A Pharmacokinetic Drug-Drug Interaction Model of Simvastatin and Verapamil in Humans

Background: Verapamil is a calcium channel blocker commonly used in treatments of hypertension. Verapamil and its active metabolite, norverapamil, are known to be CYP3A4 inhibitors. Co-administration of verapamil with CYP3A4 substrates can alter the pharmacokinetics of the substrates. Simvastatin, a commonly used HMG-CoA reductase inhibitor for the treatment of hypercholesterolemia is extensively metabolized by CYP3A4. Therefore, concomitant use of simvastatin and verapamil can increase simvastatin plasma concentration levels, resulting in a higher risk of rhabdomyolysis, a serious adverse drug reaction. Even though, pharmacokinetic data regarding the interaction between both drugs have been published, their use is limited to semi-quantitative applications. Therefore, we aimed to develop a mathematical model describing drug-drug interaction between simvastatin and verapamil in humans. Methods: Eligible pharmacokinetic interaction study between simvastatin and verapamil in humans was selected from PubMed database. The concentration-time courses from this study were digitally extracted and used for model development. Results: The drug-drug interaction between simvastatin and verapamil was modeled simultaneously with a two compartment model for verapamil with its active metabolite, norverapamil and a one compartment model for simvastatin with its active form, simvastatin hydroxy acid. The effects of verapamil and norverapamil on pharmacokinetics of simvastatin and its active form, simvastatin hydroxy acid were described by Michaelis-Menten equation. Simulated simvastatin and simvastatin hydroxy acid concentrations obtained from the final model produced a good fit to the dataset from a literature. Conclusion: The final model adequately describes pharmacokinetic interaction between simvastatin and verapamil which can be helpful in prediction of rhabdomyolysis in patients with concurrent use of these drugs.