A pharmacokinetic drug-drug interaction model of simvastatin and clarithromycin in humans

Abstract

Simvastatin is a HMG-CoA reductase Inhibitor and a substrate of CYP3A4. Clarithromycin is a commonly used macrolide antibiotics and a potent inhibitor of CYP3A4. When co-administered with simvastatin, clarithromycin can significantly increase simvastatin plasma concentration levels, thereby, increase the risk of rhabdomyolysis. At present, pharmacokinetic data of the interaction between both drugs are available. However, they are being used for semi-quantitative application only, not for quantitative prediction. We aimed to develop a mathematical model describing a drug-drug interaction between simvastatin and clarithromycin in humans. Selected pharmacokinetic interaction study was obtained from PubMed search. Concentration-time course data were subsequently extracted and used for model development. Compartmental pharmacokinetic interaction model was developed using Advanced Continuous Simulating Language Extreme (ACSLX), a FORTRAN language-based computer program. The drug-drug interaction between simvastatin and clarithromycin was modeled simultaneously with a parent-metabolite model for clarithromycin and a one-compartment model for simvastatin linked to its active form, simvastatin hydroxy acid. The simulated simvastatin concentrations obtained from the final model displayed satisfactory goodness of fit to the data from the literature. Our model could successfully describe concentration-time course of simvastatin-clarithromycin interaction. The resulting interaction model can be able to use for further development of a quantitative model predicting rhabdomyolysis occurrence in patients concurrently receiving simvastatin and clarithromycin.