Accelerating drug development: Methodology to support first-in-man pharmacokinetic studies by the use of drug candidate microdosing

Microdosing—giving a very small, sub-pharmacological dose of a new chemical entity—allows early evaluation of human pharmacokinetics under an exploratory Investigational New Drug application. This can help select a lead compound, determine the amount of material needed for early development, and set the initial Phase I dose. The pharmaceutical industry has been slow to adopt microdosing because of concerns about analytical sensitivity and possible non-linear pharmacokinetics at low doses. Accelerator mass spectrometry, the usual detection method, is expensive and requires radiolabeling. This report presents an example using LC/MS/MS after microdosing an experimental agent in cynomolgus monkeys.

Study at a glance

Abstract

Abstract Microdosing of experimental therapeutics in humans offers a number of benefits to the drug development process. Microdosing, conducted under an exploratory Investigational New Drug (IND) application, entails administration of a sub‐pharmacological dose of a new chemical entity (NCE) that allows for early evaluation of human pharmacokinetics. Such information can be pivotal for: (1) selecting a compound for full drug development from a small group of candidates; (2) defining the amount of material needed for early development; and (3) setting the initial Phase I dose regimen in humans. Appropriate safety studies must be conducted to support microdosing in humans, but the requirements are generally less extensive than those needed to support a traditional IND. To date, microdosing has not been broadly applied by the pharmaceutical industry due to concerns about analytical sensitivity and the possibility of non‐linear pharmacokinetics at extremely low doses. The primary method for detecting analytes following microdosing until now has been accelerator mass spectrometry, which is expensive, not generally available, and requires test agents to be radiolabeled. Presented in this report is an example of pharmacokinetics analysis using LC/MS/MS following microdosing of an experimental agent in cynomolgus monkeys. The results show good linearity in plasma pharmacokinetics for oral doses of 10 mg/kg (therapeutic dose) and 0.0005 mg/kg (microdose) of the test agent. The results also demonstrate the feasibility of applying standard laboratory analytics to support microdosing in humans and raise the possibility of establishing an animal model to screen for compounds having non‐linear pharmacokinetics at low dose levels. Drug Dev. Res. 68:14–22, 2007. © 2007 Wiley‐Liss, Inc.