Despite increases in sofosbuvir levels when co-administered with VEL, the impact on circulating metabolites of sofosbuvir appear less dramatic. Since the decrease in GS-331007 Cmax was modest and the AUC paremeters met the equivalence criteria, dose adjustment of Sofosbuvir or VEL does not appear to be warranted when these agents are utilized together. Given the sample size and healthy volunteer population, further studies are required to optimize clinical utilization of this combination.
Sofosbuvir vs velpatasvir
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Study Design
Mogalian, et al, sought to evaluate the effect of GS-5816 on the pharmacokinetics of sofosbuvir (SOF) and it's metabolites GS-566800 and GS-331007 and GS-566500 as well as the effect of SOF on the pharmacokinetics of velpatasvir (VEL; formerly known as GS-5816). In this open-label, fixed sequence cross over PK and safety study, 18 healthy adult males and females received one day of SOF 400 mg x 1 followed day a washout period on days 2-4. On days 5-13, patients received 150 mg of VEL each day. On day 14, patients received SOF 400 mg x 1 plus VEL 150 mg x 1. Pharmacokinetic analysis occurred at the end of day one, day 13 and day 14. Plasma PK sampling wa performed over 96 hours for SOF, GS-566500 and GS-331007 and over 24 hours for VEL.
Study Results
Sofosbuvir pharmacokinetics are described below:Parameter Mean (%CV)SOF 400 mgSOF 400 mg + VEL 150 mgGMR % (90% CI)AUC (ng*h/ml)1200 (26.7)2860 (26.3)238 (214, 264)Cmax (ng/ml)964 (47.5)1670 (30.2)181 (149, 219)Median T ½ (h)0.38 (0.34, 0.43)0.44 (0.38, 0.5)----SOF exposures were 1.8-2.4 fold higher when co-administered with GS-5816 150 mg, and this was thought likely to inhibition of P-glycoprotein or breast cancer resistance protein by GS-5816. Sofosbuvir AUC and Cmax increased 138% and 81% respectively. Increases in GS-566500 exposure were comparable to those observed with SOF when co-administered with GS-5816, but this data was not described in the conference abstract.GS 331007 Pharmacokinetics are described below:Parameter Mean (% CV)SOF 400 mgSOF 400 mg + GS-5816 150 mgGMR % (90% CI)AUC (ng*h/ml)12,100 (21.2)14,100 (21.3)116 (111, 122)Cmax (ng/ml)1110 (23.9)703 (16.9)64.2 (58.5, 70.4)Median T ½ (h)27.5 (23, 28.2)27.2 (24.7, 30.5)----GS 331007 total exposure was unaffected and Cmax was decreased by approximately 36% when SOF was co-administered with GS-5816 150 mg.GS-5816 Pharmacokinetics are described below:Parameter Mean (%CV)GS-5816 150 mgSOF 400 mg + GS 5816 150 mgGMR % (90% CI)AUC (ng*h/ml)7690 (30.5)8600 (30.3)112 (108, 116)Cmax (ng/ml)963 (24.1)1020 (24.4)106 (102, 110)Cmin (ng/ml113 (44)135 (46.6)118 (112, 124)Median T ½ (h)12.3 (11, 14.9)17.6 (17.1, 19.1)----AUC and Cmax of GS-5816 increased by 12% and 6% respectively, though this does not appear to be clinically significant.
References
E Mogalian, P German, D Brainard, J Link, J McNally, L Han, et al. Lack of a clinically significant pharmacokinetic drug-drug interaction between sofosbuvir and gs-5816 in healthy volunteers. 64rd Annual Meeting Of The American Association For The Study Of Liver Diseases. Washington DC. ; 2013.
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