Coadministration of darunavir/ritonavir (800/100 mg once daily) and ledipasvir alone (90 mg once daily) increased darunavir Cmax by 2% but decreased AUC and Cmin by 4% and 3%. Ledipasvir Cmax, AUC and Cmin increased by 45%, 39% and 39%. Coadministration with sofosbuvir alone (400 mg once daily) decreased darunavir Cmax, AUC and Cmin by 3%, 3% and 14%. Sofosbuvir Cmax and AUC increased by 45% and 34%; GS-331007 Cmax decreased by 3% and AUC increased by 24%. No dose adjustment of ledipasvir/sofosbuvir or darunavir (ritonavir boosted) is required.

When given with darunavir/ritonavir used in conjunction with tenofovir disoproxil fumarate, ledipasvir/sofosbuvir increased the concentration of tenofovir. The safety of tenofovir disoproxil fumarate in the setting of ledipasvir/sofosbuvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established. The combination should be used with caution with frequent renal monitoring, if other alternatives are not available. Simultaneous coadministration of darunavir/ritonavir (800/100 mg once daily), emtricitabine/tenofovir (200/300 mg once daily) and ledipasvir/sofosbuvir (90/40 mg once daily) was studied. Darunavir Cmax, AUC and Cmin increased by 1%, 4% and 8%; ritonavir Cmax, AUC and Cmin increased by 17%, 25% and 48%. Emtricitabine Cmax, AUC and Cmin increased by 2%, 4% and 3%; tenofovir Cmax, AUC and Cmin increased by 64%, 50% and 59%. Ledipasvir Cmax, AUC and Cmin increased by 11%, 12% and 17%; sofosbuvir Cmax and AUC decreased by 37% and 27%; Cmax, AUC and Cmin of GS-331007 increased by 10%, 20% and 26%. Staggered administration (12 hours apart) of darunavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate and ledipasvir/sofosbuvir provided similar results.

 

No clinically significant drug interactions were observed with darunavir/ritonavir and ledipasvir or sofosbuvir. Coadministration of darunavir/ritonavir (800/100 mg once daily) and ledipasvir alone (90 mg once daily) increased ledipasvir Cmax, AUC and Cmin by 45%, 39% and 39%, respectively (n=23). Coadministration of darunavir/ritonavir (800/100 mg once daily) and sofosbuvir alone (400 mg single dose) increased sofosbuvir Cmax and AUC by 45% and 34%, respectively; GS-331007 Cmax decreased by 3%, but AUC increased by 24%. No effect on the pharmacokinetic parameters of darunavir/ritonavir was observed. Coadministration of ledipasvir/sofosbuvir and regimens containing tenofovir and a HIV protease inhibitor/ritonavir may increase tenofovir concentrations. The safety of increased tenofovir concentrations in the setting of ledipasvir/sofosbuvir and a HIV protease inhibitor/ritonavir has not been established. Consider alternative HCV or antiretroviral therapy to avoid increases in tenofovir exposures. If coadministration is necessary, monitor for tenofovir-associated adverse reactions.