Received for publication May 6, 2004.
Revised July 28, 2004.
Accepted for publication July 30, 2004.

EVALUATION OF MICRODOSING STRATEGIES FOR STUDIES IN PRECLINICAL DRUG DEVELOPMENT: DEMONSTRATION OF LINEAR PHARMACOKINETICS IN DOGS OF A NUCLEOSIDE ANALOGUE OVER A 50-FOLD DOSE RANGE

Abstract

The technique of accelerator mass spectrometry (AMS) was validated successfully and utilized to study the pharmacokinetics and disposition in dogs of a preclinical drug candidate (Compound A), after oral and intravenous administration. The primary objective of this study was to examine whether Compound A displayed linear kinetics across sub-pharmacological (microdose) and pharmacological dose ranges in an animal model, prior to initiation of a human microdose study. The AMS-derived disposition properties of Compound A were comparable to data obtained via conventional techniques such as LC-MS/MS and liquid scintillation counting analyses. Compound A displayed multiphasic kinetics and exhibited low plasma clearance (5.8 mL/min/kg), a long terminal elimination half-life (17.5 hr) and high oral bioavailability (103%). Currently there are no published comparisons of the kinetics of a pharmaceutical compound at pharmacological versus sub-pharmacological doses employing microdosing strategies. The present study thus provides the first description of the full pharmacokinetic profile of a drug candidate assessed under these two dosing regimens. The data demonstrated that the pharmacokinetic properties of Compound A were similar following dosing at 0.02 mg/kg as at 1 mg/kg, indicating that in the case of Compound A, the pharmacokinetics in the dog appear to be linear across this 50-fold dose range. Moreover, the exceptional sensitivity of AMS provided a pharmacokinetic profile of Compound A, even following a microdose, which revealed aspects of the disposition of this agent that were inaccessible by conventional techniques.

Key words: bioavailability, drug development, drug disposition, pharmacokinetics

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