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

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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 (P2Y ₁₂ 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 ( C _max) and area under the plasma concentration curve from time zero to infinity (AUC _0-∞) 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. C _max and AUC _0-∞ 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.

Electronic supplementary material

The online version of this article (10.1007/s00228-018-2484-7) contains supplementary material, which is available to authorized users.

Related collections

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A formula has been developed to predict creatinine clearance (C cr ) from serum creatinine (S cr ) in adult males: Ccr = (140 – age) (wt kg)/72 × S cr (mg/100ml) (15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18–92. Values for C cr were predicted by this formula and four other methods and the results compared with the means of two 24-hour C cr’s measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr·s of 0.83; on average, the difference between predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.

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Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO).

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Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects.

Renli Teng, Stuart Oliver, Martin Hayes … (2010)

Ticagrelor [(1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol)] is a reversibly binding oral P2Y(12) receptor antagonist in development for the prevention of thrombotic events in patients with acute coronary syndromes. The pharmacokinetics, metabolism, and excretion of ticagrelor were investigated over 168 h in six healthy male subjects receiving a single oral suspension dose of 200 mg of [(14)C]ticagrelor. Ticagrelor was rapidly absorbed with a maximum plasma concentration at 1.5 h. The major active metabolite, AR-C124910XX, is formed by O-deethylation. Exposure to AR-C124910XX was 29% of peak and 40% of overall exposure to ticagrelor. In most subjects, radioactivity was undetectable in plasma after 20 h and whole blood after 12 h (half-life values of 6.3 and 4.6 h, respectively). The ratio of radioactivity in plasma to whole blood was 1.69, suggesting that ticagrelor and its metabolites are largely restricted to the plasma space. Mean radioactivity recovery was 26.5% in urine and 57.8% in feces. Major circulating components in the plasma and feces were identified as ticagrelor and AR-C124910XX, whereas in urine the major components were metabolite M5 (AR-C133913XX) and its glucuronide conjugate M4. Levels of unchanged ticagrelor and AR-C124910XX were <0.05% in the urine, indicating that renal clearance of ticagrelor and AR-C124910XX is of minor importance. Interindividual variability was small in both urine and fecal extracts with only small quantitative differences. All 10 of the metabolites were fully or partially characterized and a full biotransformation pathway was proposed for ticagrelor, in which oxidative loss of the hydroxyethyl side chain from ticagrelor forms AR-C124910XX and a second oxidative pathway leads to N-dealkylation of ticagrelor, forming AR-C133913XX.

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Author and article information

Contributors

Renli Teng: +1-484-716-5719 , renli.teng@careceutics.com

Journal

Journal ID (nlm-ta): Eur J Clin Pharmacol

Journal ID (iso-abbrev): Eur. J. Clin. Pharmacol

Title: European Journal of Clinical Pharmacology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0031-6970

ISSN (Electronic): 1432-1041

Publication date (Electronic): 30 May 2018

Publication date PMC-release: 30 May 2018

Publication date (Print): 2018

Volume: 74

Issue: 9

Pages: 1141-1148

Affiliations

[1 ]GRID grid.418152.b, AstraZeneca, ; Gaithersburg, MD USA

[2 ]Careceutics LLC, 2016 Saint Andrews Dr, Berwyn, PA 19312 USA

[3 ]GRID grid.418152.b, AstraZeneca, ; Wilmington, DE USA

[4 ]Skyview Research, Philadelphia, PA USA

[5 ]ISNI 0000 0004 4903 8253, GRID grid.477079.a, DaVita Clinical Research, ; Minneapolis, MN USA

Article

Publisher ID: 2484

DOI: 10.1007/s00228-018-2484-7

PMC ID: 6096709

PubMed ID: 29850937

SO-VID: d9220010-5359-4e9d-a5f7-bf963a332dcf

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.