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  17th International Workshop
on Clinical Pharmacology of
HIV and Hepatitis Therapy
June 8-10, 2016, Washington DC
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Grazoprevir and Elbasvir Levels 5- and 2-Fold Higher With Stribild
  17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC
Mark Mascolini
Concentrations of the direct-acting antivirals (DAAs) grazoprevir and elbasvir, coformulated as Zepatier, were 5-fold and 2-fold higher with than without elvitegravir/cobicistat plus tenofovir/emtricitabine (TDF/FTC) (Stribild) in a study of 22 healthy adults [1]. Merck investigators advised against prescribing Zepatier with Stribild.
Zepatier is licensed as a once-daily fixed-dose anti-HCV combination containing 100 mg of the NS3/4A protease inhibitor grazoprevir and 50 mg of the NS5A inhibitor elbasvir [2]. The once-daily fixed-dose antiretroviral combination Stribild contains the integrase inhibitor elvitegravir boosted by cobicistat plus TDF/FTC. Both grazoprevir and elbasvir are CYP3A and P-glycoprotein (P-gp) substrates, and grazoprevir is an OATP1B substrate. Cobicistat inhibits CYP3A, P-gp, OATP1B1/3, and BCRP.
To determine potential interactions between the two coformulations, Merck researchers recruited 22 healthy adults, 6 of them women, and enrolled them in a fixed-sequence, 3-period study. In period 1 participants took once-daily Stribild for 7 days followed by a 5-day no-drug washout. In period 2 participants took once-daily Zepatier for 10 days. In period 3 they continued Zepatier for 10 days and added Stribild for 10 days, with no washout between periods 2 and 3. Pharmacokinetics for all agents were determined over 24 hours in samples collected beginning after the last dose in each treatment period.
Cobicistat area under the concentration-time curve (AUC) was 49% higher with than without Zepatier (geometric mean ratio [GMR] 1.49, 90% confidence interval [CI] 1.42 to 1.57), while cobicistat maximum concentration (Cmax) was 39% higher with Zepatier (GMR 1.39, 95% CI 1.29 to 1.50). The Merck team proposed that Zepatier raises cobicistat exposure through CYP3A inhibition by grazoprevir.
Zepatier did not affect concentrations of elvitegravir (AUC GMR 1.10, 90% CI 1.00 to 1.21) or FTC (AUC GMR 1.07, 90% CI 1.03 to 1.10) and only slightly increased tenofovir exposure (AUC GMR 1.18, 90% CI 1.13 to 1.24).
Taking Zepatier with Stribild steeply raised concentrations of grazoprevir (AUC GMR 5.36, 90% CI 4.48 to 6.43; Cmax GMR 4.59, 90% CI 3.70 to 5.69) while doubling concentrations of elbasvir (AUC GMR 2.18, 90% CI 2.02 to 2.35; Cmax GMR 1.91, 90% CI 1.77 to 2.05). The researchers figured that coadministration of Zepatier and Stribild boosts grazoprevir exposure via CYP3A and OATP1B1 inhibition, while increasing elbasvir exposure via CYP3A inhibition.
The Merck team rated the impact of Stribild on grazoprevir "clinically relevant" and recommended against giving Stribild and Zepatier together.
1. Feng HP, Caro L, Guo Z, et al. A clinically meaningful drug-drug interaction observed between Zepatier (grazoprevir/elbasvir) and Stribild HIV fixed-dose combination in healthy subjects. 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC. Abstract O22.
2. Zepatier (elbasvir and grazoprevir). https://www.zepatier.com/