title: Exposure-Response Analyses Supporting Ticagrelor Dosing Recommendation in Patients With Prior Myocardial Infarction.
abstract: The relationships between drug exposure and the composite risk of cardiovascular (CV) death, myocardial infarction (MI), and stroke as well as the risk of TIMI major bleeding were estimated following long-term treatment with ticagrelor 60 or 90 mg twice daily in 20,942 patients with prior MI. These analyses support the primary reported efficacy and safety evaluations by showing that there were clear separations from placebo early in treatment with both doses, regardless of ticagrelor exposure, for both endpoints. In addition, the exposure-response analyses provided new insight into the contribution of individual exposure levels, rather than dose, as a predictor of events and accounted for differences in the baseline risk between patients. The predicted risks of CV death/MI/stroke were similar despite an increase in the median predicted ticagrelor average steady-state concentration from 606 nmol/L with ticagrelor 60 mg to 998 nmol/L with ticagrelor 90 mg (hazard ratios vs placebo of 0.83 and 0.81, respectively). The corresponding predicted risk of TIMI major bleeding slightly increased (hazard ratios vs placebo of 2.4 and 2.6, respectively). Apart from Japanese patients, showing a lower risk of CV death/MI/stroke, the response to ticagrelor was consistent across the study population, as supported by the combination of relatively flat exposure-response relationships in the studied exposure range, similar sensitivity to ticagrelor exposure, and small exposure differences. Consequently, the present analyses support the selection of the 60-mg dose for all demographic subgroups of patients studied.
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Röshammar
authors.affiliation: Pharmetheus, Uppsala, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Nyberg
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Andersson
authors.affiliation: AstraZeneca R&D, Gaithersburg, MD, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Stanski
authors.affiliation: University of Sheffield, Sheffield, United Kingdom.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Hamrén
mesh_terms: D000241:Adenosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009203:Myocardial Infarction / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy / Q000401:mortality*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects; D012307:Risk Factors; D000077486:Ticagrelor
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077486:Ticagrelor; D000241:Adenosine
keywords: NONMEM; PEGASUS-TIMI 54; exposure-response; ticagrelor; time-to-event