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A New Reversible and Potent P2Y12 Receptor Antagonist (ACT-246475): Tolerability, Pharmacokinetics, and Pharmacodynamics in a First-in-Man Trial

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Abstract

Background and objectives

ACT-246475 is a new reversible, selective, and potent antagonist of the platelet P2Y12 receptor. This study was a first-in-man trial investigating the tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of ACT-246475 and its di-ester prodrug (ACT-281959) in healthy males.

Methods

The study had a double-blind, randomized, ascending single-dose design with an oral formulation F1 (i.e., ACT-281959 or placebo) (Part I) and an open-label, randomized, 3-period, crossover design comparing exploratory formulations of ACT-281959 (F2) 70 mg and ACT-246475 (dF) 50 mg to F1 70 mg (Part II). In Part I, doses up to 1,000 mg were tested in 40 healthy subjects. Nine healthy subjects were enrolled in Part II. Standard safety parameters, inhibition of platelet aggregation, and ACT-246475 plasma concentrations were measured. Non-compartmental pharmacokinetic analysis was performed.

Results

All doses and formulations were well tolerated. The most frequent adverse event was headache, whereas no events of bleeding or dyspnea were reported. In Part I, ACT-246475 area under the plasma concentration-time curve (AUC) increased dose-proportionally whereas maximum plasma concentration (C max) was less than dose-proportional. The highest C max [geometric mean (95 % CI)] at 1,000 mg was 13.8 (9.7, 19.5) pmol/mL at 4.5 h post-dose, terminal half-life (t ½) was ~10 h. ACT–246475 C max and AUC0–∞ ratios of geometric means (90 % CI) using F1 as reference, for F2 were 8.5 (5.42, 13.35) and 3.4 (2.40, 4.82), respectively, and for dF 2.2 (1.42, 3.49) and 1.5 (1.07, 2.16), respectively. Mean peak platelet inhibition was 31.0 % after F1 (1,000 mg) and 47.8 % after F2.

Conclusions

Oral doses of ACT-281959 and ACT-246475 were well tolerated. Platelet inhibition correlated with ACT-246475 exposure. Exploratory formulations enhanced the bioavailability and antiplatelet effect of ACT-246475.

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Acknowledgements

The contributions of Ines Paule, PhD (Actelion Pharmaceuticals Ltd) for the design and execution of the pharmacokinetic-pharmacodynamic analysis, of Swiss Bioanalytics AG for the bioanalysis of pharmacokinetic samples, of Alexander Treiber, PhD (Actelion Pharmaceuticals Ltd) for the nonclinical (in vitro and in vivo) pharmacokinetic studies, and of Eva Caroff (Actelion Pharmaceuticals Ltd) for providing the chemical structures of the active and the prodrugs are acknowledged. The study was funded by Actelion Pharmaceuticals Ltd. D. Baldoni, S. Bruderer, M. Gutierrez, and J. Dingemanse contributed to the study design and the analysis and interpretation of the data. A. Krause contributed to the pharmacokinetic-pharmacodynamic analysis and outputs; P. Gueret contributed to the setting and the validation of the pharmacodynamic methods and the analysis of the pharmacodynamic clinical data; B. Astruc was the Principal Investigator and was responsible for the conduct of the study and the collection and interpretation of the data. All authors contributed to the preparation and review of the manuscript and approved the final version for submission.

Conflict of interest

The study was funded by Actelion Pharmaceuticals Ltd. D. Baldoni, S. Bruderer, A. Krause, M. Gutierrez, P. Gueret, B. Astruc, and J. Dingemanse had support from Actelion Pharmaceuticals Ltd for the submitted work; D. Baldoni, S. Bruderer, A. Krause, M. Gutierrez, and J. Dingemanse were full-time employees of Actelion Pharmaceuticals Ltd at the time of the study, B. Astruc is a full-time employee of Biotrial, which received funding from Actelion Pharmaceuticals Ltd, P. Gueret is a subcontracted consultant of Biotrial; no other relationships or activities that could appear to have influenced the submitted work. Authors have full control of all primary data and agree to allow the journal to review their data if requested.

Ethical standards

The study was conducted in full conformity with the principles of the Declaration of Helsinki, the EMA Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95), and the laws and regulations of France. The Ouest VI Committee for the Protection of Persons (Ethics Committee) located in Brest (France) approved the study protocol (approval number: CPP Ouest 6 - 701) and all subjects gave written informed consent after full explanation of the research involved and prior to any screening procedures.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland

    Daniela Baldoni, Shirin Bruderer, Andreas Krause, Marcello Gutierrez & Jasper Dingemanse

  2. Hemostasis Unit, University Hospital Pontchaillou, Rennes and GETBO EA 3878, Brest, France

    Pierre Gueret

  3. Biotrial, Rennes, France

    Béatrice Astruc

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  1. Daniela Baldoni
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  2. Shirin Bruderer
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  3. Andreas Krause
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  4. Marcello Gutierrez
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  6. Béatrice Astruc
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  7. Jasper Dingemanse
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Correspondence to Daniela Baldoni.

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Baldoni, D., Bruderer, S., Krause, A. et al. A New Reversible and Potent P2Y12 Receptor Antagonist (ACT-246475): Tolerability, Pharmacokinetics, and Pharmacodynamics in a First-in-Man Trial. Clin Drug Investig 34, 807–818 (2014). https://doi.org/10.1007/s40261-014-0236-8

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