The role of population pharmacokinetics in drug development in light of the Food and Drug Administration's 'Guidance for Industry: Population pharmacokinetics'

Population pharmacokinetics (PPK) has evolved from a discipline primarily a pplied to therapeutic drug monitoring to one that plays a significant role in clinical pharmacology in general and drug development in particular. In February 1999 the US Food and Drug Administration issued a 'Guidance for In dustry: Population Pharmacokinetics' that sets out the mechanisms and philo sophy of PPK and outlines its role in drug development. The application of PPK to the drug development process plays an important r ole in the efficient development of safe and effective drugs. PPK knowledge is essential for mapping the response surface, explaining subgroup differe nces, developing and evaluating competing dose administration strategies, a nd as an aid in designing future studies. The mapping of the response surfa ce is done to maximise the benefit-risk ratio, so that the impact of the in put profile and dose magnitude on beneficial and harmful pharmacological ef fects can be understood and applied to individual patients. PPK combined wi th simulation methods provides a tool for estimating the expected range of concentrations from competing dose administration strategics. Once extracte d, this knowledge can be applied to labelling or used to assess various fut ure study designs. PPK should be implemented across all phases of drug development. For pre cl inical studies, PPK can be applied to allometric scaling and toxicokinetic analyses, and is useful for determining 'first time in man' doses and expla ining toxicological results. Phase I studies provide initial understanding of the structural model and the effect of possible covariates, and may late r be used to evaluate PPK differences between patients and healthy individu als. Phase II studies provide the greatest opportunity to map the response surface. With these PPK models it is possible to gain an improved understan ding of the role of the dose on the response surface and of the range of ex pected responses. In phase III and IV studies, PPK is implemented to furthe r refine the PPK model and to explain unexpected responses. Planning for the implementation of PPK across all phases of drug developmen t is necessary, as well as planning fur individual PPK studies. planning sh ould include: defining important questions, identifying covariates and drug -drug interactions that need to be investigated, and identifying the applic ations and intended use of the model(s). The plan for each project must hav e a strategy for data management, data collection, data quality assurance, staff training for data collection, data analysis and model validation.