Prediction of Drug-Drug Interactions Arising from CYP3A induction Using a Physiologically Based Dynamic Model
Autor: | Lisa Almond, M Jamei, K Rowland-Yeo, Suzanne Tay, Oliver Hatley, Sophie Mukadam, Krystle Okialda, Jane R. Kenny, Susan Wong, Iain Gardner, Amin Rostami-Hodjegan |
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Rok vydání: | 2016 |
Předmět: |
Phenytoin
CYP3A Administration Oral Pharmaceutical Science Pharmacology Models Biological 030226 pharmacology & pharmacy 03 medical and health sciences 0302 clinical medicine In vivo medicine Cytochrome P-450 CYP3A Humans Drug Interactions RNA Messenger CYP3A4 Chemistry Carbamazepine In vitro Gastrointestinal Tract Liver Enzyme Induction Phenobarbital 030220 oncology & carcinogenesis Hepatocytes Rifampin Erratum Rifampicin medicine.drug |
Zdroj: | Drug Metabolism and Disposition. 44:821-832 |
ISSN: | 1521-009X |
Popis: | Using physiologically based pharmacokinetic modeling, we predicted the magnitude of drug-drug interactions (DDIs) for studies with rifampicin and seven CYP3A4 probe substrates administered i.v. (10 studies) or orally (19 studies). The results showed a tendency to underpredict the DDI magnitude when the victim drug was administered orally. Possible sources of inaccuracy were investigated systematically to determine the most appropriate model refinement. When the maximal fold induction (Indmax) for rifampicin was increased (from 8 to 16) in both the liver and the gut, or when the Indmax was increased in the gut but not in liver, there was a decrease in bias and increased precision compared with the base model (Indmax = 8) [geometric mean fold error (GMFE) 2.12 vs. 1.48 and 1.77, respectively]. Induction parameters (mRNA and activity), determined for rifampicin, carbamazepine, phenytoin, and phenobarbital in hepatocytes from four donors, were then used to evaluate use of the refined rifampicin model for calibration. Calibration of mRNA and activity data for other inducers using the refined rifampicin model led to more accurate DDI predictions compared with the initial model (activity GMFE 1.49 vs. 1.68; mRNA GMFE 1.35 vs. 1.46), suggesting that robust in vivo reference values can be used to overcome interdonor and laboratory-to-laboratory variability. Use of uncalibrated data also performed well (GMFE 1.39 and 1.44 for activity and mRNA). As a result of experimental variability (i.e., in donors and protocols), it is prudent to fully characterize in vitro induction with prototypical inducers to give an understanding of how that particular system extrapolates to the in vivo situation when using an uncalibrated approach. |
Databáze: | OpenAIRE |
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