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Effect of rifampicin on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Purpose

Ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, is predominantly metabolized by cytochrome P450 3A and both the parent compound and its active metabolite AR-C124910XX are substrates of P-glycoprotein. Rifampicin was used to assess the effects of CYP3A and P-glycoprotein induction on the single-dose pharmacokinetics and pharmacodynamics of ticagrelor.

Methods

Healthy volunteers received a single 180 mg oral dose of ticagrelor on days 1 and 15, and a once-daily 600 mg dose of rifampicin on days 4–17. Ticagrelor and AR-C124910XX plasma concentrations were quantified for pharmacokinetic analysis (n = 14); inhibition of platelet aggregation (IPA) was also assessed (n = 14).

Results

Compared with administration of ticagrelor alone, co-administration of ticagrelor and rifampicin significantly decreased the maximum plasma concentration (Cmax) of ticagrelor from 1091 to 297.8 ng/ml, area under the plasma concentration-time curve from time zero to infinity (AUC) of ticagrelor from 6225 to 864.0 ng.h/ml, and also decreased plasma half-life of ticagrelor from 8.4 to 2.8 h; reductions of 73 %, 86 % and 67 % respectively. With rifampicin, AR-C124910XX Cmax was unaffected, AUC was significantly decreased by 46 %, and metabolite to parent ratio for AUC increased fourfold. Although maximal IPA was unaffected, offset of ticagrelor-mediated IPA was more rapid in the presence of rifampicin; a significant reduction (27 %) in the area under the effect curve between 0 and 24 h was observed following co-administration with rifampicin.

Conclusion

Co-administration with rifampicin reduced ticagrelor exposure and resulted in a more rapid offset of ticagrelor-mediated IPA. Co-administration of strong CYP3A/P-glycoprotein inducers with ticagrelor should be discouraged.

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Acknowledgments

Medical writing support was provided by David Evans at Gardiner-Caldwell Communications, and was funded by AstraZeneca.

Conflict of interest

All authors are employees of, and this study was funded by, AstraZeneca LP (Wilmington, Delaware, USA).

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Authors and Affiliations

  1. Clinical Pharmacology, AstraZeneca LP, OW3-117, 1800 Concord Pike, PO Box 15437, Wilmington, DE, 19850-5437, USA

    Renli Teng, Patrick Mitchell & Kathleen Butler

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  1. Renli Teng
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  2. Patrick Mitchell
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Correspondence to Renli Teng.

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Teng, R., Mitchell, P. & Butler, K. Effect of rifampicin on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects. Eur J Clin Pharmacol 69, 877–883 (2013). https://doi.org/10.1007/s00228-012-1436-x

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  • DOI: https://doi.org/10.1007/s00228-012-1436-x

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