title: 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.
  
  
  OBJECTIVE
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: AstraZeneca LP, Wilmington, DE , USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Butler
authors.forename: Renli
authors.initials: R
authors.lastname: Teng
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000293:Adolescent; D000328:Adult; D003280:Contraceptives, Oral, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004347:Drug Interactions; D004967:Estrogens / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D016912:Levonorgestrel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D000077486:Ticagrelor
chemical_list: D003280:Contraceptives, Oral, Synthetic; D004967:Estrogens; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; D000077486:Ticagrelor; D000241:Adenosine