Dose-Corrected Serum Concentrations and Metabolite to Parent Compound Ratios of Venlafaxine and Risperidone from Childhood to Old Age

Abstract

Objective Comparative pharmacokinetic data about the antidepressant venlafaxine (VEN) and the antipsychotic drug risperidone (RIS) over the lifespan and especially in children and adolescents is lacking. This is the first cross-sectional study that aimed to investigate differences in dose-corrected serum concentrations (CDs) and metabolite to parent compound ratios (MPRs) of VEN and RIS across the lifespan.

Methods Patients treated with VEN and RIS at the University Hospital of Würzburg, Germany were included in the study. Serum level determinations were performed during clinical routine care. Patients with CYP2D6 influencing co-medication were excluded from analyses.

Results In 953 patients (12–93 years) treated with VEN and 552 patients (7–92 years) treated with RIS, children/adolescents (<18 years) showed 11% and 19%, and 44% and 42% lower CDs of the active moieties (CDs_AM) of VEN and RIS than adults and elderly (≥60 years) (Kruskal-Wallis tests; p ≤ 0.001). However, when CDs were normalized to body weight, a different pattern emerged. Gender differences, with higher CDs_AM in females were present in adults and elderlies but not in children/adolescents. No gender- or age-dependent difference in MPRs was found; however, 80% of MPRs of RIS in children/adolescents were below the range of “normal” CYP2D6 function for adults.

Conclusions We suggest a higher clearance as a reason for lower CDs_AM of VEN and RIS in children/adolescents compared to adults/elderlies. Metabolism of VEN or RIS by CYP2D6, characterized by MPRs, was not associated with age. However, MPRs of RIS were lower in children/adolescents, possibly due to a higher renal clearance of 9-OH-risperidone.

Key words

therapeutic drug monitoring - child - lifespan - antidepressants - antipsychotics

