N-in-1 dosing pharmacokinetics in drug discovery: experience, theoretical and practical considerations.
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.
He
Kan
K
Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, PO Box 4000, Princeton, New Jersey 08543-4000, USA.
Qian
Mingxin
M
Wong
Harvey
H
Bai
Stephen A
SA
He
Bing
B
Brogdon
Bernice
B
Grace
James E
JE
Xin
Baomin
B
Wu
Jingtao
J
Ren
Shelly X
SX
Zeng
Hang
H
Deng
Yuzhong
Y
Graden
Danielle M
DM
Olah
Timothy V
TV
Unger
Steve E
SE
Luettgen
Joseph M
JM
Knabb
Robert M
RM
Pinto
Donald J
DJ
Lam
Patrick Y S
PY
Duan
James
J
Wexler
Ruth R
RR
Decicco
Carl P
CP
Christ
David D
DD
Grossman
Scott J
SJ
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
D065692:Cytochrome P-450 CYP3A Inhibitors; D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human