Pharmacokinetic/pharmacodynamic drug–drug interactions of avatrombopag when coadministered with dual or selective CYP2C9 and CYP3A interacting drugs

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 three‐part, open‐label study. Forty‐eight hea...

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Published in:British journal of clinical pharmacology 2018-05, Vol.84 (5), p.952-960
Main Authors: Nomoto, Maiko, Zamora, Cynthia A., Schuck, Edgar, Boyd, Peter, Chang, Min‐Kun, Aluri, Jagadeesh, Siu, Y. Amy, Lai, W. George, Yasuda, Sanae, Ferry, Jim, Rege, Bhaskar
Format: Article
Language:English
Subjects:
Adolescent
Adult
cytochrome
Cytochrome P-450 CYP2C9 Inducers - pharmacology
Cytochrome P-450 CYP2C9 Inhibitors - pharmacology
Cytochrome P-450 CYP3A Inducers - pharmacology
Cytochrome P-450 CYP3A Inhibitors - pharmacology
Drug Interactions
Female
Fluconazole - pharmacology
Healthy Volunteers
Humans
Itraconazole - pharmacology
Male
Middle Aged
pharmacokinetics
physiologically based pharmacokinetics
platelet count
Platelet Count - statistics & numerical data
Receptors, Thrombopoietin - agonists
Rifampin - pharmacology
Thiazoles - adverse effects
Thiazoles - blood
Thiazoles - pharmacokinetics
Thiazoles - pharmacology
Thiophenes - adverse effects
Thiophenes - blood
Thiophenes - pharmacokinetics
Thiophenes - pharmacology
Young Adult
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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 three‐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 rifampicin 600 mg once daily for 16 days. Pharmacokinetics, pharmacodynamics (platelet count) and safety of avatrombopag were evaluated. Results Coadministration of a single 20‐mg dose of avatrombopag with fluconazole at steady‐state resulted in 2.16‐fold increase of AUC of avatrombopag, prolonged terminal elimination phase half‐life (from 19.7 h to 39.9 h) and led to a clinically significant increase in maximum platelet count (1.66‐fold). Itraconazole had a mild increase on both avatrombopag pharmacokinetics and pharmacodynamics compared to fluconazole. Coadministration of rifampicin caused a 0.5‐fold decrease in AUC and shortened terminal elimination phase half‐life (from 20.3 h to 9.84 h), but has no impact on maximum platelet count. Coadministration with interacting drugs was found to be generally safe and well‐tolerated. Conclusions The results from coadministration of fluconazole or itraconazole suggest that CYP2C9 plays a more predominant role in metabolic clearance of avatrombopag than CYP3A. To achieve comparable platelet count increases when avatrombopag is coadministered with CYP3A and CYP2C9 inhibitors, an adjustment in the dose or duration of treatment is recommended, while coadministration with strong inducers is not currently recommended.
ISSN:0306-5251
1365-2125
DOI:10.1111/bcp.13517