concerning psychotropic drugs, but patients may be
co-medicated (mostly auto-medication) with other drugs obtained from this source.
The counterfeit medications may not comply with purity and dosage standards and therefore
increase the risk for interactions.
Practical Aspects for TDM in Psychiatry
Essential for an effective TDM service is the availability of appropriate analytical
methods that produce results within a reasonable time, i. e., 48 h, and advice from
someone who understands pharmacokinetics and therapeutics [184]. As shown in [Fig. 1], the TDM process starts with the request and ends with the final decision about
how to adjust a given patient’s therapeutic regimen by the health care professional.
Fig. 1 Schematic overview of the TDM process as a guide for psychopharmacotherapy. Routine
TDM is primarily applied to drugs with a narrow therapeutic index and a well-defined
therapeutic reference range. However, TDM is useful for any psychotropic drug when
addressing special therapeutic problems such as “therapy refractoriness” or side effects
under recommended dosage.
Request for plasma concentration quantification
As mentioned above, TDM should only be requested when there is evidence that the result
will provide an answer to a specific question. If it is not clear what the question
is, the answer is of little value. Typical indications are listed in [Table 6]. A single measurement is often insufficient for problem solving. For example, a
series of measurements may be required at appropriate intervals to clarify if a low
plasma concentration is either due to poor compliance, reduced bioavailability or
abnormally rapid elimination.
TDM requests must include a completed request form ([Fig. 2]) which is essential for effective drug concentration measurements and an adequate
interpretation of the results [501]
[635]. The form should contain the patient name or code, demographic data, diagnosis,
medication, reason for the request, the commercial and the generic name of the drug
and its dose, the galenic formulation, the time of the last change of the dose, time
of blood withdrawal. A brief comment on the clinical situation should be given for
interpretation of the results. We recommend to use objective symptom rating, e. g.,
application of the clinical global impression (CGI) scale [283], to measure severity of illness and therapeutic improvement. The summary form of
the UKU scale is useful to evaluate the occurrence and severity of side effects [402]. However, documented feedback to questionnaires indicates that clinicians often
do NOT want to put that much information on the form. Moreover, the filled-in information
is often not accurate. As an alternative, feedback by phone may be offered for interested
physicians.
Fig. 2 Request form for therapeutic drug monitoring in psychiatry.
When interpretation of the results is requested from the laboratory, it is absolutely
necessary to fill out the request forms adequately and completely. Thereby computerized
ordering of TDM has advantages. It is inexpensive and it guides the ordering physician
to give the relevant information required for interpretation in a comfortable way.
Computerized ordering, however, is still not widely used. But effective packages are
on the way to become available (e. g., http://www.konbest.de).
Blood sample collection
Generally, TDM is carried out in plasma or serum samples. The analysis of whole blood,
which is long established for immunosuppressant drugs by using immunoassays [693], has been abandoned for TDM in psychiatry. There is no consensus whether plasma
or serum should be preferred. Definite experimental data are still lacking which clearly
demonstrate differences in the drug concentrations using either plasma or serum. The
few available comparisons indicate that values obtained from serum or plasma can be
used interchangeably [308]. Most psychoactive drugs are intensively bound to blood cells of plasma proteins.
Concentrations of neuropsychiatric drugs reported in this guideline refer to the total
drug fraction in accordance with the literature. For imipramine, it has been shown
that the drug is rapidly and almost totally cleared by the brain through a single
passage in the microvasculature [555]. The extraction was not significantly affected in the presence of albumin, lipoproteins
or erythrocytes. For nortriptyline, statistical relationships between free levels
of drug and clinical response were found to be insignificant [506]. Therefore it seems likely that the clinical response depends on the total drug
fraction. Analysis of psychotropic medications in other materials such as urine, spinal
fluid, tears, hairs or maternal milk have not been introduced for TDM purposes, and
no validated data are available which deal with therapeutic concentrations. Saliva
offers the advantage of non-invasive collection [20]
[25]
[356]. However, the drug concentration in saliva corresponds to the free (i. e., non-protein-bound)
fraction of the drug in blood – which is for most psychopharmacologic medications
only 10% or less of the total concentration. Thus detection problems may occur when
using saliva instead of blood plasma or serum. In any case, more data will have to
be obtained for saliva as a matrix for measurement of drug concentrations.
