A semi-mechanistic absorption model to evaluate drug–drug interaction with dabigatran: application with clarithromycin

Authors

  • Xavier Delavenne,

    Corresponding author
    1. Université de Lyon, Saint-Etienne
    2. Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, Saint-Etienne
    • Laboratoire de Pharmacologie Toxicologie, CHU Saint-Etienne, Saint-Etienne
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  • Edouard Ollier,

    1. Laboratoire de Pharmacologie Toxicologie, CHU Saint-Etienne, Saint-Etienne
    2. Université de Lyon, Saint-Etienne
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  • Thierry Basset,

    1. Laboratoire de Pharmacologie Toxicologie, CHU Saint-Etienne, Saint-Etienne
    2. Université de Lyon, Saint-Etienne
    3. Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, Saint-Etienne
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  • Laurent Bertoletti,

    1. Université de Lyon, Saint-Etienne
    2. Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, Saint-Etienne
    3. Service de Médecine Thérapeutique, CHU de Saint-Etienne, Saint-Etienne
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  • Sandrine Accassat,

    1. Service de Médecine Thérapeutique, CHU de Saint-Etienne, Saint-Etienne
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  • Arnauld Garcin,

    1. Déperpartement d'anesthésie Réanimation, CHU de Saint-Etienne, Saint-Etienne
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  • Silvy Laporte,

    1. Université de Lyon, Saint-Etienne
    2. Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, Saint-Etienne
    3. Unité de Recherche Clinique Innovation et Pharmacologie, CHU de Saint-Etienne, Saint Etienne, France
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  • Paul Zufferey,

    1. Université de Lyon, Saint-Etienne
    2. Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, Saint-Etienne
    3. Déperpartement d'anesthésie Réanimation, CHU de Saint-Etienne, Saint-Etienne
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  • Patrick Mismetti

    1. Université de Lyon, Saint-Etienne
    2. Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, Saint-Etienne
    3. Service de Médecine Thérapeutique, CHU de Saint-Etienne, Saint-Etienne
    4. Unité de Recherche Clinique Innovation et Pharmacologie, CHU de Saint-Etienne, Saint Etienne, France
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Correspondence

Dr Xavier Delavenne, EA3065, Laboratory of Pharmacology and Toxicology, University Hospital of Saint-Etienne, 42055 Saint-Etienne, France.

Tel.: +334 7712 0572

Fax: +334 7712 7820

E-mail: xavier.delavenne@chu-st-etienne.fr

Abstract

Aim

The aim of this study was to develop a PK/PD model to assess drug–drug interactions between dabigatran and P-gp modulators, using the example of clarithromycin, a strong inhibitor of P-gp.

Methods

Ten healthy male volunteers were randomized to receive in the first treatment period a single 300 mg dose of dabigatran etexilate (DE) and in the second treatment period 500 mg clarithromycin twice daily during 3 days and then 300 mg DE plus 500 mg clarithromycin on the fourth day, or the same treatments in the reverse sequence. Dabigatran plasma concentration and ecarin clotting time (ECT) were measured on 11 blood samples. Models were built using a non-linear mixed effect modelling approach.

Results

The best PK model was based on an inverse Gaussian absorption process with two compartments. The relationship between dabigatran concentration and ECT was implemented as a linear function. No continuous covariate was associated with a significant decrease in the objective function. The concomitant administration of clarithromycin induced a significant change only in DE bioavailability, which increased from 6.5% to 10.1% in the presence of clarithromycin. Clarithromycin increased peak concentration and AUC by 60.2% and 49.1% respectively.

Conclusion

The model proposed effectively describes the complex PK of dabigatran and takes into account drug–drug interactions with P-gp activity modulators, such as clarithromycin.

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