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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

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Abstract

Background

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.

Methods

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.

Results

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(\({k}_{a}\)) 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.

Conclusion

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.

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Authors and Affiliations

  1. Department of Medical Pharmacology, University of Reims Champagne-Ardenne (URCA), HERVI EA 3801, Reims University Hospital, 51100, Reims, France

    Celine Konecki & Zoubir Djerada

  2. Department of Pharmacology and Toxicology, Reims University Hospital, 51100, Reims, France

    Celine Konecki & Zoubir Djerada

  3. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    Manne Holm

  4. Karolinska University Hospital, Perioperative Medicine and Intensive Care, B31, Huddinge, Sweden

    Manne Holm

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Correspondence to Zoubir Djerada.

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Funding

The original studies were funded by a non-restricted research grant from Astra Zeneca (NSTEMI/CCS study) and a grant from the Swedish Heart and Lung foundation (MOVEMENT trial); however, the present study received no funding.

Conflicts of interest

Celine Konecki, Manne Holm, and Zoubir Djerada have no conflicts to disclose.

Ethics approval

The studies were conducted in accordance with the Declaration of Helsinki and were approved by the regional ethical review board in Stockholm.

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Written informed consent was obtained from all subjects in both studies.

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Not applicable.

Availability of data and material

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Author contributions

CK, MH and ZD wrote the manuscript, performed the research, analyzed the data, and validated the manuscript. MH and ZD designed the research.

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Konecki, C., Holm, M. & Djerada, Z. 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. Clin Pharmacokinet 62, 905–920 (2023). https://doi.org/10.1007/s40262-023-01243-5

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