Pharmacokinetic interaction between atorvastatin and fixed-dose combination of sofosbuvir/ledipasvir in healthy male Egyptian volunteers

Purpose Comorbid conditions of heart and liver disorders added to HCV-induced hepatic steatosis make co-administration of statins, and direct-acting antivirals is common in clinical practice. This study aimed to evaluate the pharmacokinetic interaction of atorvastatin and fixed-dose combination of sofosbuvir/ledipasvir FDCSL with rationalization to the underlying mechanism. Methods A randomized, three-phase crossover study that involves 12 healthy volunteers was performed. Participants received a single-dose of atorvastatin 80 mg alone, atorvastatin 80-mg plus tablets containing 400/90 mg FDCSL, or tablets containing 400/90 mg FDCSL alone. Plasma samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for atorvastatin, sofosbuvir, ledipasvir, and sofosbuvir metabolite GS-331007, and their pharmacokinetics parameters were determined. Results Compared to atorvastatin alone, the administration of FDCSL caused a significant increase in both areas under the concentration-time curve from time zero to infinity (AUC(0-infinity)) and maximum plasma concentration (C-max) of atorvastatin by 65.5% and 156.0%, respectively. Also, atorvastatin caused a significant increase in the AUC(0-infinity) and C-max of sofosbuvir by 32.0% and 11.0%, respectively. Similarly, AUC(0-infinity) and C-max of sofosbuvir metabolite significantly increased by 84.0% and 74.0%, respectively. However, ledipasvir AUC(0-infinity) showed no significant change after atorvastatin intake. The elimination rate in all drugs revealed no significant changes. Conclusion After concurrent administration of FDCSL with atorvastatin, the AUC(0-infinity) of both atorvastatin and sofosbuvir were increased. Caution should be taken with close monitoring for possible side effects after co-administration of atorvastatin and FDCSL in clinical practice.

Automated summary

In healthy volunteers, concurrent administration of atorvastatin with fixed-dose combination of sofosbuvir/ledipasvir led to increased AUC(0-infinity) of both atorvastatin and sofosbuvir. Close monitoring for possible side effects should be employed in clinical practice after co-administration of atorvastatin and FDCSL.