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Drug Metabolism and Disposition Fast Forward
First published on July 30, 2004; DOI: 10.1124/dmd.104.000422

0090-9556/04/3211-1254-1259$20.00
DMD 32:1254-1259, 2004

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

Punam Sandhu, John S. Vogel, Mark J. Rose1, Esther A. Ubick, Janice E. Brunner, Michael A. Wallace, Jennifer K. Adelsberger, Maribeth P. Baker, Paul T. Henderson, Paul G. Pearson1, and Thomas A. Baillie

Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania (P.S., M.J.R., J.E.B., J.K.A., M.P.B., P.G.P., T.A.B.) and Rahway, New Jersey (M.A.W.); and Center for Accelerator Mass Spectrometry and Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California (J.S.V., E.A.U., P.T.H.)

The technique of accelerator mass spectrometry (AMS) was validated successfully and used to study the pharmacokinetics and disposition in dogs of a preclinical drug candidate (7-deaza-2'-C-methyl-adenosine; Compound A), after oral and intravenous administration. The primary objective of this study was to examine whether Compound A displayed linear kinetics across subpharmacological (microdose) and pharmacological dose ranges in an animal model, before initiation of a human microdose study. The AMS-derived disposition properties of Compound A were comparable to data obtained via conventional techniques such as liquid chromatography-tandem mass spectrometry 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 h), and high oral bioavailability (103%). Currently, there are no published comparisons of the kinetics of a pharmaceutical compound at pharmacological versus subpharmacological doses using 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 following dosing at 0.02 mg/kg were similar to those 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 after a microdose, which revealed aspects of the disposition of this agent that were inaccessible by conventional techniques.

Address correspondence to: Dr. Punam Sandhu, Department of Drug Metabolism, WP75A-203, Merck Research Laboratories, West Point PA 19486. E-mail: punam_sandhu{at}merck.com




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