Prediction of drug-drug interactions based on time-dependent inhibition from high throughput screening of cytochrome P450 3A4 inhibition.
A method of assessing the risk of drug-drug interaction (DDI) caused by mechanism-based inhibition (MBI) was developed for early-stage drug development using cytochrome P450 (CYP) 3A4 inhibition screening data. CYP3A4 inhibition was evaluated using a fluorescent substrate with or without preincubation containing an inhibitor. The results showed that five well-known mechanism-based inhibitors, but not the competitive inhibitor ketoconazole, had lower IC(50) after preincubation, suggesting the utility of the IC(50) shift by preincubation to discern mechanism-based inhibitors. A method to approximately predict the change in the area under the concentration-time curve (AUC) of a co-administered drug by MBI was found using IC(50) shift data and the unbound mean plasma concentration of the inhibitor. From our predictions of change in the AUC for 38 drugs using this method, all mechanism-based inhibitors causing change in the AUC of more than 200% were predicted to be high risk. In conclusion, our method provides a simple assessment of the risk of DDI from mechanism-based inhibitors, especially in the early stages of drug development.
Sekiguchi
Nobuo
N
Pre-Clinical Research Department, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan. sekiguchinbo@chugai-pharm.co.jp
Higashida
Atsuko
A
Kato
Motohiro
M
Nabuchi
Yoshiaki
Y
Mitsui
Tetsuya
T
Takanashi
Kenji
K
Aso
Yoshinori
Y
Ishigai
Masaki
M
D000465:Algorithms; D019540:Area Under Curve; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007654:Ketoconazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects*; D008954:Models, Biological; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000737:chemistry; D013379:Substrate Specificity
D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole