Sofosbuvir/Velpatasvir/Voxilaprevir versus Tenofovir Alafenamide
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Study Design
The Phase 1 program evaluated DDIs between sofosbuvir/velpatasvir/voxilaprevir (S/V/V) and drug transporter and CYP probes, immunosuppressants, HIV antiretrovirals (ARV), and oral contraceptives (OC). S/V/V 400/100/ 100 mg ± VOX 100 mg was administered to healthy volunteers to achieve systemic VOX exposures observed across the HCV-infected patient population, as appropriate.
Study Results
S/V/V did not alter the PK of bictegravir, cobicistat, darunavir, elvitegravir, emtricitabine, rilpivirine, tenofovir alafenamide (TAF) or Tenofovir (from TAF or tenofovir disoproxil fumarate).
Unboosted ARV regimens generally did not alter SOF, GS-331007, VEL or VOX PK except VEL AUC was ↓53% when administered with efavirenz (EFV); co-use of EFV with S/V/V is not recommended.
Study Conclusions
The authors concluded that sofosbuvir/velpatasvir/voxilaprevir could be safely coadministered with Tenofovir alafenamide
References
Garrison KL, Kirby B, Stamm LM, Ma G, Vu A. Drug-drug interaction profile of sofosbuvir/velpatasvir/voxilaprevir fixed-dose combination. Ilc: International Liver Conference. Amsterdam, Netherlands. 2017; April 2017.
Tenofovir Alafenamide versus Sofosbuvir/Velpatasvir/Voxilaprevir Study Two
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Study Design
The DDI studies were multiple-dose, randomized, and cross-over in design. Subjects received HIV ARV regimens including bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) 50/200/25 mg, FTC/rilpivirine (RPV)/TAF 200/25/25 mg, elvitegravir (EVG)/cobicistat (COBI)/FTC/TAF 150/150/ 200/10 mg, or darunavir (DRV) 800 mg + ritonavir (RTV) 100 mg + FTC/tenofovir disoproxil fumarate (TDF) 200/300 mg and HCV DAAs SOF/VEL/VOX (400/100/100 mg) + VOX (100 mg), alone or in combination. The additional 100 mg of VOX was administered to the healthy subjects to approximate systemic VOX exposures observed in the HCV-infected population. Steady-state plasma concentrations of SOF, its predominant circulating nucleoside metabolite GS-331007, VEL, VOX, and ARVs were analyzed and PK parameters were calculated. Geometric least-squares means ratios and 90% confidence intervals (combination vs alone) for PK parameters (AUC, Cmax, and Ctau [as applicable]) were estimated and compared against lack of PK alteration boundaries of 70% to 143% for all analytes. Safety assessments were conducted throughout the study.
Study Results
116 of 120 enrolled subjects (n=30/cohort) completed the studies; overall, 4 subjects discontinued due to withdrawal of consent. The majority of adverse events (AEs) were Grade 1 or 2 and there were no discontinuations due to AEs and no serious AEs. Overall exposure (AUC) of BIC, FTC, RPV, DRV, and EVG was unaltered by coadministration with SOF/VEL/VOX. COBI and RTV AUC were 50% and 45% higher, respectively, when administered with SOF/VEL/VOX. TAF and TFV AUC were 52% to 58% higher and 67% to 79% higher, respectively, when the unboosted regimens were administered with SOF/ VEL/VOX. TAF and TFV AUC from EVG/COBI/ FTC/TAF were unaltered when coadministered with SOF/VEL/VOX. TFV AUC from DRV+RTV+ FTC/TDF was 39% higher when administered with SOF/VEL/VOX. Overall exposure (AUC) of SOF and VEL were unaltered following administration of SOF/ VEL/VOX with the ARV regimens. GS-331007 was 43% higher when EVG/COBI/FTC/TAF was administered with SOF/VEL/VOX. VOX AUC was unaffected by administration with unboosted regimens, but higher VOX AUC (143% to 171%) were observed with boosted ARV regimens.
