title: Pharmacokinetic interaction study of ticagrelor and cyclosporine in healthy volunteers.
abstract: OBJECTIVE
  Patients with acute coronary syndrome and certain co-morbidities may receive ticagrelor, a reversibly binding P2Y(12) receptor antagonist, and cyclosporine, a commonly used immunosuppressant drug. This study assessed the potential pharmacokinetic drug-drug interaction between ticagrelor and cyclosporine.
  
  
  METHODS
  In this single-centre, open-label, three-treatment, three-period crossover study (NCT01504906), healthy volunteers (n = 26) randomly received each of three treatments: cyclosporine (600 mg single oral dose) plus ticagrelor (180 mg single oral dose); cyclosporine alone; ticagrelor alone. Treatments were separated by a washout period of ≥14 days. Plasma concentrations of ticagrelor and its active metabolite (AR-C124910XX) and blood concentrations of cyclosporine were analyzed, and pharmacokinetic parameters were calculated. Safety and tolerability were assessed.
  
  
  RESULTS
  Compared with ticagrelor alone, the geometric least squares mean (LSM) ratio (90 % confidence interval [CI]) for the ticagrelor area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) was 2.83 (2.63-3.06), and the maximum plasma concentration (C(max)) was 2.30 (2.06-2.58), in the presence of cyclosporine. Co-administration of cyclosporine with ticagrelor significantly increased AR-C124910XX AUC(∞) (1.33 [1.23-1.42]) and decreased C(max) (0.85 [0.76-0.94]). Ticagrelor had no effect on cyclosporine pharmacokinetic parameters, as the 90 % CIs of the LSM ratios were all within the 0.80-1.25 no-effect range. Co-administration of ticagrelor and cyclosporine was generally well tolerated.
  
  
  CONCLUSIONS
  Co-administration of cyclosporine with ticagrelor increased exposure to ticagrelor and its active metabolite and had no effect on cyclosporine pharmacokinetic parameters. The magnitude of cyclosporine's effect on ticagrelor pharmacokinetics does not warrant dose adjustment of ticagrelor.
authors.affiliation: Clinical Pharmacology, AstraZeneca LP, FOC W1-677, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE, 19850-5437, USA, renli.teng@astrazeneca.com.
authors.forename: Renli
authors.initials: R
authors.lastname: Teng
authors.forename: Mirjana
authors.initials: M
authors.lastname: Kujacic
authors.forename: Judith
authors.initials: J
authors.lastname: Hsia
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000328:Adult; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004347:Drug Interactions / Q000502:physiology; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D008297:Male; D058921:Purinergic P2Y Receptor Antagonists / Q000493:pharmacokinetics*; D000077486:Ticagrelor; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D058921:Purinergic P2Y Receptor Antagonists; D016572:Cyclosporine; D000077486:Ticagrelor; D000241:Adenosine