With few exceptions, TDM relies on trough steady-state plasma concentrations. Blood
should therefore be collected after at least 4 drug elimination half-lives after the
start of or a change in dosage and during the terminal ß-elimination phase. For most
psychotropic drugs, elimination half-lives vary between 12 and 36 h ([Table 5]). Notable exceptions are quetiapine, trazodone, or venlafaxine, which display elimination
half-lives around 6 h. Fluoxetine and aripiprazole have longer elimination half-lives.
In clinical practice, the appropriate sampling time for most psychoactive drugs is
one week after stable daily dosing and immediately before ingestion of the morning
dose, which usually is 12–16 h (or 24 h if the drug is given once daily in the morning)
after the last medication. If, for logistics reasons, blood can only be collected
late in the morning, the patient should not be medicated before blood withdrawal.
In an outpatient setting it is important to indicate exactly the time of administration
of the last dose for interpretation. Trough levels can then be extrapolated by pharmacokinetic
modelling.
In patients treated with a depot preparation of an antipsychotic drug, blood should
be sampled immediately before the next injection. Formulations of antipsychotic drugs
such as haloperidol decanoate or risperidone microspheres are characterised by a slow
absorption after intramuscular administration. Maximum plasma concentration of first
generation depot antipsychotics are reached after 1–14 days after injection, and the
apparent elimination half-life is 2–3 weeks [647]. Similar properties exhibits the newly introduced paliperidone palmitate [131]. For risperidone microspheres the mean time to peak concentrations is 4 weeks and
its plasma half life 4–6 days [647]. For other drugs delivered in extended or retarded release formulations like paliperidone
[70] or quetiapine [212], special attention has to be given to the time of drug intake for correct interpretation
(see [Table 5]). In these formulations, the time of maximum plasma concentration is delayed but
the elimination half-life remains essentially unchanged. The long acting olanzapine
pamoate is a new depot formulation [399]. The salt slowly releases olanzapine from the injection site into the muscle tissue.
However, it dissolves rapidly when it is in contact with blood or plasma. The latter
results in high plasma concentrations and may lead to marked sedation and delirium,
the so called post-injection syndrome [399]
[647]. Considering this special problem it could be useful to control plasma concentrations
of olanzapine shortly (i. e., about 2 h) after the i. m. injection to monitor if plasma
concentrations increase. This approach, however, relies on the rapid quantification
of olanzapine.
TDM may of course be carried at any time after drug ingestion if unexpected side effects
are observed. It is not necessary to measure trough levels, but the dosing schedule
should be reported for interpretation.
Storage and shipment of blood samples
When samples must be stored and sent frozen, it is required to prepare serum or plasma
before freezing, since it is not possible to prepare serum or plasma from frozen blood.
With few exceptions, serum or plasma samples can be stored in the dark (at 4 ℃) for
at least 24 h, and most drug samples can be sent without freezing [305]. Exceptions are light and/or oxygen sensitive substances. For the determination
of bupriopion or methylphenidate, however, serum samples must be frozen or extracted
and stabilized immediately after blood withdrawal and centrifugation (see [Table 5]). Olanzapine must be stored frozen (̶20℃) if not analysed within 72 h [305]. The laboratory should give instructions on its web site or the request form how
to collect (plasma volume, labelling of the samples), store and mail the sample.
Laboratory measurements
Selective and sensitive analytical methods for the quantitative evaluation of drugs
and their metabolites (analytes) are essential for the successful conduct of TDM.
Methods must be validated which includes all of the procedures that demonstrate that
a particular method used for quantitative measurement of analytes in a given biological
matrix is reliable and reproducible for the intended use. The fundamental parameters
for this validation include (1) accuracy, (2) precision, (3) selectivity, (4) sensitivity,
(5) reproducibility and (6) stability. Validation involves documenting, through the
use of specific laboratory investigations, that the performance characteristics of
the method are suitable and reliable for the intended analytical applications. The
acceptability of analytical data corresponds directly to the criteria used to validate
the method [114]
[219].
