Clinical pharmacokinetic registration file for NDA and ANDA procedures

Pharmacokinetics is a relatively young branch of the life sciences, which has developed rapidly in the last 15-20 years, thanks to a series of analytical achievements that have allowed drug concentrations to be measured in biological matrices with highly selective and sensitive methods. Most old drugs and all new drugs have been investigated in depth to determine their absorption, distribution, metabolism and elimination. This has produced a huge body of data which have characterized drugs through so-called fingerprint parameters. Today, pharmacokinetics plays a vital role throughout drug development from initial non-clinical studies to clinical trials. In new drug development, simultaneous efforts in pharmacodynamic and pharmacokinetic studies have produced a high degree of synergy, the most useful expression of which is the identification of a therapeutic window, where this can be achieved. Dose linearity/proportionality, gender effect, metabolism and possible polymorphism, studies on neonates/children and on elderly and diseased patients and the population approach, relative and absolute bioavailability, possible interactions and the possible presence of a deep compartment in the distribution are other important applications of pharmacokinetics. Major new developments in pharmaceutical technology which have produced controlled-release delivery systems and the market introduction of generics would never have occurred but for the active contribution of pharmacokinetics. This review is devoted to the investigations needed to prepare appropriate pharmacokinetic registration files for new drug applications (NDAs) and abbreviated or abridged new drug applications (ANDAs) required for generic drugs. Scientific literature, operating guidelines and personal experience are the basis of this review, which describes a number of relevant examples in several specific areas.