Pharmacokinetic Aspects of Multiple Dose Studies

Abstract

The development of a new chemical entity (NCE) in man is highly regulated and normally starts with a single ascending dose study (SAD) followed by a multiple ascending dose study (MAD), both in young healthy volunteers using the route and dose regime proposed in the final product. The aim of a MAD study is to establish the safety, maximum tolerated dose, and pharmacokinetics of the NCE on repeated dosing, usually to steady state. This chapter describes the pharmacokinetic aspects of MAD studies and some of the design modifications that can be included in the study design. The MAD may be one of the few opportunities for assessing the pharmacokinetics of the compound in detail following multiple dosing, albeit not usually in patients. Previous data from the SAD should be used to optimize the design of the MAD including blood sampling regime, lower limit of sensitivity for the bioanalytical assay, and pharmacokinetic analysis. In addition to the pharmacokinetics and safety, the design should consider the need to characterize drug-related material in urine, carry out a preliminary assessment of the metabolic route, and characterize the potential for CYP3A4 induction. Suggestions are also provided for an approach when the impact of prandial status is unknown and more frequent dosing other than once daily is required.