For psychoactive drugs, chromatographic techniques (gas chromatography (GC), and high-performance
liquid chromatography (HPLC), in combination with suitable detection methods, are
preferred [186]. They are sufficiently precise, accurate and robust and can be adapted to the analysis
of a huge number of drugs. A disadvantage is the need for sample preparation before
chromatographic separation and hence a limited sample throughput. Throughput can be
enhanced by automated sample preparation prior to GC or HPLC. Some laboratories have
introduced HPLC with column switching which allows direct injection of plasma or serum
into the HPLC system. Such procedures are available for a number of antidepressant
[269]
[292]
[293]
[294]
[297]
[298]
[702]
[710] and antipsychotic drugs [368]
[369]
[571]
[572]
[573]
[709]
[710]
[711]
[712]. Another high-throughput chromatographic method is liquid chromatography coupled
with mass spectroscopy (LC-MS) especially tandem MS (LC-MS/MS). LC/MSMS methods can
be applied to almost any psychotropic drug including metabolites [577]. They are most sensitive and selective and can be used without time-consuming sample
preparation. Many compounds can be analysed simultaneously. An excellent example is
the LC-MS/MS method described by Kirchherr and Kühn-Felten [366]. This method was validated for over 50 psychoactive drugs. Disadvantageous for LC-MS/MS
methods are high costs. Moreover, quantification can be problematic due to ion suppression
and the availability of suitable calibration standards, preferentially deuterated
analogues [584].
In case of suspected intoxications, TDM methods should enable drug analysis within
1–2 h [215]. For this purpose automated methods are advantageous.
The laboratory should not only analyse the drug but also its active metabolites, e. g.,
bupropion plus hydroxybupropion, clomipramine plus desmethylclomipramine, fluoxetine
plus norfluoxetine, naltrexone plus naltrexol, risperidone plus 9-hydroxyrisperidone
or venlafaxine plus O-desmethylvenlafaxine ([Table 5]). For some drugs, the determination of metabolites that do not contribute to the
overall clinical effect (e. g., norsertraline, normirtazapine, norcitalopram) is also
useful to monitor drug adherence of the patient [546], to get information on his/her capacity to metabolise drugs, or to interprete drug-drug
interactions when drugs are involved exhibiting enzyme inhibiting or inducing properties
([Table 2]). “Normal” ratios of concentrations of metabolites to parent drugs that are expected
in 68.3% of the patients are listed in [Table 3]. Any ratio outside the reported “normal” range should be considered as a signal
pointing to individual abnormalities due to a drug-drug-interaction, gene polymorphism,
altered liver function, non-adherence or drug intake few hours before blood withdrawal.
The assay of enantiomers of chiral compounds requires either stereoselective derivatisation
of the drugs prior to their quantification, or their separation by chiral chromatographic
GC or HPLC columns. LC-MS/MS may be the method of choice. As an example, the TDM of
the enantiomers of methadone using a classical detection method such as fluorescence
or ultraviolet light absorption is often jeopardized by comedication or by coconsumption
drugs of abuse. These problems may be circumvented by use of a mass detector, preferably
a tandem mass spectrometer.
Within the therapeutic reference range, intraday- and interday precision should not
exceed 15% (coefficient of variation) and accuracy should not deviate more than 15%
from the nominal value [114]
[219].
To ensure quality and reliability of plasma concentrations assays, internal and external
quality control procedures are mandatory. Samples must contain suitable internal standards,
and each series of samples must include internal control samples. If standards are
not available commercially, they should be prepared by personnel other than those
performing the assays and by separate weighing of reference material. Reporting of
results requires that the results of the quality controls are within the expected
range. If quality controls are outside the expected range, the reason underlying the
outlier needs to be clarified and documented.
The laboratory has to participate in an external quality assessment scheme, although this is not a legal requirement in all countries. For neuropsychiatric
drugs, the first external quality program was introduced by Cardiff Bioanalytical
Services Ltd in 1972 [720]. It has currently 450 participants from 36 countries (http://www.heathcontrol.com). Instand e. V. (www.instanddev.de/ringversuche/) is another recommended provider
of external control, the external quality control scheme was recently expanded to
multiple psychoactive drugs samples. Moreover, reference materials are also available
from forensic chemistry (http://www.pts-gtfch.de/).
Communication of results
The concentration of the psychoactive drug as well as that of active metabolites contributing
to the therapeutic action should be reported with reference ranges ([Table 5]) either in mass or molar units. We recommend the use of mass units to relate concentration
to dose. Laboratories vary in the presentation of their results. The clinician should
take note of the units (i. e., ng/mL, μg/L, μmol/L, or nmol/L) in which the results
of the analysis are expressed. This is especially recommended for comparisons of TDM
values obtained from different laboratories or with those in the literature. To transform
molar units into mass units and vice versa conversion factors are given in [Table 5].
