Pharmacokinetic model for the inhibition of simvastatin metabolism by itraconazole

Background: Concomitant use of simvastatin, a HMG-CoA reductase inhibitor, with a potent CYP3A4 inhibitor, itraconazole, can result in a serious drug-drug interaction induced severe adverse event, rhabdomyolysis. Even though pharmacokinetic data regarding such interaction are available, they cannot be used for quantitative prediction. For this reason, we aimed to develop a pharmacokinetic model for predicting the magnitude of inhibition of simvastatin metabolism by itraconazole. Methods: Published data involving pharmacokinetic of simvastatin, itraconazole, and pharmacokinetic interaction between simvastatin and itraconazole were selected from PubMed search. Serum simvastatin concentrations were subsequently extracted and used for model development. Advanced Continuous Simulating Language Extreme (ACSLX) was used for modeling. Results: The drug-drug interaction model between simvastatin and itraconazole was simultaneously modeled using a one compartment parent-metabolite model for simvastatin, and a two-compartment model for itraconazole. Conclusion: The final drug-drug interaction model can adequately describe the actual simvastatin concentrations. Model application can be of advantage for dosing adjustment to avoid serious adverse effects resulted from concomitant use of both drugs.