Kacper Wnuk1, Katarzyna Buszko1, Jacek Kubica2
1Department of Biostatistics and Biomedical Systems Theory, Nicolaus Copernicus University, 2Department of Cardiology, Nicolaus Copernicus University
Objectives: Ticagrelor is a P2Y12 receptor antagonist used to prevent thrombotic events in patients with acute coronary syndromes. Morphine, commonly administered for pain relief in these patients, has been reported to delay the onset of action of oral antiplatelet agents, including ticagrelor, potentially due to interactions affecting gastrointestinal motility and drug absorption [1, 2]. Understanding the pharmacokinetic (PK) interactions between morphine and ticagrelor is crucial for optimizing antiplatelet therapy in clinical settings. This study aimed to develop a population PK model to characterize the PK profile of ticagrelor and its active metabolite (AR-C124910XX) in healthy volunteers and to assess the impact of morphine co-administration on the PK parameters of ticagrelor and its metabolite. Methods: A randomized, open-label, crossover study was conducted involving healthy volunteers to elucidate the PK interactions between ticagrelor and morphine. Participants received a 180 mg oral loading dose of ticagrelor alone and in combination with an intravenous dose of morphine (5 mg), with a washout period between treatments to eliminate carryover effects. Serial blood samples were collected at predetermined intervals up to 6 hours post-dose to measure plasma concentrations of ticagrelor and its active metabolite, AR-C124910XX. Plasma concentrations were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods, ensuring high sensitivity and specificity. A population PK model was developed using nonlinear mixed-effects modeling (NONMEM®, version 7.5) to describe the concentration-time profiles of ticagrelor and its metabolite. Covariate analysis was performed to evaluate the effect of morphine co-administration on the PK parameters of ticagrelor and its metabolite, including absorption rate constant, distribution volumes, and clearance rates. Results: The PK profiles of ticagrelor and its metabolite were best described by a two-compartment model (with additional compartments for metabolite AR-C124910XX and gall bladder) with transit compartment absorption and first-order elimination (including enterohepatic recirculation). Co-administration of morphine resulted in a significant change in ticagrelor absorption, evidenced by a decrease in the absorption rate constant (0.640 vs. 0.213 1/h, p=0.009). However, morphine did not significantly affect the distribution or elimination parameters of ticagrelor or its metabolite. These findings align with previous studies that have reported similar delays in the absorption of oral P2Y12 inhibitors when co-administered with morphine, attributing the effect to morphine’s influence on gastrointestinal motility and drug transit time. Conclusion: Morphine co-administration delays the absorption of ticagrelor without altering its systemic clearance or the PK of its active metabolite. These findings suggest that the concomitant use of morphine may delay the antiplatelet effect of ticagrelor, which is critical information for managing acute coronary syndrome patients requiring pain management.
[1] Hobl, E. L., Reiter, B., Schoergenhofer, C., Schwameis, M., Derhaschnig, U., Kubica, J., … & Jilma, B. (2016). Morphine decreases ticagrelor concentrations but not its antiplatelet effects: a randomized trial in healthy volunteers. European journal of clinical investigation, 46(1), 7-14. [2] Buszko, K., Kubica, K., Hobl, E. L., Adamski, P., Wnuk, K., Jilma, B., & Kubica, J. (2021). Pharmacokinetic modeling of morphine’s effect on plasma concentrations of ticagrelor and its metabolite in healthy volunteers. Frontiers in Physiology, 12, 663170.
Reference: PAGE 33 (2025) Abstr 11751 [www.page-meeting.org/?abstract=11751]
Poster: Drug/Disease Modelling - Absorption & PBPK