Publication History

Received: 13 July 2020
Received: 22 October 2020

Accepted: 29 October 2020

Article published online:
08 December 2020

• References

• 1 FDA. FDA approves the first drug to treat irritability associated with autism, risperdal. Silver Spring; 2006
• 2 FDA. Drug approved for two psychiatric conditions in children and adolescents. Silver Spring; 2007
• 3 Glennon J, Purper-Ouakil D, Bakker M. et al. Paediatric European Risperidone Studies (PERS): Context, rationale, objectives, strategy, and challenges. Eur Child Adolesc Psychiatry 2014; 23: 1149-1160
• 4 Bachmann CJ, Lempp T, Glaeske G. et al. Antipsychotic prescription in children and adolescents: An analysis of data from a German statutory health insurance company from 2005–2012. Dtsch Arztebl Int 2014; 111: 25-34
• 5 Taurines RW, A. Greenhill L, Gerlach M. Psychiatric Drugs in Children and Adolescents-Basic Pharmacology and Practical Applications. Wien: Springer; 2014
• 6 Hiemke C, Bergemann N, Clement HW. et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017. Pharmacopsychiatry 2018; 51: 9-62
• 7 Gerlach M, Greenhill L, Warnke A. Special features of psychopharmacological therapy in children and adolescents. In Gerlach M, Warnke A, Greenhill L. Psychiatric Drugs in Children and Adolescents. Wien: Springer; 2014: 61-74
• 8 Kearns GL, Abdel-Rahman SM, Alander SW. et al. Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349: 1157-1167
• 9 Unterecker S, Hiemke C, Greiner C. et al. The effect of age, sex, smoking and co-medication on serum levels of venlafaxine and O-desmethylvenlafaxine under naturalistic conditions. Pharmacopsychiatry 2012; 45: 229-235
• 10 Megens AA, Awouters FH, Schotte A. et al. Survey on the pharmacodynamics of the new antipsychotic risperidone. Psychopharmacology (Berl) 1994; 114: 9-23
• 11 Aravagiri M, Yuwiler A, Marder SR. Distribution after repeated oral administration of different dose levels of risperidone and 9-hydroxy-risperidone in the brain and other tissues of rat. Psychopharmacology (Berl) 1998; 139: 356-363
• 12 Strolin Benedetti M, Whomsley R, Baltes EL. Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations. Expert Opin Drug Metab Toxicol 2005; 1: 447-471
• 13 Bebia Z, Buch SC, Wilson JW. et al. Bioequivalence revisited: influence of age and sex on CYP enzymes. Clin Pharmacol Ther 2004; 76: 618-627
• 14 Tamminga WJ, Wemer J, Oosterhuis B. et al. CYP2D6 and CYP2C19 activity in a large population of Dutch healthy volunteers: Indications for oral contraceptive-related gender differences. Eur J Clin Pharmacol 1999; 55: 177-184
• 15 Tan JL, Eastment JG, Poudel A. et al. Age-related changes in hepatic function: An update on implications for drug therapy. Drugs Aging 2015; 32: 999-1008
• 16 Springer-Verlag GmbH, Heidelberg. PSIAC. cited: March 18, 2019
• 17 Tolledo EC, Miksys S, Gonzalez FJ. et al. Propranolol is a mechanism-based inhibitor of CYP2D and CYP2D6 in humanized CYP2D6-transgenic mice: effects on activity and drug responses. Br J Pharmacol 2020; 177: 701-712
• 18 Benkert O, Hippius H. Kompedium der Psychiatrischen Pharmakotherapie. Springer-Verlag; 2017
• 19 Scherf-Clavel M, Deckert J, Menke A. et al. Smoking is associated with lower dose-corrected serum concentrations of escitalopram. J Clin Psychopharmacol 2019; 39: 485-488
• 20 Scherf-Clavel M, Samanski L, Hommers LG. et al. Analysis of smoking behavior on the pharmacokinetics of antidepressants and antipsychotics: evidence for the role of alternative pathways apart from CYP1A2. Int Clin Psychopharmacol 2019; 34: 93-100
• 21 Chromsystems Instrumental & Chemicals GmbH. Effizientes Drug Monitoring mit LC-MS/MS www.Chromsystems.de 2019
• 22 Chromsystems Instrumental & Chemicals GmbH. MassTox TDM Series A Parameter-Set Antidepressiva 1/Extended im Serum/Plasma 2015
• 23 Chromsystems Instrumental & Chemicals GmbH. MassTox TDM Series A Parameter-Set Neuroleptika 1/Extended im Serum/Plasma 2019
• 24 INSTAND Gesellschaft zur Förderung der Qualitätssicherung in medizinischen Laboratorien e. V 2020; https://www.instand-ev.de/ueber-instand-ev/instand-ev.html cited: February 10, 2020
• 25 Mullen S. Major depressive disorder in children and adolescents. Ment Health Clin 2018; 8: 275-283
