Methods in Clinical Pharmacology

Abstract

Early clinical development is often referred to as the “Valley of Death” in clinical trials because of the challenges involved in the translation from preclinical research to First in Human (FIH). The high attrition rate of drugs is widely attributable to the lack of data from the very basic and mechanistic assumptions made during the earliest phases of computational PK and screening, the limited preclinical studies executed in two species, and then the animal model factors used for allometric scaling. Phase 1 is the first time that a novel compound is dosed to healthy normal volunteers, or in some specific cases, to patients with a targeted disease. The objective during this phase is to evaluate the risk to benefit to humans and to gain understanding of the administered doses and systemic drug concentrations, correlated to any observed adverse events via the route of administration intended for the product (IV, oral, subcutaneous, etc.). Increasingly, this phase is also concerned with pharmacodynamics, or physiological effects exerted by the novel drug over time. This chapter is divided in two parts. The first part will elucidate the considerations which go into the design of early clinical research studies including drug disposition, pharmacokinetics, and pharmacodynamics and then clinical pharmacology clinical trial design, elements, and endpoints are examined in the second part.