Research Articles
N-in-1 Dosing Pharmacokinetics in Drug Discovery: Experience, Theoretical and Practical Considerations

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Abstract

N-in-1 (or cassette) dosing pharmacokinetics (PK) has been used in drug discovery for rapid assessment of PK properties of new chemical entities. However, because of potential for drug–drug interactions this procedure is still controversial. This study was to retrospectively evaluate the N-in-1 dosing approach in drug discovery with an emphasis on the potential for drug–drug interactions. The systemic clearance, volume of distribution, oral bioavailability, and renal excretion of the 31 lead compounds in rats, dogs or chimpanzees were significantly correlated between the N-in-1 dosing and discrete studies with r values of 0.69, 0.91, 0.53, and 0.83 (p < 0.005 for all), respectively. PK parameters for 11 quality control compounds which were involved in 194 N-in-1 studies for screening approximately 1000 compounds had coefficient of variations of less than 70%. The intrinsic microsomal clearances generated from the N-in-1 and discrete incubations were nearly identical (r = 0.97, p < 0.0001). The intrinsic clearances of quality control compound from the N-in-1 incubations were consistent with its discrete CLint estimate (cv: 5.4%). Therefore, N-in-1 dosing is a useful approach in drug discovery to quickly obtain initial PK estimates. Potential drug–drug interactions that result in confounding PK estimates do not occur as frequently as expected. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:2568–2580, 2008

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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