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

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