الفهرس 
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Abstract
Purpose: Comorbid conditions of heart and liver disorders added to HCV-induced hepatic steatosis makes co administration of statins and direct acting antivirals is common in clinical practice. This study aimed to evaluate the pharmacokinetic interaction of atorvastatin or lovastatin and fixed dose combination of sofosbuvir/ledipasvir “FDCSL” with rationalization to the underlying mechanism.
Method: A randomized, three- phases crossover study involves 12 healthy volunteers was performed. Participants received a single dose of atorvastatin 80 mg or lovastatin 40mg alone, atorvastatin 80 mg or lovastatin 40mg 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 sofosbuvir, ledipasvir and sofosbuvir metabolite “GS-331007” and their pharmacokinetics parameters were determined.
Results: atorvastatin caused a significant increase in the systemic exposure of SOF as indicated by an increase in AUC0−∞ and Cmax by 32% and 12%, respectively. In addition, AUC0-∞ and Cmax of GS 331007 were increased by 74% and 85%, respectively after atorvastatin intake. However, atorvastatin caused non-significant change in the hepatic elimination of sofosbuvir, and sofosbuvir metabolite as indicated by the non-significant in K and half life.
Regarding LDV, there was no significant change in LDV bioavailability after atorvastatin intake.
On the other hand, the co-administration of Lovastatin with FDCSL increased the bioavailability of sofosbuvir, its metabolite and ledipasvir (AUC0-∞ increase by 15%, 27.65%, and 50%, respectively and Cmax increase by 12.08%, 22% and35.6%, respectively). However, lovastatin caused non-significant change in the hepatic elimination of sofosbuvir, sofosbuvir metabolite and ledipasvir as indicated by the non-significant in K and half life.
Conclusion: After concurrent administration of FDCSL with atorvastatin or lovastatin, the AUC0−∞ of sofosbuvir were increased. Caution should be taken with close monitoring for possible side effects after co-administration of both statins and FDCSL in clinical practice.
Keywords: Atorvastatin, Lovastatin, Ledipasvir, Sofosbuvir, GS-331007,
P-glycoprotein, Pharmacokinetic interaction