title: 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 CL(int) 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.
authors.affiliation: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, PO Box 4000, Princeton, New Jersey 08543-4000, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: He
authors.forename: Mingxin
authors.initials: M
authors.lastname: Qian
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Bai
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.forename: Bernice
authors.initials: B
authors.lastname: Brogdon
authors.forename: James E
authors.initials: JE
authors.lastname: Grace
authors.forename: Baomin
authors.initials: B
authors.lastname: Xin
authors.forename: Jingtao
authors.initials: J
authors.lastname: Wu
authors.forename: Shelly X
authors.initials: SX
authors.lastname: Ren
authors.forename: Hang
authors.initials: H
authors.lastname: Zeng
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Deng
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Graden
authors.forename: Timothy V
authors.initials: TV
authors.lastname: Olah
authors.forename: Steve E
authors.initials: SE
authors.lastname: Unger
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Pinto
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
authors.forename: James
authors.initials: J
authors.lastname: Duan
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
authors.forename: David D
authors.initials: DD
authors.lastname: Christ
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Grossman
mesh_terms: D000818:Animals; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D002679:Pan troglodytes; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D010599:Pharmacokinetics; D051381:Rats
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human