Pharmacokinetics and Dose Recommendations for Cyclosporine and Tacrolimus When Coadministered With ABT-450, Ombitasvir, and Dasabuvir

ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 (150mg coadministered with ritonavir 100mg once daily), ombitasvir (25mg once daily), and dasabuvir (400mg twice daily) on the pharmacokinetics, safety, and tolerability of a single dose of cyclosporine (30mg) or tacrolimus (2mg) in healthy volunteers (N = 12 per study). In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C-24), and area under the concentration-time curve from time 0 to infinity (AUC(infinity)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C-24 and AUC(infinity) were 17-fold and 57-fold, respectively, of either agent alone. Cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen.