RT Journal Article
SR Electronic
T1 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
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1254
OP 1259
DO 10.1124/dmd.104.000422
VO 32
IS 11
A1 Punam Sandhu
A1 John S. Vogel
A1 Mark J. Rose
A1 Esther A. Ubick
A1 Janice E. Brunner
A1 Michael A. Wallace
A1 Jennifer K. Adelsberger
A1 Maribeth P. Baker
A1 Paul T. Henderson
A1 Paul G. Pearson
A1 Thomas A. Baillie
YR 2004
UL http://dmd.aspetjournals.org/content/32/11/1254.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics