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Effect of ticagrelor on the pharmacokinetics of ethinyl oestradiol and levonorgestrel in healthy volunteers.

Author(s): Butler K, Teng R

Affiliation(s): AstraZeneca LP, Wilmington, DE , USA.

Publication date & source: 2011-08, Curr Med Res Opin., 27(8):1585-93. Epub 2011 Jun 21.

Publication type: Randomized Controlled Trial; Research Support, Non-U.S. Gov't

BACKGROUND: Cytochrome P450 3 A is involved in ticagrelor and ethinyl oestradiol/levonorgestrel metabolism; so a potential drug-drug interaction may occur. OBJECTIVES: To assess: ticagrelor effects on ethinyl oestradiol/levonorgestrel pharmacokinetics, endogenous sex hormone levels; ethinyl oestradiol/levonorgestrel effects on ticagrelor pharmacokinetics; tolerability of ticagrelor + ethinyl oestradiol/levonorgestrel. METHODS: This trial was a randomized, double-blind, two-way crossover, single-center study. Twenty-two healthy female volunteers (on stable ethinyl oestradiol/levonorgestrel) received 90 mg ticagrelor or placebo twice daily with ethinyl oestradiol/levonorgestrel (0.03 mg/0.15 mg; Nordette) on cycle days 1-21. Volunteers crossed over treatment on day 1/cycle 2. Pharmacokinetic parameters were evaluated on cycle day 21, and endogenous hormones assayed on cycle days 1, 7, 14 and 21. CLINICAL TRIAL REGISTRATION NUMBER: NCT006895906. RESULTS: Ethinyl oestradiol absorption was rapid (median t(max) approximately 1 hour), and was not affected by ticagrelor. Ticagrelor co-administration (90% confidence interval [CI]) increased AUC(0-tau), C(min), and C(max) of ethinyl oestradiol by 20% (1.03-1.40), 20% (0.96-1.50) and 31% (1.18-1.44), respectively. Ticagrelor had no effect on levonorgestrel pharmacokinetic parameters versus placebo (90% CI: AUC(0-tau) 0.97-1.10; C(min) 0.94-1.10; C(max) 1.02-1.16). Steady-state ticagrelor, and AR-C124910XX (major and equally pharmacologically active metabolite), AUC(0-tau), C(max), and t(max) were comparable with published findings. Pre-dose ticagrelor and AR-C124910XX plasma concentrations were higher on cycle day 21 versus days 7 and 14. Endogenous sex hormone plasma levels were unaffected by ticagrelor. Co-administration of ticagrelor with ethinyl oestradiol/levonorgestrel was well tolerated. Study limitations included: no ticagrelor-only arm; only one type of oral contraceptive; short study duration; using oestradiol/levonorgestrel pharmacokinetic parameters as surrogate marker for contraceptive efficacy. CONCLUSIONS: Ticagrelor co-administration with ethinyl oestradiol/levonorgestrel increased ethinyl oestradiol exposure by approximately 20%, with no effect on levonorgestrel pharmacokinetics. No clinically relevant effect on contraceptive efficacy is expected with ethinyl oestradiol/levonorgestrel and ticagrelor co-administration.

Page last updated: 2011-12-09

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