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

Abstract

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.

* Nordette is a registered trade name of Duramed Pharmaceuticals, Inc., Cincinnati, OH, USA.

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−τ, 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−τ 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−τ, 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.

Keywords::

• Antiplatelet therapy
• Ethinyl oestradiol
• Levonorgestrel
• P2Y₁₂ receptor antagonist
• Pharmacokinetics
• Ticagrelor

Transparency

Declaration of funding

AstraZeneca funded this study.

Declaration of financial/other relationships

K.B. and R.T. are employees of AstraZeneca.

Acknowledgements

The authors thank Dr A Martinez (Principal Investigator) and the team at SeaView Research, Miami, FL, USA. H Sillén (Bioanalysis Responsible Scientist; AstraZeneca R&D, Mölndal, Sweden), staff at York Bioanalytical Solutions, York, UK, and Quality Data Services, King of Prussia, PA, USA are acknowledged for their contribution to the pharmacokinetic sample analyses and data management. The authors thank Cheryl Wei (Statistician, AstraZeneca LP, Wilmington, DE, USA) for statistical support. Editorial support in the preparation of this manuscript was provided by Jackie Phillipson (Medical Writer, Gardiner–Caldwell Communications); this support was funded by AstraZeneca.

Notes

* Nordette is a registered trade name of Duramed Pharmaceuticals, Inc., Cincinnati, OH, USA.

* Nordette is a registered trade name of Duramed Pharmaceuticals, Inc., Cincinnati, OH, USA.