Methods and Findings in Experimental and Clinical Pharmacology
Vol. 25, Suppl. A, 2003
ISSN 0379-0355
Copyright 2003 Prous Science, S.A.
CCC: 0379-0355/2003
http://www.prous.com

Exploratory and Confirmatory Studies in Humans: Relevant Criteria in Pharmacokinetics

J. Ramis

Servicio de Metabolismo y Farmacocinética, Ipsen Pharma, S.A., Grupo Beaufour-Ipsen

The step that follows drug discovery, lead candidate selection and basic preclinical development studies of a new chemical entity is the evaluation of efficacy and safety in humans. Phase I clinical studies are located at the interface between the end of preclinical testing and the start of human studies. Pharmacokinetic concepts, together with pharmacodynamic and toxicity studies, are helpful in extrapolating preclinical data from animal species to humans and facilitating first dose in man and dose escalation studies. Two different approaches have been used: allometry and the physiologically-based method. The allometric approach is useful when linear kinetics of drug disposition, low or similar extent of protein binding and drug elimination predominantly via physical or mechanical processes occurs in the different animal species. When metabolism is the major elimination pathway of a drug in animals and also expected to be so in humans, the physiologically-based approach offers an adequate alternative.

The safety and tolerability of escalating single-dose treatments is established in the first Phase I study. Pharmacokinetic or drug concentration-driven dose escalation is a good complementary tool to the classical escalation methods based in pharmacological or toxicological response. Issues related to bioavailability or nonlinear pharmacokinetics are immediately apparent and can be readily addressed. These studies use the highest doses that will ever be administered over the course of development and are the first opportunity to determine pharmacokinetics and, if possible, pharmacodynamics in humans.

The next Phase I studies are preliminary bioavailability and pharmacokinetic profile in humans after single or multiple dose administration. At this point, a drug labeled single-dose ADME study in humans should also be included to obtain data of extended absorption, elimination, metabolites and mass balance. The study of inter-intravariability is relevant in estimating the sample size of further pharmacokinetic assays.

Pharmacokinetic studies during Phase II are conducted to answer further questions about pharmacokinetic linearity, bioavailability and metabolism in humans. An intravenous formulation, if possible, allows the unambiguous evaluation of clearance, distribution volume and bioavailability. During this phase of drug development, the first trial of a new drug in patients normally occurs and first pharmacokinetic data is performed. Studies in patients implies more restrictive conditions in the study design, so that information obtained in previous pharmacokinetic studies allows improvement in the number of extractions and enhancement in the extraction times.

In Phase III clinical studies, pharmacokinetic studies are focused on characterizing the remaining unknown sources of pharmacokinetic variability and identifying subpopulations of patients who may have special risks or require dosage regimen adjustments. Two complementary approaches are used: characterizing pharmacokinetics variability in the patients participating in the Phase III clinical studies (population pharmacokinetics) and initiating small, focused pharmacokinetic studies examining conditions that might be expected to affect pharmacokinetics. This involves studies such as food interaction, renal and hepatic impairment, elderly or pediatric populations, bioequivalence of definitive proposed marketed dosage forms and drug-drug interaction. A bioequivalence study of definitive marketed dosage forms proposed for marketing should also be carried out during this clinical phase.

An approach of the different pharmacokinetic studies that should be performed during Phases I to III of clinical development has been summarized. Nevertheless, the design, the order and type of the different studies proposed can vary according to the drug and therapeutically characteristics the studies proposed should be adapted to each individual drug under development.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 25, Suppl. A, 2003
ISSN 0379-0355 Copyright 2003 Prous Science, S.A. CCC: 0379-0355/2003 http://www.prous.com