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.