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Randomized Controlled Trial
. 2018 Sep;74(9):1141-1148.
doi: 10.1007/s00228-018-2484-7. Epub 2018 May 30.

Pharmacokinetics and pharmacodynamics of ticagrelor in subjects on hemodialysis and subjects with normal renal function

Renli Teng  1   2 , Sharen Muldowney  3 , Yonggang Zhao  4 , Jolene Kay Berg  5 , Jonathan Lu  3 , Naeem D Khan  3
Affiliations
Randomized Controlled Trial

Pharmacokinetics and pharmacodynamics of ticagrelor in subjects on hemodialysis and subjects with normal renal function

Renli Teng et al. Eur J Clin Pharmacol. 2018 Sep.

Abstract

Purpose: This single-dose, randomized, open-label, parallel-group, and crossover study assessed pharmacokinetics (PK), pharmacodynamics (PD), and safety of ticagrelor in subjects on hemodialysis versus healthy subjects.

Methods: Hemodialysis subjects were randomized, receiving a single ticagrelor 90-mg dose 1 day post-hemodialysis or just before hemodialysis, with an intervening washout of ≥ 7 days. Healthy subjects (creatinine clearance ≥ 90 mL/min) received a single ticagrelor 90-mg dose. PK, PD (P2Y12 reaction units [PRU], inhibition of platelet aggregation [IPA]), and safety were evaluated.

Results: Twenty-seven subjects (14 hemodialysis, 13 healthy) received ticagrelor. The mean maximum plasma concentration (Cmax) and area under the plasma concentration curve from time zero to infinity (AUC0-∞) of ticagrelor were 598.4 ng/mL and 3256.1 ng·h/mL, respectively, in pre-hemodialysis subjects; 560.3 ng/mL and 3015.1 ng·h/mL, respectively, in post-hemodialysis subjects; and 370.8 ng/mL and 2188.8 ng·h/mL, respectively, in healthy subjects. Cmax and AUC0-∞ of AR-C124910XX, the active metabolite, were 152.3 ng/mL and 1144.2 ng·h/mL, respectively, in pre-hemodialysis subjects; 130.8 ng/mL and 1127.8 ng·h/mL, respectively, in post-hemodialysis subjects; and 111.7 ng/mL and 1000.4 ng·h/mL, respectively, in healthy subjects. Mean IPA time curves over 24 h post-dose were almost indistinguishable for all three treatments. The greatest reduction in mean PRU occurred approximately 2 h post-dose for all three treatments. No safety or tolerability issues were identified.

Conclusion: Hemodialysis resulted in modestly higher exposure to ticagrelor and AR-C124910XX, with no clinically significant effect on PD or tolerability. Accordingly, no dose adjustment is required for hemodialysis patients. Timing of hemodialysis has little impact on ticagrelor PK, or the effect of ticagrelor on IPA.

Keywords: Hemodialysis; Pharmacodynamics; Pharmacokinetics; Ticagrelor.

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Conflict of interest statement

Conflict of interest

S. Muldowney and N.D. Khan are employees and shareholders of AstraZeneca. Y. Zhao is a former consultant to AstraZeneca. R. Teng and J. Lu are former employees of AstraZeneca. J. Berg is an employee of DaVita Clinical Research and a principal investigator in the trial.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1
Fig. 1
Mean (SD) of plasma concentration time curves for a ticagrelor and b AR-C124910XX for hemodialysis and healthy subjects. HD hemodialysis, SD standard deviation
Fig. 2
Fig. 2
Mean (SD) inhibition of platelet aggregation (IPA) time curves for ticagrelor in hemodialysis and healthy subjects. HD hemodialysis, SD standard deviation
Fig. 3
Fig. 3
Inhibition of platelet aggregation (IPA) concentration curves for ticagrelor in hemodialysis and healthy subjects. HD hemodialysis
Fig. 4
Fig. 4
Mean (SD) P2Y12 reaction unit (PRU) time curves for ticagrelor in hemodialysis and healthy subjects. HD hemodialysis, SD standard deviation
See this image and copyright information in PMC

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