Pharmacokinetic/pharmacodynamic drug-drug interactions of avatrombopag when co-administered with dual or selective CYP2C9 and CYP3A interacting drugs

Summary

Aims

Avatrombopag, a thrombopoietin receptor agonist, is a substrate of cytochrome P450 (CYP) 2C9 and CYP3A. We assessed three drug-drug interactions of avatrombopag as a victim with dual or selective CYP2C9/3A inhibitors and inducers.

Methods

This was a 3-part, open-label study. Forty-eight healthy subjects received single 20 mg doses of avatrombopag alone or with one of 3 CYP2C9/3A inhibitors or inducers: fluconazole 400 mg once daily for 16 days, itraconazole 200 mg twice daily on Day 1 and 200 mg once daily on Days 2-16, or rifampin 600 mg once daily for 16 days. Pharmacokinetics, pharmacodynamics (platelet count), and safety of avatrombopag were evaluated.

Results

Co-administration of a single 20-mg dose of avatrombopag with fluconazole at steady-state resulted in 2.16-fold increase of AUC of avatrombopag, prolonged t½ (from 19.7 h to 39.9 h) and clinically significant increase in E_max (1.66-fold). Itraconazole had a mild increase on both avatrombopag pharmacokinetics and pharmacodynamics compared to fluconazole. Co-administration of rifampin caused a 0.5-fold decrease in AUC, shortened t½ (from 20.3 h to 9.84 h), and without any impact of E_max. Co-administration with interacting drugs was found to be generally safe and well-tolerated.

Conclusions

The results from co-administration of fluconazole or itraconazole suggest that CYP2C9 plays a predominant role in metabolic clearance of avatrombopag than CYP3A. To achieve comparable platelet count increases when avatrombopag is co-administered with CYP3A and CYP2C9 inhibitors, an adjustment in the dose or duration of treatment is recommended, while co-administration with strong inducers is not currently recommended.

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