Study Conclusions
Study treatments were well tolerated. There were no clinically relevant changes in the PK of ARVs, SOF, GS-331007, or VEL with coadministration. Unboosted regimens did not impact VOX PK; higher VOX exposures were observed with boosted ARV regimens.
References
Garrison K, Mogalian E, Zhang H, Ma G, West S, Martin H. Evaluation of drug-drug interactions between sofosbuvir/velpatasvir/voxilaprevir and boosted or unboosted hiv antiretroviral regimens. International Workshop On Clinical Pharmacology Of Antiviral Therapy. Chicago, IL, USA. 18; June 2017.
Tenofovir Alafenamide versus Sofosbuvir/Velpatasvir/Voxilaprevir Study Two
^
Study Design
The DDI studies were multiple-dose, randomized, and cross-over in design. Subjects received HIV ARV regimens including bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) 50/200/25 mg, FTC/rilpivirine (RPV)/TAF 200/25/25 mg, elvitegravir (EVG)/cobicistat (COBI)/FTC/TAF 150/150/ 200/10 mg, or darunavir (DRV) 800 mg + ritonavir (RTV) 100 mg + FTC/tenofovir disoproxil fumarate (TDF) 200/300 mg and HCV DAAs SOF/VEL/VOX (400/100/100 mg) + VOX (100 mg), alone or in combination. The additional 100 mg of VOX was administered to the healthy subjects to approximate systemic VOX exposures observed in the HCV-infected population. Steady-state plasma concentrations of SOF, its predominant circulating nucleoside metabolite GS-331007, VEL, VOX, and ARVs were analyzed and PK parameters were calculated. Geometric least-squares means ratios and 90% confidence intervals (combination vs alone) for PK parameters (AUC, Cmax, and Ctau [as applicable]) were estimated and compared against lack of PK alteration boundaries of 70% to 143% for all analytes. Safety assessments were conducted throughout the study.
Study Results
116 of 120 enrolled subjects (n=30/cohort) completed the studies; overall, 4 subjects discontinued due to withdrawal of consent. The majority of adverse events (AEs) were Grade 1 or 2 and there were no discontinuations due to AEs and no serious AEs. Overall exposure (AUC) of BIC, FTC, RPV, DRV, and EVG was unaltered by coadministration with SOF/VEL/VOX. COBI and RTV AUC were 50% and 45% higher, respectively, when administered with SOF/VEL/VOX. TAF and TFV AUC were 52% to 58% higher and 67% to 79% higher, respectively, when the unboosted regimens were administered with SOF/ VEL/VOX. TAF and TFV AUC from EVG/COBI/ FTC/TAF were unaltered when coadministered with SOF/VEL/VOX. TFV AUC from DRV+RTV+ FTC/TDF was 39% higher when administered with SOF/VEL/VOX. Overall exposure (AUC) of SOF and VEL were unaltered following administration of SOF/ VEL/VOX with the ARV regimens. GS-331007 was 43% higher when EVG/COBI/FTC/TAF was administered with SOF/VEL/VOX. VOX AUC was unaffected by administration with unboosted regimens, but higher VOX AUC (143% to 171%) were observed with boosted ARV regimens.
Study Conclusions
Study treatments were well tolerated. There were no clinically relevant changes in the PK of ARVs, SOF, GS-331007, or VEL with coadministration. Unboosted regimens did not impact VOX PK; higher VOX exposures were observed with boosted ARV regimens.
References
Garrison K, Mogalian E, Zhang H, Ma G, West S, Martin H. Evaluation of drug-drug interactions between sofosbuvir/velpatasvir/voxilaprevir and boosted or unboosted hiv antiretroviral regimens. International Workshop On Clinical Pharmacology Of Antiviral Therapy. Chicago, IL, USA. 18; June 2017.
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