2017 - Budapest - Hungary

PAGE 2017: Drug/Disease modelling - Other topics
Bengt Hamrén

Pharmacokinetic and exposure-response analyses supporting ticagrelor dosing recommendation in patients with prior myocardial infarction (PEGASUS-TIMI 54)

Hamrén B (1), Röshammar D (1), Nyberg J (2), Bergstrand M (2), Andersson T (1) Storey RF (3), Stanski D (4)

(1) AstraZeneca R&D Gothenburg, Sweden, (2) Pharmetheus, Uppsala, Sweden, (3) University of Sheffield, United Kingdom, (4) AstraZeneca R&D Gaithersburg, USA.

Objectives: To characterise the pharmacokinetics (PK) of ticagrelor and its active metabolite and further, to describe the exposure-response relationships between drug exposure and the composite risk of cardiovascular (CV) death, myocardial infarction (MI) and stroke as well as the risk of TIMI (the Thrombolysis In Myocardial Infarction) major bleeding during long-term treatment with ticagrelor in patients with prior MI.

Methods: Population PK (n=4426) and time-to-event exposure-response analyses (n=20942) were performed in patients with prior MI during long-term treatment with either placebo, 60 or 90 mg of ticagrelor (the PEGASUS-TIMI 54 study). 

Results: The PK of ticagrelor and its active metabolite was stable over time. Multiple statistically significant covariates were identified, however only body weight was found to affect the apparent ticagrelor clearance (CL/F) greater than 20%. The exposure-response analyses supported the primary reported efficacy results and showed clear separation between placebo and active treatment. In addition, the exposure-response analyses provided 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.

Conclusions: The ticagrelor exposure-response relationships were relatively flat and consistent across the study population. These analyses supported the selection of the 60 mg dose for all demographic subgroups of patients studied.



References: 
[1] Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Oude Ophuis T, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held P, Braunwald E, Sabatine MS; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med (2015) May 7 (ClinicalTrials.gov Identifier: NCT02663713)
[2] Röshammar D, Bergstrand M, Andersson T, Storey RF, Hamrén B. Population pharmacokinetics of ticagrelor and AR-C124910XX in patients with prior myocardial infarction. Int J Clin Pharmacol Ther (2017) Jan 30. [3] Röshammar D, Nyberg J, Andersson T, Stanski D, Storey RF, Hamrén B. Exposure-Response Analyses Supporting Ticagrelor Dosing Recommendation in Patients With Prior Myocardial Infarction. J Clin Pharmacol (2016) Nov 18


Reference: PAGE 26 (2017) Abstr 7264 [www.page-meeting.org/?abstract=7264]
Poster: Drug/Disease modelling - Other topics
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