title: Integration of Physiologically-Based Pharmacokinetic Modeling into Early Clinical Development: An Investigation of the Pharmacokinetic Nonlinearity.
abstract: BMS-911543, a promising anticancer agent, exhibited time-dependent and dose-dependent nonlinear pharmacokinetics (PKs) in its first-in-human (FIH) study. Initial physiologically based pharmacokinetic (PBPK) modeling efforts using CYP1A2-mediated clearance kinetics were unsuccessful; however, further model analysis revealed that CYP1A2 time-dependent inhibition (TDI) and perhaps other factors could be keys to the nonlinearity. Subsequent experiments in human liver microsomes showed that the compound was a time-dependent inhibitor of CYP1A2 and were used to determine the enzyme inactivation parameter values. In addition, a rat tissue distribution study was conducted and human plasma samples were profiled to support the refinement of the PBPK model. It was concluded that the interplay between four BMS-911543 properties, namely, low solubility, saturation of the metabolizing enzyme CYP1A2, CYP1A2 TDI, and CYP1A2 induction likely resulted in the time-dependent and dose-dependent nonlinear PKs. The methodology of PBPK model-guided unmasking of compound properties can serve as a general practice for mechanistic understanding of a new compound's disposition.
authors.affiliation: Department of Biotransformation, Bristol-Myers Squibb Princeton, New Jersey, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Biotransformation, Bristol-Myers Squibb Princeton, New Jersey, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gan
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb Princeton, New Jersey, USA ; Clinical Pharmacology & PPDM, Japan Development, MSD K.K. Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yoshitsugu
authors.affiliation: Department of Biotransformation, Bristol-Myers Squibb Princeton, New Jersey, USA.
authors.forename: X
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Biotransformation, Bristol-Myers Squibb Princeton, New Jersey, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Lutz
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb Princeton, New Jersey, USA ; Quantitative Clinical Pharmacology, AstraZeneca Waltham, Massachusetts, USA.
authors.forename: E
authors.initials: E
authors.lastname: Masson
authors.affiliation: Department of Biotransformation, Bristol-Myers Squibb Princeton, New Jersey, USA.
authors.forename: W G
authors.initials: WG
authors.lastname: Humphreys