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DAAs Grazoprevir and Elbasvir Boost Levels of Rosuvastatin But Not Pravastatin
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16th International Workshop on Clinical
Pharmacology of HIV and Hepatitis
Therapy, May 26-28, 2015, Washington, DC
Mark Mascolini
Grazoprevir and elbasvir, direct-acting antivirals (DAAs) being investigated as a fixed-dose combination for HCV infection, raised levels of rosuvastatin but not pravastatin in healthy volunteers [1]. Neither statin had a significant impact on exposure of the DAAs.
At doses of 100 and 50 mg once daily, coformulated grazoprevir (an HCV NS3/4A protease inhibitor) and elbasvir (an NS5A replication complex inhibitor) achieved high 12-week sustained virologic response rates in treatment-naive cirrhotic or noncirrhotic people with chronic genotype 1, 4, or 6 infection in a 421-person randomized trial [2].
Both DAAs are potential BCRP inhibitors but not OATP1B inhibitors, and grazoprevir is a weak CYP3A4 inhibitor. Rosuvastatin is a substrate of OATP1B, BCRP, and CYP2C9. Pravastatin is an OATP1B substrate and a minor BCRP and CYP3A4 substrate. Previous work disclosed a clinically relevant jump in atorvastatin exposure with grazoprevir, and limiting the atorvastatin dose to 20 mg with coadministration has been proposed. Research has disclosed no clinically relevant interactions between pitavastatin and grazoprevir.
In these two- or three-period trials, 24 healthy adults first took 10 mg of rosuvastatin or 40 mg of pravastatin alone. After this single dose, the rosuvastatin group took no drug for 3 days, then took 200 mg of grazoprevir once daily for 9 days and rosuvastatin on day 7. With no drug washout, the group then took standard-dose grazoprevir/elbasvir for 11 days and rosuvastatin on day 9. The pravastatin group started 9 days of grazoprevir/elbasvir immediately after the single pravastatin dose, then took pravastatin again on day 9. Merck investigators calculated geometric mean ratios (GMRs) and 90% confidence intervals (CI) for area under the concentration-time curve (AUC) and maximum concentration (Cmax) for statin + grazoprevir +/- elbasvir/statin alone.
No serious adverse events arose. One person stopped study drugs because of increased creatine phosphokinase unrelated to these agents. Participants tolerated grazoprevir and elbasvir well.
Grazoprevir alone raised rosuvastatin AUC 85% (GMR 1.85, 90% CI 1.56 to 2.19) and more than quadrupled rosuvastatin Cmax (GMR 4.25, 90% CI 3.25 to 5.56). Adding elbasvir to grazoprevir further inflated rosuvastatin AUC (GMR 2.68, 90% CI 2.26 to 3.17) and Cmax (GMR 5.49, 90% CI 4.29 to 7.04). Rosuvastatin did not significantly affect the AUC or Cmax of grazoprevir or elbasvir.
When taken with grazoprevir and elbasvir, pravastatin exposure rose only modestly, at a GMR of 1.28 (90% CI 1.08 to 1.51) for AUC and 1.28 (90% CI 1.05 to 1.55) for Cmax. Pravastatin had little impact on the AUC or Cmax of grazoprevir or elbasvir.
The greater increase in rosuvastatin Cmax than AUC with the DAAs, the researchers proposed, indicates presystemic inhibition of rosuvastatin efflux by grazoprevir or grazoprevir/elbasvir in the liver and/or gut via BCRP. The greater impact of grazoprevir/elbasvir than grazoprevir alone suggested to the Merck team that both DAAs are intestinal BCRP inhibitors.
The investigators proposed that the rosuvastatin dose should not exceed 10 mg daily when given with grazoprevir/elbasvir, while pravastatin dosing does not have to change. They added that people in phase 2 and 3 trials of these two DAAs have taken pravastatin, rosuvastatin (up to 10 mg daily), and atorvastatin (up to 20 mg daily) with good tolerance and no safety concerns.
Merck submitted a new-drug application for grazoprevir/elbasvir for treatment of chronic genotype 1, 4, or 6 infection [3].
References
1. Caro L, Marshall W, Feng H, et al. Coadministration of HCV protease inhibitor grazoprevir with HCV NS5A inhibitor elbasvir has no effect on pravastatin but increases rosuvastatin exposure in healthy subjects. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. May 26-28, 2015. Washington, DC. Abstract 17.
2. Zeuzem S, Ghalib R, Rajender Reddy K, et al. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic HCV genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med. Published online 24 April 2015 doi:10.7326/M15-0785. http://annals.org/article.aspx?articleid=2279766
3. Business Wire. Merck submits U.S. new drug application for grazoprevir/elbasvir, an investigational once-daily, single tablet combination therapy, for treatment of chronic hepatitis C genotypes 1, 4, and 6 infection. May 28, 2015. http://www.businesswire.com/news/home/20150528006341/en/Merck-Submits-U.S.-Drug-Application-GrazoprevirElbasvir-Investigational#.VWh_AUa3q_Q
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