Lack of response or side effects despite therapeutic dosing: drug-drug interactions? An indication for Therapeutic Drug Monitoring (TDM)

Introduction: About 6–10% of all occurring adverse drug reactions result from drug-drug interactions [1,2]. This incidence increases in the presence of risk factors, such as age or genetic constitution. Many harmful drug interactions are preventable, and TDM is an effective tool in that. Case reports: The following two cases illustrate the need for TDM. 1) A 68 years old schizophrenic patient suffered from a paralytic ileus due to clozapine intoxication (clozapine 1732ng/ml, recommended: 350–600ng/ml) after installing the combination with fluvoxamine, this in spite of a dose reduction of clozapine of 50%. 2) A 63 years old depressed patient treated with lithium and venlafaxine and ibuprofen experienced lithium intoxication (1.66mmol/l (ref. 0.5–1.2)) after doubling the dose of ibuprofen. Discussion: Drugs susceptible for relevant pharmacokinetic interactions (highly metabolized by liver enzymes, low bioavailability and a narrow therapeutic range) are primary candidates for TDM. Patients' predispositions, such as hepatic and/or renal dysfunction, genetic constitution (i.e. polymorphisms of drug metabolizing enzymes) and comorbidities also contribute to the extent and/or the consequences of the deviation of drug plasma levels. One should also consider active metabolites and how their plasma levels might be influenced, as well as the time range in which interactions may take place (i.e. considering the half-life of the involved drugs and the period of latency for enzyme induction processes). Conclusions: TDM is an essential part of keeping co-medications safe; however, in order to keep TDM effective and economic, drug- and patient-specific conditions need to be taken into account. References: [1] Buclin et al. Grundlagen der Arzneimitteltherapie, Documed, Basel, 2005. [2] Obreli Neto et al. J Pharm Pharm Sci. 2012 Jan;15(2):332–43.