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.
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.
Department of Drug Metabolism, WP75A-203, Merck Research Laboratories, West Point, PA 19486, USA. punam_sandhu@merck.com.
Punam
P
Sandhu
John S
JS
Vogel
Mark J
MJ
Rose
Esther A
EA
Ubick
Janice E
JE
Brunner
Michael A
MA
Wallace
Jennifer K
JK
Adelsberger
Maribeth P
MP
Baker
Paul T
PT
Henderson
Paul G
PG
Pearson
Thomas A
TA
Baillie
D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D009705:Nucleosides / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000032:analysis / Q000378:metabolism*
D009705:Nucleosides; D004364:Pharmaceutical Preparations