Evaluation of the potential for pharmacokinetic interaction between tirabrutinib and levonorgestrel/ethinyl estradiol in healthy female volunteers.

Abstract

Tirabrutinib (TIRA), a potent and nonreversible oral Bruton tyrosine kinase inhibitor, is evaluated for treatment of certain hematological malignancies and inflammatory diseases. A drug-drug interaction study to evaluate the effect of TIRA on the pharmacokinetics of the oral contraceptive levonorgestrel (LEVO)/ethinyl estradiol (EE) was conducted in healthy female participants (N = 26). Participants received a single dose of LEVO (150 mcg)/EE (30 mcg) alone (reference), and on day 12 of a 15-day regimen of TIRA 160 mg once-daily (test). Intensive blood sampling for determination of LEVO, EE, and TIRA plasma concentrations was conducted, and safety was assessed throughout the study. Pharmacokinetic interactions were evaluated using 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of the test versus reference treatments. The GLSM (90% CI) ratios of area under the concentration-time curve from zero to infinity (AUCinf ; LEVO: 0.95, 95% CI: 0.88-1.03, EE: 1.10, 95% CI: 1.05-1.16) and maximum plasma concentration (Cmax ; LEVO: 0.85, 95% CI: 0.74-0.98, EE: 1.07, 95% CI: 0.98-1.18) were within the prespecified 0.70 to 1.43 no effect bounds; and the AUC ratios met the stricter 0.80 to 1.25 equivalence bounds. Study treatments were generally well-tolerated. In conclusion, co-administration with TIRA did not alter the exposure of LEVO/EE, and accordingly LEVO/EE containing oral contraceptives can serve as a contraception method for participants on TIRA 160 mg (or lower) daily doses.

• Authors: Ganesh Cherala, Cara Nelson, Ying Guo, Anubhav Mathur, Thomas Tarnowski, Ahmed A Othman
• Journal: Clinical and translational science (Clin Transl Sci) Vol. 15 Issue 6 Pg. 1492-1499 (06 2022) ISSN: 1752-8062 [Electronic] United States
• PMID: 35266297 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Gilead Sciences, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Chemical References

• Imidazoles
• Pyrimidines
• Ethinyl Estradiol
• Levonorgestrel
• tirabrutinib

Topics

• Drug Interactions
• Ethinyl Estradiol (adverse effects)
• Female
• Humans
• Imidazoles
• Levonorgestrel (adverse effects)
• Pyrimidines
• Volunteers