Research ArticlesN-in-1 Dosing Pharmacokinetics in Drug Discovery: Experience, Theoretical and Practical Considerations
Section snippets
INTRODUCTION
The failure rate of drug development due to inappropriate pharmacokinetics (PK) has decreased over the last decade, which is mainly attributed to PK optimization in early drug discovery.1,2 Many in vitro, in vivo and in silico technologies have been developed and applied to drug discovery to evaluate the absorption, distribution, metabolism, excretion, and PK properties of new chemical entities.3,4 Because the conventional in vivo single compound discrete PK profiling is time and
Compounds and Chemical Reagents
Discovery compounds covering various therapeutic areas were synthesized at the Department of Medicinal Chemistry at Bristol-Myers Squibb Co. and DuPont Pharmaceuticals Company. 7-Benzyloxy-4-(trifluoromethyl)-coumarin, 7-hydroxy-4-(trifluoromethyl)-coumarin, supersomes™ comprised of baculovirus insect cell-expressed human cytochrome P450 (CYP) 3A4, coexpressed CYP-NADPH reductase, and cytochrome b5 were purchased from GENTEST Cooperation (Woburn, MA); NADPH was purchased from Sigma Co. (St.
Variations of Pharmacokinetic Parameters of the Quality Control Compounds
Eleven compounds from various programs that were studied in discrete IV and PO PK studies were selected as quality controls (references or bench markers) for the N-in-1 dosing PK studies in rats, dogs, and chimpanzees (Tab. 1). As shown in Table 1, the quality controls have diverse PK characteristics. The CL estimates range from 0.6 to 2.3 L/h/kg, Vdss from 0.3 to 17.2 L/kg, and F from 10% to 86% in rats, dogs, and chimpanzees. The CV values of the three important PK parameters of the quality
DISCUSSION
The utility of N-in-1 or cassette dosing PK studies in drug discovery is controversial and has been debated from both theoretical and practical points of views.12,13 Aside from the obvious bioanalytical challenges, the most widely debated issue concerning N-in-1 dosing centers around potential drug–drug interactions. The most commonly discussed drug–drug interactions that can confound PK estimates from N-in-1 studies are interactions due to inhibition of drug metabolizing enzymes and/or
CONCLUSIONS
Our results from 194 N-in-1 studies indicate that N-in-1 dosing PK study can generate reliable PK data for lead optimization in a more efficient manner than discrete study. Potential drug–drug interactions that result in confounding PK estimates do not occur as frequently as expected. Optimization of N-in-1 study design should further minimize the potentials for drug–drug interactions. In general, N-in-1 dosing PK is a useful approach in drug discovery to quickly obtain PK estimates for many
Acknowledgements
We thank Foster Brown, Grant Demond, and Andrew Leamy for handling the animal studies, Denette Murphy, Minli Xie, and Rodney Vickery for their formulation support.
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