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Effect of Sex, Use of Pantoprazole and Polymorphisms in SLC22A1, ABCB1, CES1, CYP3A5 and CYP2D6 on the Pharmacokinetics and Safety of Dabigatran

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Abstract

Introduction

Dabigatran is a direct oral anticoagulant (DOAC) used for the treatment of several thrombotic conditions. To date, very few pharmacogenetic studies on dabigatran were published. We aimed to investigate the influence of 59 polymorphisms in 15 genes (including CES1, UGT and CYP that encode enzymes and ABCB1 and SLC that encode transporters), concomitant treatment with pantoprazole and demographic characteristics (including sex or race) on dabigatran pharmacokinetics and safety.

Methods

This was a candidate gene pharmacogenetic study. The study population comprised 107 volunteers enrolled in two dabigatran bioequivalence clinical trials; they were genotyped with a ThermoFisher QuantStudio 12K Flex OpenArray instrument. SPSS software v.21 was used for statistical analysis.

Results

Women showed a higher exposure to dabigatran compared to men. The concomitant treatment with pantoprazole was associated with a decreased exposure to the drug. CYP2D6 poor metabolizers (PMs) were related to lower clearance (Cl/F) (p = 0.049) and a tendency was observed towards higher area under the curve (AUC), maximum concentration (Cmax) and to lower volume of distribution (Vd/F) (p < 0.10). SLC22A1 haplotype was related to pharmacokinetic variability (p < 0.05). The remaining genes (including CYP, UGT1A1 and ABCB1) had no effect on dabigatran pharmacokinetics (p > 0.10). Women showed more adverse drug reactions (ADR) compared to men (0.40 ± 0.68 vs 0.15 ± 0.41 ADR per person, p = 0.03) and SLC22A1 mutant haplotype was related to a lower risk of nausea (p = 0.02).

Conclusion

Sex, concomitant use of pantoprazole and SLC22A1, CYP2D6 and CYP3A5 polymorphism had an effect on dabigatran pharmacokinetics and safety. Previously published pharmacogenetic predictors, namely CES1 or ABCB1 polymorphisms, had no effect on pharmacokinetics and safety. This study is of interest as it increases the scarce pharmacogenetic information on dabigatran.

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Acknowledgements

The authors are thankful to the volunteers and the effort of the staff of the Clinical Trial Unit of Hospital Universitario de La Princesa.

Funding

D. Koller is financed by the H2020 Marie Sklodowska-Curie Innovative Training Network 721236 grant. Marcos Navares-Gómez is co-financed by the European Social Fund and the Youth European Initiative, grant number PEJ-2018-TL/BMD-11080. No Rapid Service Fee was received by the journal for the publication of this article.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authorship Contributions

Pablo Zubiaur, Miriam Saiz-Rodríguez, Dolores Ochoa, Marcos Navares-Gómez, Gina Mejía, Manuel Román, Dora Koller, Paula Soria-Chacartegui, Susana Almenara and Francisco Abad-Santos contributed to drafting and revising the manuscript. Pablo Zubiaur and Francisco Abad-Santos designed the research. Pablo Zubiaur, Miriam Saiz-Rodríguez, Marcos Navares-Gómez, Dora Koller and Paula Soria-Chacartegui conducted all experiments and statistical analyses.

Disclosures

Francisco Abad-Santos and Dolores Ochoa have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Cinfa, FAES Farma, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Italfarmaco, Janssen-Cilag, Kern Pharma, Normon, Novartis, Servier, Silverpharma, Teva, and Zambon. Pablo Zubiaur, Miriam Saiz-Rodríguez, Marcos Navares-Gómez, Gina Mejía, Manuel Román, Dora Koller, Paula Soria-Chacartegui and Susana Almenara have nothing to disclose.

Compliance with Ethics Guidelines

The study population comprised healthy volunteers enrolled in two bioequivalence clinical trials performed in the clinical trial unit of Hospital Universitario de La Princesa (UECHUP), Madrid (Spain). They were accomplished under the guidelines of Good Clinical Practice and complied with Spanish legislation on clinical research in humans. Both were approved and authorised by the Hospital’s Research Ethics Committee (CEIm) (protocol numbers 3646 and 3736, respectively) and the Spanish Drugs Agency (AEMPS). All subjects gave their informed consent for the clinical trial and 107 of them for the pharmacogenetic study. This research complied with international standards, including the Declaration of Helsinki 1964 and its later amendments.

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Authors and Affiliations

  1. Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Faculty of Medicine, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain

    Pablo Zubiaur, Miriam Saiz-Rodríguez, Dolores Ochoa, Marcos Navares-Gómez, Gina Mejía, Manuel Román, Dora Koller, Paula Soria-Chacartegui, Susana Almenara & Francisco Abad-Santos

  2. Unidad de Investigación Clínica y Ensayos Clínicos (UICEC) del Hospital Universitario de La Princesa, Plataforma SCReN (Spanish Clinical Research Network), Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain

    Pablo Zubiaur, Dolores Ochoa, Gina Mejía, Manuel Román & Francisco Abad-Santos

  3. Research Unit of Hospital Universitario de Burgos (HUBU), Castilla y León, Spain

    Miriam Saiz-Rodríguez

  4. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain

    Francisco Abad-Santos

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  1. Pablo Zubiaur
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Corresponding author

Correspondence to Francisco Abad-Santos.

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Zubiaur, P., Saiz-Rodríguez, M., Ochoa, D. et al. Effect of Sex, Use of Pantoprazole and Polymorphisms in SLC22A1, ABCB1, CES1, CYP3A5 and CYP2D6 on the Pharmacokinetics and Safety of Dabigatran. Adv Ther 37, 3537–3550 (2020). https://doi.org/10.1007/s12325-020-01414-x

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