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DAAs Glecaprevir and Pibrentasvir Double Levels of Statins and Dabigatran
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18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago
Mark Mascolini
Glecaprevir and pibrentasvir, direct-acting antivirals (DAAs) studied as combination therapy for HCV infection, more than doubled exposure of pravastatin, rosuvastatin, and the anticoagulant dabigatran etexilate (Pradaxa) [1]. Abbvie researchers who conducted the study recommend low doses of the statins with glecaprevir/pibrentasvir and dabigatran dosing according to region-specific labeling for use with P-gp inhibitors.
Pravastatin, rosuvastatin, and dabigatran are substrates of drug transporters inhibited by glecaprevir and pibrentasvir. Pravastatin is an OATP1B1/3 substrate, rosuvastatin a substrate of OATP1B1/3 and BRCP, and dabigatran a substrate of P-gp. To test for possible interactions between the DAAs and the other three drugs, Abbvie investigators compared pravastatin (10 mg daily), rosuvastatin (5 mg daily), or dabigatran (single 150-mg doses) alone or with glecaprevir/pibrentasvir (400/120 mg once daily with the statins, 300/120 mg once daily with dabigantran). Twelve healthy volunteers took part in each of the three comparisons.
One person dropped out of the rosuvastatin study because of a grade 2 panic attack judged unrelated to the single dose of glecaprevir/pibrentasvir taken before the attack. One person quit the dabigatran study for grade 1 chemical exposure unrelated to study drug. Other adverse events were mild, and the investigators saw no ECG abnormalities or abnormal lab values.
Giving multiple doses of glecaprevir/pibrentasvir with pravastatin increased pravastatin maximum concentration (Cmax) 2.2-fold and area under the concentration-time curve over 24 hours (AUC24) 2.3-fold. Multiple doses of the DAAs boosted rosuvastatin Cmax 5.6-fold and AUC24 2.2-fold. Dabigatran Cmax climbed 2.0-fold and AUCinf 2.4-fold with multiple doses of glecaprevir/pibrentasvir. With pravastatin, glecaprevir Cmax was 59% higher and AUC24 44% higher. The statins and dabigatran had no other consequential effects on levels of glecaprevir or pibrentasvir.
The Abbvie team concluded that glecaprevir/pibrentasvir significantly increased exposure of pravastatin, rosuvastatin, and dabigatran. When given with the DAAs, a pravastatin dose should be halved and rosuvastatin should be given at a maximum dose of 10 mg daily. With the DAAs, dabigantran "should be dosed per region-specific labeling on use with P-gp inhibitors."
Abbvie has filed an FDA application for coformulated glecaprevir/pibrentasvir given as 8-week once-daily treatment of all major HCV genotypes [2].
Reference
1. Kosloski M, Zhao W, Li H, et al. Drug-drug interactions of glecaprevir and pibrentasvir with pravastatin, rosuvastatin, or dabigatran etexilate. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago. Abstract O_18.
2. Abbvie press release. AbbVie submits new drug application to U.S. FDA for its investigational regimen of glecaprevir/pibrentasvir (G/P) for the treatment of all major genotypes of chronic hepatitis C. December 19, 2016. https://news.abbvie.com/news/abbvie-submits-new-drug-application-to-us-fda-for-its-investigational-regimen-glecaprevirpibrentasvir-gp-for-treatment-all-major-genotypes-chronic-hepatitis-c.htm
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