Proposing advancement criteria for efficient DMPK triage of new chemical entities.
With the goal of refining our discovery DMPK workflow, we conducted a retrospective analysis on internal Celgene compounds by calculating the physicochemical properties and gathering data from several assays including solubility, rat and human liver S9 stability, Caco-2 permeability, and rat intravenous (iv.) and oral pharmacokinetics. Our analysis identified plasma clearance to be most statistically relevant for prediction of oral exposure. In rat, compounds with rat S9 stability of ≥70% at 60 min and a plasma clearance of ≤43 ml/min/kg had the greatest chance of achieving oral exposures above 3 µM.h. Compounds with the dual advantage of plasma clearance ≤43 ml/min/kg and Caco-2 permeability ≥8 × 10(-6) cm/s or efflux ratio ≤8 were highly likely to achieve those oral exposures. Implementation of these criteria leads to a significant increase in efficiency, good pharmacokinetic properties, cost savings and a reduction in the use of animals.
Celgene Corporation, 10300 Campus Point Dr, Suite 100, San Diego, CA 92121, USA.
Ashutosh
A
Kulkarni
Jennifer
J
Riggs
Cindy
C
Phan
April
A
Bai
Andrew
A
Calabrese
Tao
T
Shi
Mehran F
MF
Moghaddam
D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D018938:Caco-2 Cells; D002460:Cell Line; D002463:Cell Membrane Permeability; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D012372:ROC Curve; D051381:Rats; D012995:Solubility
D004364:Pharmaceutical Preparations