• 26 Sigurdsson HP, Hefner G, Ben-Omar N. et al. Steady-state serum concentrations of venlafaxine in patients with late-life depression. Impact of age, sex and BMI. J Neural Transm (Vienna) 2015; 122: 721-729
• 27 Molden E, Waade RB, Hoff M. et al. Impact of aging on serum concentrations of risperidone and its active metabolite in patients with known CYP2D6 genotype. Basic Clin Pharmacol Toxicol 2016; 119: 470-475
• 28 Schoretsanitis G, Stegmann B, Hiemke C. et al. Pharmacokinetic patterns of risperidone-associated adverse drug reactions. Eur J Clin Pharmacol 2016; 72: 1091-1098
• 29 Emslie GJ, Findling RL, Yeung PP. et al. Venlafaxine ER for the treatment of pediatric subjects with depression: results of two placebo-controlled trials. J Am Acad Child Adolesc Psychiatry 2007; 46: 479-488
• 30 Klampfl K, Taurines R, Preuss A. et al. Serum concentrations, therapeutic response and side effects in children and adolescents with impulsive-aggressive symptoms during risperidone therapy. Pharmacopsychiatry 2010; 43: 58-65
• 31 Gagliano A, Germano E, Pustorino G. et al. Risperidone treatment of children with autistic disorder: effectiveness, tolerability, and pharmacokinetic implications. J Child Adolesc Psychopharmacol 2004; 14: 39-47
• 32 Pozzi M, Cattaneo D, Baldelli S. et al. Therapeutic drug monitoring of second-generation antipsychotics in pediatric patients: An observational study in real-life settings. Eur J Clin Pharmacol 2016; 72: 285-293
• 33 Wang ZZ, Deng SH, Lu HY. et al. Effect of venlafaxine dosage, valproic acid concentration, sex, and age on steady state dose-corrected concentrations of venlafaxine and O-desmethylvenlafaxine: a retrospective analysis of therapeutic drug monitoring data in a Chinese population. Hum Psychopharmacol 2020; 35: e2733
• 34 Matalova P, Urbanek K, Anzenbacher P. Specific features of pharmacokinetics in children. Drug Metab Rev 2016; 48: 70-79
• 35 Cipriani A, Zhou X, Del Giovane C. et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. The Lancet 2016; 388: 881-890
• 36 Doroudgar S, Perry PJ, Lackey GD. et al. An 11-year retrospective review of venlafaxine ingestion in children from the California Poison Control System. Hum Exp Toxicol 2016; 35: 767-774
• 37 Fekete S, Hiemke C, Gerlach M. Dose-related concentrations of neuro-/psychoactive drugs expected in blood of children and adolescents. Ther Drug Monit 2020; 42: 315-324
• 38 Sherwin CM, Saldana SN, Bies RR. et al. Population pharmacokinetic modeling of risperidone and 9-hydroxyrisperidone to estimate CYP2D6 subpopulations in children and adolescents. Ther Drug Monit 2012; 34: 535-544
• 39 Koons NJ, Suresh MR, Schlotman TE. et al. Interrelationship between sex, age, blood volume, and vo2max. Aerosp Med. Hum Perform 2019; 90: 362-368
• 40 Castberg I, Westin AA, Skogvoll E. et al. Effects of age and gender on the serum levels of clozapine, olanzapine, risperidone, and quetiapine. Acta Psychiatr Scand 2017; 136: 455-464
• 41 Aichhorn W, Weiss U, Marksteiner J. et al. Influence of age and gender on risperidone plasma concentrations. J Psychopharmacol 2005; 19: 395-401
• 42 McCune JS, Lindley C, Decker JL. et al. Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan. J Clin Pharmacol 2001; 41: 723-731
• 43 Hagg S, Spigset O, Dahlqvist R. Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharmacol 2001; 51: 169-173
• 44 Labbe L, Sirois C, Pilote S. et al. Effect of gender, sex hormones, time variables and physiological urinary pH on apparent CYP2D6 activity as assessed by metabolic ratios of marker substrates. Pharmacogenetics 2000; 10: 425-438
• 45 Meibohm B, Beierle I, Derendorf H. How important are gender differences in pharmacokinetics?. Clin Pharmacokinet 2002; 41: 329-342
• 46 Tanaka E. Gender-related differences in pharmacokinetics and their clinical significance. J Clin Pharm Ther 1999; 24: 339-346
• 47 Hommos MS, Glassock RJ, Rule AD. Structural and functional changes in human kidneys with healthy aging. J Am Soc Nephrol 2017; 28: 2838-2844
• 48 Macaluso M, Oliver H, Sohail Z. Pharmacokinetic drug evaluation of paliperidone in the treatment of schizoaffective disorder. Expert Opin Drug Metab Toxicol 2017; 13: 871-879
• 49 Sangkuhl K, Stingl JC, Turpeinen M. et al. PharmGKB summary: Venlafaxine pathway. Pharmacogenet Genomics 2014; 24: 62-72