Quantitative prediction of CYP3A induction-mediated drug-drug interactions in clinical practice.
Drug Metab Pharmacokinet
; 57: 101010, 2024 Aug.
Article
in En
| MEDLINE
| ID: mdl-39043066
ABSTRACT
There have been no reports on the quantitative prediction of CYP3A induction-mediated decreases in AUC and Cmax for drug candidates identified as a "victims" of CYP3A induction. Our previous study separately evaluated the fold-induction of hepatic and intestinal CYP3A by known inducers using clinical induction data and revealed that we were able to quantitatively predict the AUC ratio (AUCR) of a few CYP3A substrates in the presence and absence of CYP3A inducers. In the present study, we investigate the predictability of AUCR and also Cmax ratio (CmaxR) in additional 54 clinical studies. The fraction metabolized by CYP3A (fm), the intestinal bioavailability (Fg), and the hepatic intrinsic clearance (CLint) of substrates were determined by the in vitro experiments as well as clinical data used for calculating AUCR and CmaxR. The result showed that 65-69% and 65-67% of predictions were within 2-fold of observed AUCR and CmaxR, respectively. A simulation using multiple parameter combinations suggested that the variability of fm and Fg within a certain range might have a minimal impact on the calculation output. These findings suggest that clinical AUCR and CmaxR of CYP3A substrates can be quantitatively predicted from the preclinical stage.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Drug Interactions
/
Cytochrome P-450 CYP3A
/
Cytochrome P-450 CYP3A Inducers
Limits:
Humans
Language:
En
Journal:
Drug Metab Pharmacokinet
Journal subject:
FARMACOLOGIA
/
METABOLISMO
Year:
2024
Document type:
Article
Country of publication:
Reino Unido