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

• Published in: Journal of pharmaceutical sciences Vol. 97; no. 7; pp. 2568 - 2580
• Main Authors: He, Kan, Qian, Mingxin, Wong, Harvey, Bai, Stephen A., He, Bing, Brogdon, Bernice, Grace, James E., Xin, Baomin, Wu, Jingtao, Ren, Shelly X., Zeng, Hang, Deng, Yuzhong, Graden, Danielle M., Olah, Timothy V., Unger, Steve E., Luettgen, Joseph M., Knabb, Robert M., Pinto, Donald J., Lam, Patrick Y.S., Duan, James, Wexler, Ruth R., Decicco, Carl P., Christ, David D., Grossman, Scott J.
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.07.2008; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Animals; Biological and medical sciences; Biological Availability; cassette doing; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dogs; Drug Design; drug discovery; Drug Evaluation, Preclinical - methods; Drug Interactions; drug-drug interactions; General pharmacology; Humans; In Vitro Techniques; Male; Medical sciences; Metabolic Clearance Rate; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Models, Biological; N-in-1 dosing; Pan troglodytes; Pharmaceutical Preparations - administration & dosage; Pharmaceutical technology. Pharmaceutical industry; Pharmacokinetics; Pharmacology. Drug treatments; Rats; cassette doing; pharmacokinetics; N-in-1 dosing; drug discovery; drug–drug interactions; Drug; drug-drug interactions; Pharmaceutical technology; Drug interaction; Pharmacokinetics; Research and development
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.21196

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