Negative Impact of ST-Segment Elevation Myocardial Infarction and Morphine Dose on Ticagrelor Uptake and Pharmacodynamics: A Population PK/PD Analysis of Pooled Individual Participant Data.

Abstract

Ticagrelor is widely used in patients with stable and acute coronary artery disease. Understanding the factors that influence its pharmacokinetics (PK) and pharmacodynamics (PD) could improve therapeutic outcomes. We therefore performed a pooled population PK/PD analysis using individual patient data from two studies. We focused on the impact of morphine administration and ST-segment elevation myocardial infarction (STEMI) on the risk of high platelet reactivity (HPR) and dyspnea. A parent-metabolite population PK/PD model was developed based on data from 63 STEMI, 50 non-STEMI, and 25 chronic coronary syndrome (CCS) patients. Simulations were then run to evaluate the risk of non-response and adverse events associated with the identified variability factors. The final PK model consisted of first-order absorption with transit compartments, distribution with two compartments for ticagrelor and one compartment for AR-C124910XX (active metabolite of ticagrelor), and linear elimination for both drugs. The final PK/PD model was an indirect turnover model with production inhibition. Morphine dose and STEMI, independently, had a significant negative effect on the absorption rate (reduction of log([Formula: see text]) by 0.21×morphine dose (mg) and by 2.37 in STEMI patients, both p<0.001), and the presence of STEMI significantly impacted both efficacy and potency (both p<0.001). The simulations run with the validated model showed a high rate of non-response in patients with those covariates (RR 1.19 for morphine, 4.11 for STEMI and 5.73 for morphine and STEMI, all three p<0.001). By increasing ticagrelor dosage, the negative morphine effect was reversible in patients without STEMI and just limited in patients with STEMI. The developed population PK/PD model confirmed the negative impact of morphine administration and presence of STEMI on ticagrelor PK and antiplatelet effect. Increasing ticagrelor doses seems effective in morphine users without STEMI, whereas the STEMI effect is not entirely reversible.