1. There is an increasing appreciation of the relevance of pharmacokinetics of drugs during evaluation of their safety for human clinical use. Regulatory requirements for clinical pharmacokinetic data have progressively 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 establish reliable dose response (both therapeutic and toxic) relationships must be an important objective. 3. Concurrent developments in our understanding of the pharmacological effects (therapeutic or toxic) of metabolites, the interethnic and interindividual differences in drug responses and the toxicological aspects of drug chirality now provide compelling reasons for the roles of bioactivation, pharmacogenetics and stereochemical factors to be addressed in pharmacokinetic studies during the clinical development of drugs. 4. Apart from the traditional pharmacokinetic studies following single and multiple doses in healthy volunteers, patients and special subgroups, reliable dose-response curves for therapeutic and toxic effects must be established in well-designed controlled studies using a wide range of doses. Often, doses lower than those recommended have a much improved risk/benefit ratio. 5. Secondary pharmacology of the drug and its active metabolites must be defined for assessment of safety (adverse reactions and pharmacokinetic and pharmacodynamic drug-drug interactions) in high dose/concentration situations. 6. The enzyme systems responsible for the metabolism of a drug must be identified followed by rational investigations of drug-drug and drug-disease interactions both from the efficacy and safety viewpoints. 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 intraindividual levels must be fully explored during all phases of the clinical development 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 surprisingly, enantiomers of a drug differ significantly in their pharmacokinetics and pharmacodynamics. The possibility of interactions between 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 justified. 8. Analysis of population pharmacokinetics offers an approach by which to examine the roles of various factors which are likely to be clinically relevant for the safe and effective use of drugs.(ABSTRACT TRUNCATED AT 400 WORDS)