The dose-concentration-effect relationships - the basis for TDM. A critical appraisal

Therapeutic Drug Monitoring (TDM) is based on a series of theoretical assumptions, a clinical pharmacological rationale, scientific documentation and a practical implementation, respecting the theoretical and scientific basis. The clinical pharmacological rationale for TDM; a pharmacokinetic variability exceeding therapeutic index and dose titration on the basis of clinical or paraclinical measurements not being feasible, limits TDM to a minor fraction of all drugs available. The theoretical assumption that blood concentration measurements reflect/predict the tissue/receptor concentration and the clinical endpoints, requires several points to be considered such as concentration fluctuations, protein binding, active metabolites, etc. A relatively constant ratio between blood and tissue/receptor concentration is generally assumed, but the important role of transporter proteins, with inter- and intraindividual variability due to polymorphisms, inducers and inhibitors seriously challenge this basic assumption. Concentration-effect relationships concerns groups of patients and indicate the probability of a given response (therapeutic/toxic) at a given concentration. Dose-effect and concentration-effect studies of drugs like digoxin, lithium and antidepressants have shown that the dose-effect or concentration-effect curves for therapeutic effect and tolerability are flat and overlapping. Dose-effect studies, now standard in drug development, represent a unique possibility to examine dose-concentration-effect relationships of new drugs. (C) 2001 Elsevier Science B.V. All rights reserved.