title: Pharmacokinetics and pharmacodynamics of ticagrelor in patients with stable coronary artery disease: results from the ONSET-OFFSET and RESPOND studies.
abstract: OBJECTIVE
  Ticagrelor, the first reversibly binding oral P2Y(12) receptor antagonist, improves outcomes in patients with acute coronary syndromes (ACS) compared with clopidogrel. In the ONSET-OFFSET study (parallel group trial) and the RESPOND study (crossover trial), the pharmacodynamic effects of ticagrelor were compared with clopidogrel in patients with coronary artery disease (CAD). We now report the pharmacokinetic analyses of ticagrelor, and the exposure-inhibition of platelet aggregation (IPA) relationships from these studies.
  
  
  METHODS
  Patients were treated with ticagrelor (180 mg loading dose, 90 mg twice daily maintenance dose) or clopidogrel (600 mg loading dose, 75 mg once daily maintenance dose) in addition to aspirin (acetylsalicylic acid) [75-100 mg once daily]. Ticagrelor administration was for 6 weeks in ONSET-OFFSET. In RESPOND, ticagrelor was given for 14 days before or after 2 weeks of clopidogrel in patients classified as clopidogrel responders or non-responders. Pharmacokinetics and IPA were evaluated following the loading and last maintenance doses. Exposure-IPA relationships were evaluated using a sigmoid maximum effect (E(max)) model.
  
  
  METHODS
  The outcome measures were ticagrelor and AR-C124910XX (active metabolite) pharmacokinetics and exposure-IPA relationships in both trials, including the effect of prior clopidogrel exposure, and effects in clopidogrel responders and non-responders in RESPOND.
  
  
  RESULTS
  In ONSET-OFFSET, maximum (peak) plasma concentration (C(max)), time to C(max) (t(max)) and area under the plasma concentration-time curve from time 0 to 8 hours (AUC(8)) for ticagrelor were 733 ng/mL, 2.0 hours and 4130 ng · h/mL, respectively; and for AR-C124910XX were 210 ng/mL, 2.1 hours and 1325 ng · h/mL, respectively. E(max) estimates were IPA >97%. Trough plasma ticagrelor (305 ng/mL) and AR-C124910XX (121 ng/mL) concentrations were 5.2 and 7.7 times higher than respective concentration producing 50% of maximum effect (EC(50)) estimates. In RESPOND, ticagrelor mean C(max) and AUC(8) following 2-week dosing were comparable between clopidogrel responders (724 ng/mL and 3983 ng · h/mL, respectively) and non-responders (764 ng/mL and 3986 ng · h/mL, respectively). Pharmacokinetics of ticagrelor were unaffected by prior clopidogrel dosing. E(max) estimates were IPA >96% for both responders and non-responders. Trough plasma concentrations were sufficient to achieve high IPA.
  
  
  CONCLUSIONS
  Ticagrelor pharmacokinetics in stable CAD patients were comparable to previous findings in stable atherosclerotic and ACS patients, and were not affected by prior clopidogrel exposure or clopidogrel responsiveness. Ticagrelor effectively inhibited platelet aggregation, and trough plasma concentrations of ticagrelor and AR-C124910XX were sufficient to result in high IPA in stable CAD patients.
authors.affiliation: Department of Cardiology, Århus University Hospital, Århus C, Denmark. steehust@rm.dk
authors.forename: Steen E
authors.initials: SE
authors.lastname: Husted
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
authors.forename: Kevin
authors.initials: K
authors.lastname: Bliden
authors.forename: Udaya S
authors.initials: US
authors.lastname: Tantry
authors.forename: Lene
authors.initials: L
authors.lastname: Høimark
authors.forename: Kathleen
authors.initials: K
authors.lastname: Butler
authors.forename: Cheryl
authors.initials: C
authors.lastname: Wei
authors.forename: Renli
authors.initials: R
authors.lastname: Teng
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gurbel
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000368:Aged; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy*; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D058921:Purinergic P2Y Receptor Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C561701:AR C124910XX; D058921:Purinergic P2Y Receptor Antagonists; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine