title: Evaluation of the pharmacokinetic interaction between ticagrelor and venlafaxine, a cytochrome P-450 2D6 substrate, in healthy subjects.
abstract: OBJECTIVE
  Ticagrelor is a reversibly binding P2Y12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). Ticagrelor has been shown in vitro to be a weak inhibitor of cytochrome P-450 (CYP) 2D6, a clinically important enzyme for the metabolism of many drugs. This study assessed the effects of coadministration of ticagrelor on the pharmacokinetics of the CYP2D6 substrate venlafaxine. The impact of venlafaxine on ticagrelor pharmacokinetic parameters was also investigated.
  
  
  METHODS
  Healthy subjects (N = 22) received a single 180-mg oral dose of ticagrelor on days 1 and 9 and oral doses of venlafaxine on day 4 (37.5 mg BID) and days 5 through 10 (75 mg BID). Plasma concentrations of ticagrelor, venlafaxine, and their metabolites (AR-C124910XX and O-desmethylvenlafaxine [ODV], respectively) were quantified for pharmacokinetic analyses. Safety and tolerability were assessed throughout the study.
  
  
  RESULTS
  Overall, 19 of 25 subjects were male; 14 were white, 10 were black, and 1 was Asian. Mean (SD) age was 26 (6) years, and mean (SD) body mass index was 24.3 (2.9) kg/m(2). Ticagrelor had no effect on overall exposure to venlafaxine, as assessed by the AUC0-τ (geometric least squares mean ratio, 110.32 ng · h/mL [90% CI, 106.27-114.52]). Venlafaxine Cmax was increased by 22% in the presence of ticagrelor (121.83 ng/mL [90% CI, 111.80-132.75]). ODV AUC0-τ and Cmax were unaffected by coadministration with ticagrelor (98.71 ng · h/mL [90% CI, 96.61-100.85] and 101.44 ng/mL [90% CI, 98.34-104.65], respectively). Venlafaxine had no effect on the Cmax or AUC0-∞ of ticagrelor (96.54 ng/mL [90% CI, 85.03-109.61] and 89.67 ng · h/mL [90% CI, 82.78-97.14]) or AR-C124910XX (106.39 ng/mL [90% CI, 96.10-117.78] and 106.32 ng · h/mL [90% CI, 97.28-116.21], respectively). Ticagrelor and venlafaxine were well tolerated whether given alone or in combination.
  
  
  CONCLUSIONS
  Ticagrelor had no clinically relevant effect on the plasma levels of venlafaxine and its CYP2D6-generated active metabolite, ODV. On the basis of these data, ticagrelor is not expected to affect CYP2D6-mediated drug metabolism to a clinically relevant extent. Venlafaxine had no effect on the pharmacokinetics of ticagrelor.
authors: AstraZeneca LP, Wilmington, Delaware. Electronic address: renli.teng@astrazeneca.com.
authors: Renli
authors: R
authors: Teng
authors: AstraZeneca, Mölndal, Sweden.
authors: Mirjana
authors: M
authors: Kujacic
authors: AstraZeneca LP, Wilmington, Delaware.
authors: Judith
authors: J
authors: Hsia
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D000069468:Desvenlafaxine Succinate / Q000097:blood; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000077486:Ticagrelor; D000069470:Venlafaxine Hydrochloride / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C561701:AR C124910XX; D058921:Purinergic P2Y Receptor Antagonists; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride; D019389:Cytochrome P-450 CYP2D6; D000077486:Ticagrelor; D000241:Adenosine; D000069468:Desvenlafaxine Succinate
keywords: CYP2D6; drug–drug interaction; pharmacokinetics; ticagrelor; venlafaxine