Does morphine administration affect ticagrelor conversion to its active metabolite in patients with acute myocardial infarction? A sub-analysis of the randomized, double-blind, placebo- -controlled IMPRESSION trial

Background. Therapy with aspirin and one of the platelet P2Y12 receptor inhibitors, preferably ticagrelor or prasugrel, is the mainstay of acute myocardial infarction (AMI) treatment. Morphine is the most commonly used analgesic in AMI patients. The IMPRESSION study was the first randomized trial to confirm that morphine use in this clinical setting leads to a delayed and attenuated exposure to ticagrelor and its active metabolite (AR-C124910XX). The mechanism underlying this drug-drug interaction remains hypothetical. Material and methods. A post hoc sub-analysis of the IMPRESSION study, a phase IV, single center, randomized, double-blind, placebo-controlled trial, was performed to examine whether morphine administration interferes with the proportion of AR-C124910XX produced from ticagrelor in AMI patients. Pharmacokinetic results of all subjects pretreated with placebo (n = 35) and morphine (n = 35) were analyzed. The ratio of total exposure to AR-C124910XX to total exposure to ticagrelor for 12 h was used to illustrate the rate of ticagrelor metabolism. Total exposure to investigated compounds was measured as the area under the plasma concentration-time curve (AUC). Results. The ratios of AUC(0–12) for AR-C124910XX to AUC(0–12) for ticagrelor were comparable between morphine and placebo pretreated patients (20.9 [13.9–34.6] v. 24.7 [18.1–29.6] %; p = 0.58). Importantly, visual inspection of the relationship between AUC(0–12) for AR-C124910XX and AUC(0–12) for ticagrelor revealed that regression lines for the morphine and placebo groups were located closely to each other, with a tendency for superimposing. Additionally, we observed similar values of slope coefficients for both study arms in the linear regression equations illustrating the relationship between AUC(0–12) for AR-C124910XX and AUC(0–12) for ticagrelor (0.19 [± 0.03] v. 0.21 [± 0.04]; p for the statistical significance of both slope coefficients < 0.0001). Conclusions. In the IMPRESSION study, conversion of ticagrelor to AR-C124910XX in AMI patients was not affected by morphine administration