When drug concentrations are below the limit of quantification (LOQ), which refers
to the lowest concentration of the standard curve that can be measured with at least
20% accuracy and precision, this limit should be indicated.
The results should be available for decision making within a clinically meaningful
time. Although 24 h TDM service would be desirable, 48 h turnaround time is sufficient
in most cases. In case of suspected intoxications, a few hours service is necessary
[215]. To assist rapid intervention in patients at risk for toxicity or loss of tolerability,
prompt information (phone call) of the treating physician is required when the laboratory
measures drug concentrations above the “laboratory alert level” which was newly defined
(see above) in the present consensus guidelines ([Table 5]).
Interpretation of results
We recommend that interpretation and pharmacologic advice are provided with every
report. Expert interpretation of a drug concentration measurement and the adequate
use of the information are essential to ensure the full clinical benefit of TDM. Reporting
of results with inclusion of dose recommendations and other comments must be guided
by the best available evidence. Expert knowledge may be necessary to calculate dose
corrections or to analyse drug-drug interactions. It is therefore advantageous for
the clinician to choose a laboratory that offers this service. Otherwise, the treating
physician, a clinical pharmacologist or a trained expert of the clinic has to interpret
the results. Access to specialist advice is also necessary if TDM results suggest
that genotyping may be advisable [335].
Diagnosis and drug dose are important information for interpretation, since they permit
a judgement on whether a result is plausible or not. Moreover, it must be controlled
if blood samples were collected under recommended conditions, especially when the
plasma concentration is unexpectedly high in an outpatient. When the drug was taken
a few hours before blood sampling the drug concentration can be several-fold higher
than the trough level.
For the interpretation of the results, it should not only be considered whether the
plasma concentration of the drug is within the “therapeutic reference range” ([Table 5]). It must also be considered if the drug plasma concentration is consistent with
the dose ([Table 4]). A plasma concentration may be outside the therapeutic reference range, just because
a low or high dose was taken. In addition, it is wise to take into account the level
of evidence underlying the “therapeutic reference range” of the particular drug ([Table 5]). It should also be considered if the daily drug dose was given as a single or a
multiple dose.
Often it is necessary to deal with pharmacokinetic properties such as metabolic pathways,
enzymes involved and substrate and inhibitor properties of all drugs taken by the
patient for interpretation of the results. Supportive information is therefore given
in the present updated guidelines showing literature based substrate ([Table 1]) and inhibitor or inducer properties of drugs ([Table 3]) to deal with possible drug-drug interactions.
Any drug concentration outside its dose-related reference range ([Table 5]) should alert the TDM laboratory to actively look for non-average pharmacokinetic
drug disposition of the patient, drug-drug-interactions, gene polymorphisms that give
rise to poor or ultra rapid metabolism, altered function of the excretion organs liver
and kidneys, age and/or disease-related changes in the patient’s pharmacokinetics,
compliance (adherence) problems, a non-steady state and even signal interference from
other medications that the patient may not have declared to the prescribing physician
(e. g., St. John’s wort) in the laboratory analysis. It may also be informative to
calculate the dose related reference range ([Table 4]) if the drug concentration lies outside the recommended therapeutic reference range
([Table 5]) [285].
Plasma concentrations must be interpreted with the clinical presentation in mind.
Recommendations on dosage changes constitute the most frequent advice. Other information
which could be of help for the physician are those related to genetic polymorphisms,
risks of pharmacokinetic interactions in the case of polypragmasy, pharmacokinetic
properties of the drug in patients belonging to a ”special population”, e. g., elderly
patients, or patients with hepatic or renal insufficiency. For the treatment of pain,
relatively low plasma concentrations of tricyclic antidepressants may be sufficient.
They may be within the “dose related reference range” ([Table 4]) but outside the “therapeutic reference range” of [Table 5] which was established for the indication of depression.
A laboratory may recommend that an additional sample should be taken after a certain
period, because in cases with unusually low or high plasma concentrations, repeated
measurements may help to decide whether the patient’s adherence is inconstant (irregular
intake of the drug) or whether the patient is an abnormal metabolizer.
