The quantitative prediction of CYP-mediated drug interaction by physiologically based pharmacokinetic modeling.
OBJECTIVE
The objective is to confirm if the prediction of the drug-drug interaction using a physiologically based pharmacokinetic (PBPK) model is more accurate. In vivo Ki values were estimated using PBPK model to confirm whether in vitro Ki values are suitable.


METHODS
The plasma concentration-time profiles for the substrate with coadministration of an inhibitor were collected from the literature and were fitted to the PBPK model to estimate the in vivo Ki values. The AUC ratios predicted by the PBPK model using in vivo Ki values were compared with those by the conventional method assuming constant inhibitor concentration.


RESULTS
The in vivo Ki values of 11 inhibitors were estimated. When the in vivo Ki values became relatively lower, the in vitro Ki values were overestimated. This discrepancy between in vitro and in vivo Ki values became larger with an increase in lipophilicity. The prediction from the PBPK model involving the time profile of the inhibitor concentration was more accurate than the prediction by the conventional methods.


CONCLUSIONS
A discrepancy between the in vivo and in vitro Ki values was observed. The prediction using in vivo Ki values and the PBPK model was more accurate than the conventional methods.
Kato
Motohiro
M
Pre-clinical Research Department, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. katomth@chugai-pharm.co.jp
Shitara
Yoshihisa
Y
Sato
Hitoshi
H
Yoshisue
Kunihiro
K
Hirano
Masaru
M
Ikeda
Toshihiko
T
Sugiyama
Yuichi
Y
D000465:Algorithms; D019540:Area Under Curve; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D005544:Forecasting; D007668:Kidney / Q000378:metabolism; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System