Glecaprevir/Pibrentasvir versus Dabigatran
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Study Design
Phase 1 studies evaluated the pharmacokinetics and safety of pravastatin 10 mg daily alone and with GLE 400 mg + PIB 120 mg daily, rosuvastatin 5 mg daily alone and with PIB 400 mg + PIB 120 mg daily, or single doses of dabigatran etexilate 150 mg alone and with GLE 300 mg + PIB 120 mg daily. Twelve healthy subjects participated in each of the three study arms (total 36). Blood samples were collected and pharmacokinetic parameters (maximum concentration [Cmax], area under the concentration-time curve [AUCinf or AUC24], and/or trough concentration [C24]) were estimated. Pharmacokinetic interactions of GLE+ PIB with pravastatin, rosuvastatin, or dabigatran were assessed by a repeated measures analysis using SAS.
Study Results
Coadministration with multiple GLE + PIB doses increased exposures of pravastatin (↑ 2.2-fold Cmax, ↑ 2.3-fold AUC24), rosuvastatin (↑ 5.6-fold Cmax, ↑ 2.2-fold AUC24), and dabigatran (↑ 2.0-fold Cmax, ↑ 2.4-fold AUCinf). GLE exposure was higher (↑Cmax 59%, ↑ AUC24 44%) with pravastatin, but PIB exposure was unaffected (≤24% difference). GLE and PIB exposures were similar (≤25% difference) with rosuvastatin or dabigatran etexilate. One subject was discontinued from the rosuvastatin study arm after receiving a single dose of GLE + PIB alone due to the event of panic attack (Grade 2), which was assessed by the investigator as having no reasonable possibility of being related to study drug. One subject discontinued from the dabigatran study arm due to chemical exposure (Grade 1) assessed by the investigator as having no reasonable possibility of being related to study drug. All other adverse events were mild in severity. No clinically significant vital signs, ECG or laboratory measurements were observed during the course of the study.
Study Conclusions
GLE + PIB significantly increased the exposure of pravastatin, rosuvastatin and dabigatran. Given the magnitude of the interaction and therapeutic index of the drugs, pravastatin and rosuvastatin can be used with GLE and PIB at reduced doses. Pravastatin dose should be reduced by 50% and rosuvastatin dose should be limited to 10 mg QD when administered with GLE and PIB. Use of dabigatran etexilate with GLE and PIB is not recommended.
References
Kosloski M, Zhao W, Li H, Wang S, Valdes J, Kort J. Drug-drug interactions of glecaprevir and pibrentasvir with pravastatin, rosuvastatin, or dabigatran etexilate. International Workshop In Clinical Pharmacology Of Antiviral Therapy. Chicago, IL, USA. 18; June 2017.
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