Sofosbuvir/Velpatasvir/Voxilaprevir versus Ethinyl Estradiol/Norgestimate
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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
No changes in ethinyl estradiol (EE) or norgestrel PK were seen when S/V/V was administered with EE/norgestimate; use of OCs with S/V/V is allowed.
Study Conclusions
The authors stated that because sofosbuvir/velpatasvir/voxilaprevir did not adversely impact pharmacokinetics of ethinyl estradiol or norgestrel, coadministration of these agents was not expected to result in adverse effects
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.
Sofosbuvir/Velpatasvir/Voxilaprevir versus Ethinyl Estradiol/Norgestimate Garrison Abstract
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Study Design
This was an open-label, fixedsequence, Phase 1 study in fifteen healthy (HCVuninfected) female subjects. Subjects not using NGM/EE were enrolled into Part A (lead-in) and received NGM/EE for 1 menstrual cycle prior to enrollment into Part B of the study. Subjects on NGM/EE could enroll into Part B directly.
In Part B, subjects received NGM/EE for 2 sequential cycles. In cycle 1, NGM/EE was administered alone. In cycle 2, SOF/VEL/VOX (400/100/100 mg) + VOX (100 mg) was coadministered with NGM/EE for 7 days (Days 8-14) of the cycle, where the largest change in follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH) would be observed if contraceptive efficacy were compromised. The additional 100 mg of VOX was administered to the healthy subjects to approximate systemic VOX exposures observed in the HCV-infected population. Safety assessments were conducted throughout the study. Plasma concentrations of norgestimate, norelgestromin (NGMN), norgestrel (NG), EE, SOF and GS-331007 (predominant circulating metabolite), VEL, and VOX were analyzed on Day 14 of each cycle (as appropriate). Geometric least squares mean ratios (GLSM) and 90% confidence intervals (CIs) for AUCtau, Cmax and Ctau were estimated with lack of PK alteration bounds of 70 to 143%. Quantitation of pharmacodynamic (PD) markers, including follicle-stimulating hormone (FSH; Day 14), luteinizing hormone (LH; Day 14), and progesterone (Day 21) was conducted in both cycles.
Study Results
Study treatments were generally well tolerated. Headache was reported at similar frequencies during both treatments (each 40%), while gastrointestinal disorders were more frequently reported during treatment with NGM/EE + SOF/VEL/VOX (67%) compared with NGM/EE alone (20%). All treatment-emergent AEs were mild (Grade 1) or moderate (Grade 2). Similar systemic exposures (AUCtau, Cmax, and Ctau) of NGMN and NG (active metabolites of NGM) and EE were observed following administration of NGM/EE alone or in combination with SOF/VEL/VOX. The 90% Cis of the GLSM ratios for AUCtau, Cmax, and Ctau of NGMN, NG, and EE were all within the lack of PK alteration boundaries of 70% to 143%.
Norgestimate was not quantifiable for all subjects at most time points. FSH, LH, and progesterone values were similar in both cycles.
Study Conclusions
The author’s concluded that coadministration of SOF/VEL/VOX with NGM/EE was safe and well tolerated. Based on PK and PD results, no loss in contraceptive efficacy is expected upon administration of oral contraceptives containing NGM/EE with SOF/VEL/VOX.
References
Garrison K, Ma G, Stamm L, Ling J, Mathias A. Lack of pharmacokinetic drug-drug interaction between norgestimate/ethinyl estradiol and sofosbuvir/velpatasvir/voxilaprevir. International Workshop On Clinical Pharmacology Of Antiviral Therapy. Chicago, IL, USA. 18; June 2017.
Sofosbuvir/Velpatasvir/Voxilaprevir versus Ethinyl Estradiol/Norgestimate Garrison Abstract
^
Study Design
This was an open-label, fixedsequence, Phase 1 study in fifteen healthy (HCVuninfected) female subjects. Subjects not using NGM/EE were enrolled into Part A (lead-in) and received NGM/EE for 1 menstrual cycle prior to enrollment into Part B of the study. Subjects on NGM/EE could enroll into Part B directly.
In Part B, subjects received NGM/EE for 2 sequential cycles. In cycle 1, NGM/EE was administered alone. In cycle 2, SOF/VEL/VOX (400/100/100 mg) + VOX (100 mg) was coadministered with NGM/EE for 7 days (Days 8-14) of the cycle, where the largest change in follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH) would be observed if contraceptive efficacy were compromised. The additional 100 mg of VOX was administered to the healthy subjects to approximate systemic VOX exposures observed in the HCV-infected population. Safety assessments were conducted throughout the study. Plasma concentrations of norgestimate, norelgestromin (NGMN), norgestrel (NG), EE, SOF and GS-331007 (predominant circulating metabolite), VEL, and VOX were analyzed on Day 14 of each cycle (as appropriate). Geometric least squares mean ratios (GLSM) and 90% confidence intervals (CIs) for AUCtau, Cmax and Ctau were estimated with lack of PK alteration bounds of 70 to 143%. Quantitation of pharmacodynamic (PD) markers, including follicle-stimulating hormone (FSH; Day 14), luteinizing hormone (LH; Day 14), and progesterone (Day 21) was conducted in both cycles.
Study Results
Study treatments were generally well tolerated. Headache was reported at similar frequencies during both treatments (each 40%), while gastrointestinal disorders were more frequently reported during treatment with NGM/EE + SOF/VEL/VOX (67%) compared with NGM/EE alone (20%). All treatment-emergent AEs were mild (Grade 1) or moderate (Grade 2). Similar systemic exposures (AUCtau, Cmax, and Ctau) of NGMN and NG (active metabolites of NGM) and EE were observed following administration of NGM/EE alone or in combination with SOF/VEL/VOX. The 90% Cis of the GLSM ratios for AUCtau, Cmax, and Ctau of NGMN, NG, and EE were all within the lack of PK alteration boundaries of 70% to 143%.
Norgestimate was not quantifiable for all subjects at most time points. FSH, LH, and progesterone values were similar in both cycles.
Study Conclusions
The author’s concluded that coadministration of SOF/VEL/VOX with NGM/EE was safe and well tolerated. Based on PK and PD results, no loss in contraceptive efficacy is expected upon administration of oral contraceptives containing NGM/EE with SOF/VEL/VOX.
References
Garrison K, Ma G, Stamm L, Ling J, Mathias A. Lack of pharmacokinetic drug-drug interaction between norgestimate/ethinyl estradiol and sofosbuvir/velpatasvir/voxilaprevir. International Workshop On Clinical Pharmacology Of Antiviral Therapy. Chicago, IL, USA. 18; June 2017.
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