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  15th International Workshop on
Clinical Pharmacology
of HIV and Hepatitis Therapy
May 19- 21, 2014, Washington, DC
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Clinically Relevant Interactions Between GS5816 HCV NS5A Inhibitor and Probe Drugs
  15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 19- 21, 2014, Washington, DC
Mark Mascolini
GS-5816, a second-generation HCV NS5A replication complex inhibitor, had potentially clinically relevant interactions with inducers and inhibitors of certain transporters and metabolizing enzymes, according to results of a 5-cohort study of healthy volunteers [1].
Now in phase 2 trials, GS-5816 has in vitro activity against HCV genotypes 1 through 6 and against HCV resistant to first-generation NS5A inhibitors [2]. Gilead Sciences investigators conducted these phase 1 studies to assess potential interactions between GS-5816 and probe substrates (pravastatin, rosuvastatin, or digoxin) or inhibitors and inducers of enzymes and drug transporters (ketoconazole, rifampin, or cyclosporine). Previous work showed that GS-5816 is an inhibitor of transporters OATP, P-gp, and BCRP, and a substrate for P-gp and CYP3A4 and CYP2C8 enzymes.
This open-label single- and multiple-dose crossover study involved 5 cohorts of 76 total healthy volunteers. In each cohort volunteers were randomized to 100 mg of GS-5816 plus the probe agent or to GS-5816 or the probe alone. The researchers calculated geometric least squares means ratios and 90% confidence intervals for area under the concentration-time curve (AUC) and maximum concentration (Cmax) of GS-5816 and probe drugs.
About 60% of volunteers were men, and age averaged about 35 years. Across the five study groups, 58% to 83% were white and 17% to 42% black. Ethnically, most participants in every study group were Hispanic.
Most treatment-emergent adverse events were grade 1. One volunteer had a grade 3 panic attack 2 days after taking a single 0.25-mg dose of digoxin and dropped out of the study.
The following interactions emerged:
-- GS-5816 taken with the OATP1B1/1B3 substrate pravastatin resulted in approximately a 35% increase in pravastatin AUC and a 28% increase in pravastatin Cmax. GS-5816 taken with the OATP/BCRP substrate rosuvastatin resulted in approximately a 2.7-fold increase in rosuvastatin AUC and a 2.6-fold increase in rosuvastatin Cmax. On the basis of these findings, the Gilead researchers concluded that GS-5816 may be classified as a weak OATP inhibitor and a moderate BCRP inhibitor.
-- GS-5816 taken with the P-gp substrate digoxin resulted in approximately a 34% increase in digoxin AUC and an 88% increase in digoxin Cmax. These findings indicate that therapeutic monitoring would be called for when combining digoxin with GS-5816.
-- GS-5816 taken with the potent CYP3A/CYP2C8/P-gp inducer rifampin resulted in approximately an 82% decrease in GS-5816 AUC and a 71% decrease in GS-5816 Cmax. As a result, GS-5816 should not be used with potent CYP/P-gp inducers.
-- GS-5816 taken with the potent CYP3A/CYP2C8/P-gp inhibitor ketoconazole resulted in approximately a 70% increase in GS-5816 AUC and a 29% increase in GS-5816 Cmax. These findings suggest inhibition of enzyme/drug transport systems affects GS-5816 only modestly, so the HCV drug can be taken with potent CYP/Pg-P inhibitors without dose adjustment.
-- GS-5816 taken with the mixed OATP/P-gp/MRP2/CYP3A inhibitor cyclosporine resulted in approximately a doubling in GS-5816 AUC and a 56% increase in GS-5816 Cmax. The Gilead investigators proposed that GS-5816 can be administered with OATP and mixed-transporter inhibitors.
1. Mogalian E, German P, Yang C, et al. Evaluation of transporter and cytochrome P450-mediated drug-drug interactions between pan-genotypic HCV NS5A inhibitor GS-5816 and phenotypic probe drugs. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. May 19-21, 2014. Washington, DC. Abstract O_07.
2. Cheng G, Tian Y, Yu M, et al. GS-5816, a second-generation HCV NS5A inhibitor with potent antiviral activity, broad genotypic coverage, and a high resistance barrier. EASL 48th Annual Meeting. April 24-28, 2013. Amsterdam. http://www.natap.org/2013/EASL/EASL_34.htm