title: Predicting drug-drug interactions involving multiple mechanisms using physiologically based pharmacokinetic modeling: a case study with ruxolitinib.
abstract: Physiologically based pharmacokinetic modeling was applied to characterize the potential drug-drug interactions for ruxolitinib. A ruxolitinib physiologically based pharmacokinetic model was constructed using all baseline PK data in healthy subjects, and verified by retrospective predictions of observed drug-drug interactions with rifampin (a potent CYP3A4 inducer), ketoconazole (a potent CYP3A4 reversible inhibitor) and erythromycin (a moderate time-dependent inhibitor of CYP3A4). The model prospectively predicts that 100-200 mg daily dose of fluconazole, a dual inhibitor of CYP3A4 and 2C9, would increase ruxolitinib plasma concentration area under the curve by ∼two-fold, and that as a perpetrator, ruxolitinib is highly unlikely to have any discernible effect on digoxin, a sensitive P-glycoprotein substrate. The analysis described here illustrates the capability of physiologically based pharmacokinetic modeling to predict drug-drug interactions involving several commonly encountered interaction mechanisms and makes the case for routine use of model-based prediction for clinical drug-drug interactions. A model verification checklist was explored to harmonize the methodology and use of physiologically based pharmacokinetic modeling.
authors: Incyte Corporation, Wilmington, Delaware, USA.
authors: J G
authors: JG
authors: Shi
authors: G
authors: G
authors: Fraczkiewicz
authors: W V
authors: WV
authors: Williams
authors: S
authors: S
authors: Yeleswaram
mesh_terms: D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004077:Digoxin / Q000493:pharmacokinetics; D004347:Drug Interactions; D004917:Erythromycin / Q000494:pharmacology; D005215:Fasting; D015725:Fluconazole / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008954:Models, Biological; D009570:Nitriles; D011446:Prospective Studies; D011720:Pyrazoles / Q000493:pharmacokinetics*; D011743:Pyrimidines; D012189:Retrospective Studies; D012293:Rifampin / Q000494:pharmacology
chemical_list: D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D004917:Erythromycin; D004077:Digoxin; C540383:ruxolitinib; D015725:Fluconazole; D007654:Ketoconazole; D012293:Rifampin