CLINICAL PHARMACOKINETICS - CURRENT REQUIREMENTS AND FUTURE PERSPECTIVES FROM A REGULATORY POINT-OF-VIEW

1. There is an increasing appreciation of the relevance of pharmacokin etics of drugs during evaluation of their safety for human clinical us e. Regulatory requirements for clinical pharmacokinetic data have prog ressively evolved to emphasize and address these safety implications. 2.. Historically the dose schedules usually recommended have been too high, often with serious consequences. Therefore, the need to establis h reliable dose response (both therapeutic and toxic) relationships mu st be an important objective. 3. Concurrent developments in our unders tanding of the pharmacological effects (therapeutic or toxic) of metab olites, the interethnic and interindividual differences in drug respon ses and the toxicological aspects of drug chirality now provide compel ling reasons for the roles of bioactivation, pharmacogenetics and ster eochemical factors to be addressed in pharmacokinetic studies during t he clinical development of drugs. 4. Apart from the traditional pharma cokinetic studies following single and multiple doses in healthy volun teers, patients and special subgroups, reliable dose-response curves f or therapeutic and toxic effects must be established in well-designed controlled studies using a wide range of doses. Often, doses lower tha n those recommended have a much improved risk/benefit ratio. 5. Second ary pharmacology of the drug and its active metabolites must be define d for assessment of safety (adverse reactions and pharmacokinetic and pharmacodynamic drug-drug interactions) in high dose/concentration sit uations. 6. The enzyme systems responsible for the metabolism of a dru g must be identified followed by rational investigations of drug-drug and drug-disease interactions both from the efficacy and safety viewpo ints. Factors responsible for alterations in the functional expression of this enzyme system must be identified and the safety and efficacy implications of these findings at interethnic, inter- and intraindivid ual levels must be fully explored during all phases of the clinical de velopment of the drug. This should lead to carefully designed patient subgroup-specific dose schedules which maximize the risk/benefit ratio for all patients. 7. Drugs operate in a chiral environment and, not s urprisingly, enantiomers of a drug differ significantly in their pharm acokinetics and pharmacodynamics. The possibility of interactions betw een enantiomers of a drug and of enantioselective interactions should be examined. These should be thoroughly investigated and the decision to market a racemic mixture or one of its enantiomers must be justifie d. 8. Analysis of population pharmacokinetics offers an approach by wh ich to examine the roles of various factors which are likely to be cli nically relevant for the safe and effective use of drugs. 9. This pape r reviews, with examples, the general regulatory requirements and futu re perspectives for clinical pharmacokinetic data, with special refere nce to the dose-response relationship, activity of metabolites, chiral ity, pharmacogenetics and the value of population-based approaches to identify subsets of patient populations of pharmacokinetic interest.