GS-9674 versus Dabigabran
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Study Design
To evaluate GS-9674 as a perpetrator of DDIs, healthy subjects (N = 18–24 per cohort) were administered a single dose of midazolam (MDZ 2 mg; CYP3A4 probe), dabigatran etexilate (DE 75 mg; P-gp probe), pravastatin (PRA 40 mg; OATP probe), rosuvastatin (ROS 10 mg; BCRP/OATP probe), or atorvastatin (ATV 10 mg; CYP3A/OATP probe), alone or in combination with GS-9674 (100 mg). To evaluate GS-9674 as an object of DDIs, subjects (N = 18–24 per cohort) were administered a single dose of GS-9674 100 mg alone or in combination with inhibitors or inducers: single doses of rifampin (SD RIF 600 mg; OATP inhibitor) or cyclosporine A (CsA 600 mg; OATP/MRP2/P-gp inhibitor) or multiple doses of voriconazole (VORI 200 mg BID for 4 days; CYP3A inhibitor), gemfibrozil (GFZ 600 mg BID for 4 days; CYP2C8 inhibitor), or after RIF (MD RIF 600 mg QD for 7 days; CYP/OATP/P-gp inducer). Safety was assessed by routine clinical and laboratory monitoring throughout the study. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were estimated for AUCinf and Cmax.
Study Results
In this study, 108 subjects were dosed. GS-9674 was well tolerated: no Grade 3 AEs, SAEs or AEs leading to treatment discontinuation were observed. There was no effect of GS-9674 on MDZ, DE, PRA, or ROS PK. GS-9674 slightly increased ATV AUCinf (39%). GFZ moderately increased GS-9674 AUCinf (75%) while VORI had no effect on AUCinf. Both SD RIF and CsA significantly increased GS-9674 exposure and MD RIF significantly decreased GS-9674 exposure.
Study Conclusions
All study treatments were generally well tolerated. GS- 9674 is not a clinically relevant inhibitor of OATP, BCRP, P-gp or CYP3A. The slight increase in ATV exposure does not warrant ATV dose adjustment. Hepatic OATP plays a significant role in GS-9674 PK with CYP2C8, and potentially P-gp, contributing to a lesser extent and minimal contribution from CYP3A. Based on these data, coadministration of GS-9674 with potent OATP inhibitors or potent or moderate inducers of OATP/CYP2C8/P-gp is not recommended. GS-9674 may be administered with CYP3A or CYP2C8 inhibitors without dose modification.
References
Nelson CH, Kirby BJ, Lu N, Djedjos CS, Myers RP, Xiao D. Evaluation of cytochrome p450 and transporter mediated drug-drug interactions with the farsenoid x receptor agonist gs-9674 and phenotypic probe substrates and inhibitors/inducers. Ilc: International Liver Congress. Amsterdam, Netherlands. 17; April 2017.
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