title: Population pharmacokinetics of ticagrelor in patients with acute coronary syndromes.
abstract: OBJECTIVE
  Ticagrelor is an orally administered antiplatelet agent used to reduce thrombotic events in patients with acute coronary syndromes. Data from two studies in patients with acute coronary syndromes with large amounts of pharmacokinetic (PK) data (phase IIb DISPERSE-2 study (n = 609)); phase III PLATO PK substudy (n = 6,381)), along with non-linear mixed effects modeling software, were used to develop population PK models for ticagrelor and its metabolite, AR-C124910XX, and to evaluate the impact of demographic and clinical factors on the PK of ticagrelor and AR-C124910XX.
  
  
  METHODS
  32 covariates relating to disease history, biomarkers, clinical chemistry, and concomitant medications were assessed.
  
  
  RESULTS
  A one-compartment model with population mean PK parameters of firstorder absorption rate constant (0.67/h), apparent systemic clearance (14 L/h), and apparent volume of distribution (221 L) was shown to best describe the PK profile of ticagrelor. Patients co-administered moderate CYP3A inducers or inhibitors increased (by 110%, 95% confidence interval (CI), 52 - 192%) or decreased (by 64%, 95% CI, 39 - 73%) apparent ticagrelor clearance, respectively, while habitual smoking decreased apparent ticagrelor clearance by 22% (95% CI, 19 - 25%). Ticagrelor bioavailability was 21% (95% CI, 19 - 22%) lower at treatment initiation (visit 1) versus subsequent visits. Compared with Caucasian patients, ticagrelor bioavailability was 39% (95% CI, 33 - 46%) higher in Asian patients and 18% (95% CI, 6 - 28%) lower in Black patients.
  
  
  CONCLUSIONS
  In the current analyses, the population PK models developed for ticagrelor and AR-C124910XX described the data obtained in the DISPERSE-2 and PLATO studies well, and were consistent with previous phase I PK studies.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Li
authors.forename: Weifeng
authors.initials: W
authors.lastname: Tang
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
authors.forename: Steen
authors.initials: S
authors.lastname: Husted
authors.forename: Renli
authors.initials: R
authors.lastname: Teng
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People; D001682:Biological Availability; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D058921:Purinergic P2Y Receptor Antagonists / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077486:Ticagrelor; D014018:Tissue Distribution; D044465:White People; D055815:Young Adult
chemical_list: C561701:AR C124910XX; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D000077486:Ticagrelor; D000241:Adenosine