The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the pharmaceutical research and manufacturers of America.
Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes caused by new molecular entities (NMEs) is of concern because such compounds can be responsible for clinically relevant drug-drug interactions (DDI). Although the biochemistry underlying mechanism-based inactivation (MBI) of P450 enzymes has been generally understood for several years, significant advances have been made only in the past few years regarding how in vitro time-dependent inhibition data can be used to understand and predict clinical DDI. In this article, a team of scientists from 16 pharmaceutical research organizations that are member companies of the Pharmaceutical Research and Manufacturers of America offer a discussion of the phenomenon of TDI with emphasis on the laboratory methods used in its measurement. Results of an anonymous survey regarding pharmaceutical industry practices and strategies around TDI are reported. Specific topics that still possess a high degree of uncertainty are raised, such as parameter estimates needed to make predictions of DDI magnitude from in vitro inactivation parameters. A description of follow-up mechanistic experiments that can be done to characterize TDI are described. A consensus recommendation regarding common practices to address TDI is included, the salient points of which include the use of a tiered approach wherein abbreviated assays are first used to determine whether NMEs demonstrate TDI or not, followed by more thorough inactivation studies for those that do to define the parameters needed for prediction of DDI.
Grimm
Scott W
SW
AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA.
Einolf
Heidi J
HJ
Hall
Steven D
SD
He
Kan
K
Lim
Heng-Keang
HK
Ling
Kah-Hiing John
KH
Lu
Chuang
C
Nomeir
Amin A
AA
Seibert
Eleanore
E
Skordos
Konstantine W
KW
Tonn
George R
GR
Van Horn
Robert
R
Wang
Regina W
RW
Wong
Y Nancy
YN
Yang
Tian J
TJ
Obach
R Scott
RS
D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015195:Drug Design; D004345:Drug Industry; D004347:Drug Interactions; D014453:Glucuronosyltransferase; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013997:Time Factors
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D014453:Glucuronosyltransferase