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A pharmacokinetic interaction study of ticagrelor and digoxin in healthy volunteers

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Purpose

Ticagrelor is a reversibly binding P2Y12 receptor antagonist for the prevention of atherothrombotic events in patients with acute coronary syndrome. Previous in vitro studies showed that ticagrelor is a substrate and inhibitor of P-glycoprotein (ABCB1). Therefore, we examined the potential interaction between digoxin, a P-glycoprotein substrate, and ticagrelor by evaluating the pharmacokinetics, safety, and tolerability.

Methods

This was a randomized, double-blind, two-period crossover study in healthy volunteers (n = 20). Pharmacokinetic parameters of digoxin and ticagrelor were evaluated following co-administration of ticagrelor 400 mg qd or placebo on days 1–16, and digoxin (0.25 mg bid on day 6 and 0.25 mg qd on days 7–14).

Results

Co-administration of ticagrelor increased the digoxin maximum plasma concentration by 75 %, from 1.8 ng/ml to 3.0 ng/ml (Gmean ratio [GMR] 1.75 [95 % CI, 1.52–2.01]); minimum plasma concentration by 31 %, from 0.5 ng/ml to 0.7 ng/ml (GMR 1.31, 1.13–1.52); and mean area under the curve by 28 %, from 16.8 ng · h/ml to 21.0 ng · h/ml (GMR 1.28, 1.12–1.46), compared with placebo. Renal clearance of digoxin was unaffected by the presence of ticagrelor. Digoxin had no effect on the pharmacokinetics of ticagrelor or its active metabolite, AR-C124910XX. Co-administration of ticagrelor and digoxin was well tolerated.

Conclusions

Collectively, these results indicate that ticagrelor is a weak inhibitor of the P-glycoprotein transporter. Based on these findings, it is recommended that serum concentrations of drugs like digoxin (P-glycoprotein transporter substrates with a narrow therapeutic range) are monitored when initiating or changing ticagrelor therapy.

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Acknowledgments

The authors wish to thank Kenneth Lasseter (lead investigator) and the team at the clinical pharmacology unit for conducting the study. Staff at York Bioanalytical Solutions (York, UK) and PPD Development (Richmond, VA, USA) are acknowledged for their contribution to the pharmacokinetic sample analyses. Statistical support was provided by Stephanie Dunbar, PhD. Editorial support in the preparation of this manuscript was provided by David Evans, PhD (Medical Writer, Gardiner-Caldwell Communications).

Funding sources

Editorial support was funded by AstraZeneca.

Authors’ contributions

Both authors participated in research design, performed the data analysis, and wrote or contributed to the writing of the manuscript.

Conflicts of interest

This study was funded by AstraZeneca. The authors are employees of AstraZeneca.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, AstraZeneca LP, FOC W1-677, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE, 19850-5437, USA

    Renli Teng & Kathleen Butler

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Correspondence to Renli Teng.

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Teng, R., Butler, K. A pharmacokinetic interaction study of ticagrelor and digoxin in healthy volunteers. Eur J Clin Pharmacol 69, 1801–1808 (2013). https://doi.org/10.1007/s00228-013-1543-3

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