Since the interpretation of TDM results relies on complex quantitative relationships,
training in clinical psychopharmacology and pharmacokinetics and the application of
TDM is essential. Regular conferences with discussion of the interpretation of real
cases are most helpful for learning. It is also recommended that junior psychiatrists
interpret the results under supervision of an expert.
Clinical decision making
A TDM result is a guide to proper dosing of the individual patient. The physician
has to be aware that, under optimal conditions, reporting of results with inclusion
of dose recommendations and other comments by the laboratory is guided by the best
available evidence [310]. The laboratory, however, has only a restricted knowledge of the clinical situation.
On the other hand, most treating physicians have limited pharmacokinetic knowledge.
Therefore it is essential to be aware that optimal TDM is an interdisciplinary task
that requires close communication between laboratory and clinical experts.
If the plasma concentration of the drug is within the therapeutic reference range,
an adaptation of the dose is, of course only recommended when clinical reasons, such
as adverse effects or non-response clearly justify such a decision. Evidently, the
treating physician has to decide whether the treatment strategy is to be changed or
not. On the other hand, when the advice given on the TDM report is not followed, the
reason for this course of action must be substantiated to allow evaluation of the
treating physician’s decision should the patient come to harm. Recommendations for
such an evaluation in a court of law have been recently published by the TDM-AGNP
group [741].
In patients with abnormally rapid elimination it may be useful to prescribe a dose
above the maximal recommended dose, since such patients can exhibit drug concentrations
below the reference range under standard doses. However, the medication should be
changed if the patient exhibited sufficiently high drug concentrations for a sufficiently
long treatment period, i. e., for at least 2 weeks, and did not improve by at least
20%.
When adverse effects are associated with clinical improvement under recommended doses, measurement of
the plasma concentration may clarify if side effects are related to exceedingly high
drug levels in the blood. In this situation, the dose can be decreased, normally without
risk of loss of action.
For the treatment with antidepressant or antipsychotic drugs, there is good evidence
that clinical non-improvement at week 2 is highly predictive for later response and
remission [119]
[138]
[392]
[620]
[621]
[638]. Especially the absence of early improvement appears to be a highly reliable predictor
of later non-response [358]. For dose titration with antidepressant and antipsychotic drugs we therefore recommend
to include symptom rating by the treating physician [138] at baseline and at week 2 in addition to drug concentration measurements. [Fig. 3] summarizes the above recommendations in a flow chart.
Fig. 3 TDM-guided dose titration of antidepressant or antipsychotic drug treatment (adapted
from [311]). Clinical decision making has to consider the clinical improvement, the duration
of treatment, and steady-state concentration of the drug in plasma or serum. The steady-state
is reached by 94% after 4 elimination half-lives of the drug or active metabolites
(see [Table 5]).
When further plasma concentration measurements are recommended after a modification
of the dose or after prescription of a comedication that is known to inhibit or enhance
the metabolism of the drug to be measured, the next TDM should be delayed until steady-state
conditions are reached again. For this, the terminal elimination half-life of the
drug has to be considered ([Table 5]).
Pharmacogenetic tests in addition to TDM
Concentrations outside the reference range may be due to gene polymorphisms that give
rise to slow/rapid metabolizers. As a consequence, the laboratory may also suggest
that a pharmacogenetic test should be carried out [14]
[144]
[158]
[193]
[335]
[362]
[365]
[377]
[623]
[624]
[675]. Genotyping, however, is not available in all TDM laboratories, and we recommend
consultation of specialized laboratories for interpretation of the results.
Situations and cases where pharmacogenetic tests could advantageously be combined
with TDM are explained in more detail by Jaquenoud Sirot and coworkers [335]. Some of the most important indications for the combination of genotyping with TDM
are the following:
-
the patient is treated with a substrate the metabolism of which shows a wide interindividual
variability;
-
a drug is characterized by a small therapeutic index: risk of toxicity in the case
of a genetically impaired metabolism, or on the other hand, risk of non-response due
to an ultra- rapid metabolism and the inability to reach therapeutic drug levels;
-
the patient presents unusual plasma concentrations of the drug or its metabolite(s)
and genetic factors are suspected to be responsible;
-
the patient suffers from a chronic illness, which requires life-long treatment.
In a patient who is genotyped as a PM or UM, the medication should not automatically
be replaced by another as suggested by some authors, but the dose can often be adapted,
using clinical judgement and TDM.