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

Baldoni, Daniela; Bruderer, Shirin; Krause, Andreas; Gutiérrez, M Rayo; Guéret, P.; Astruc, B; Dingemanse, Jasper

doi:10.1007/s40261-014-0236-8

Cited by 33 publications

(45 citation statements)

References 33 publications

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“…Plasma concentrations of ACT‐246475 were determined using a validated liquid chromatography coupled to tandem mass spectrometry assay with a lower limit of quantification of 1 ng/mL . The method was linear in the concentration range 1‐2000 ng/mL.…”

Section: Methodsmentioning

confidence: 99%

“…ACT‐246475 is a potent, reversible, and selective nonthienopyridine antagonist of the P2Y 12 receptor that is being developed for subcutaneous (SC) self‐administration using an injector for the early treatment intervention of a suspected acute myocardial infarction . Preclinical studies using the ferric chloride model in rats showed that ACT‐246475 displays a wider therapeutic window with respect to bleeding risk than clopidogrel and ticagrelor .…”

mentioning

confidence: 99%

“…Preclinical studies using the ferric chloride model in rats showed that ACT‐246475 displays a wider therapeutic window with respect to bleeding risk than clopidogrel and ticagrelor . In the first‐in‐human study, oral administration of the prodrug (ACT‐281959) and the active moiety ACT‐246475 was well tolerated, characterized by rapid absorption and elimination, but produced low exposure to ACT‐246475 and hence limited pharmacodynamic (PD) effects . A SC formulation of the active moiety ACT‐246475 has recently been developed.…”

mentioning

confidence: 99%

“…ACT-246475 is a potent, reversible, and selective nonthienopyridine antagonist of the P2Y 12 receptor that is being developed for subcutaneous (SC) selfadministration using an injector for the early treatment intervention of a suspected acute myocardial infarction. 11 Preclinical studies using the ferric chloride model in rats showed that ACT-246475 displays a wider therapeutic window with respect to bleeding risk than clopidogrel 12 and ticagrelor. 13 In the first-inhuman study, oral administration of the prodrug (ACT-281959) and the active moiety ACT-246475 was well tolerated, characterized by rapid absorption and elimination, but produced low exposure to ACT-246475 and hence limited pharmacodynamic (PD) effects.…”

mentioning

confidence: 99%

“…13 In the first-inhuman study, oral administration of the prodrug (ACT-281959) and the active moiety ACT-246475 was well tolerated, characterized by rapid absorption and elimination, but produced low exposure to ACT-246475 and hence limited pharmacodynamic (PD) effects. 11 A SC formulation of the active moiety ACT-246475 has recently been developed.…”

mentioning

confidence: 99%

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Clinical Pharmacology of the Reversible and Potent P2Y₁₂ Receptor Antagonist ACT‐246475 After Single Subcutaneous Administration in Healthy Male Subjects

Juif

Boehler

Dobrow³

et al. 2018

The Journal of Clinical Pharma

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ACT-246475 is a selective and reversible P2Y receptor antagonist inducing inhibition of platelet aggregation (IPA). A randomized, double-blind, placebo-controlled, parallel-design study was performed to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating single subcutaneous doses of ACT-246475 (1, 2, 4, 8, 16, or 32 mg) in healthy male subjects (N = 8 per dose, 3:1 active:placebo ratio). Pharmacodynamic effects were assessed based on maximum platelet aggregation and P2Y reaction units using light transmission aggregometry and VerifyNow assays, respectively. ACT-246475 was safe and well tolerated up to 32 mg based on adverse event data and absence of clinically relevant changes in hematology, biochemistry, vital signs, and electrocardiogram variables. Median time to reach maximum plasma concentration was 0.5-0.75 hours, and geometric mean terminal half-life ranged from 1.3 to 9.2 hours across the tested dose range. Exposure to ACT-246475 was dose proportional across all dose groups. The maximal %IPA was reached within 30 minutes after subcutaneous administration of ACT-246475. A dose-dependent duration and extent of effect were observed based on area under the effect curve and maximum effect data. Similar results were observed for maximum platelet aggregation and P2Y reaction units. The %IPA was ≥85% at doses ≥2 mg. This level of %IPA was extended to at least 12 hours in the 32-mg dose group. The safety and pharmacokinetic/pharmacokinetic profile with quick onset and adequate duration of IPA support further investigation in patients with coronary artery disease.

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Section: Methodsmentioning

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Clinical Pharmacology of the Reversible and Potent P2Y₁₂ Receptor Antagonist ACT‐246475 After Single Subcutaneous Administration in Healthy Male Subjects

Juif

Boehler

Dobrow³

et al. 2018

The Journal of Clinical Pharma

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The Case for an Unblinded Modeler in Early Clinical Development

Krause

Henrich

Dingemanse

2019

The Journal of Clinical Pharma

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The current trend for clinical pharmacology is toward more complex studies (eg, umbrella protocols covering single and multiple ascending doses, food effect, metabolism pathways), requiring many decisions to be made during their conduct. This article discusses guidance of such early clinical studies by modeling and simulation. The ability to make use of all available information each time new data become available during the study requires the modeling scientist to be unblinded. This must of course not jeopardize the blinding of the clinical team, and this article discusses how unblinding can be prevented. Although modeling and simulation are established for guidance of the drug development process overall, they are not frequently used for guidance on a small scale, that is, during studies with the largest uncertainty, the first‐in‐human studies. Application of a quantitative model backbone makes early clinical drug development a more efficient process and provides additional safety for healthy subjects and patients. Real clinical impact is illustrated by 3 case studies that show different contributions from unblinded modeling: dose escalation based on safety data, modeling and predicting with explicit incorporation of in vitro data, and dose escalation supported by unblinded analysis of adverse event data, which resulted in new insights of the clinical team without being unblinded and made it possible to proceed with dose escalation and to extend the study with an up‐titration group.

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Pharmacokinetic/pharmacodynamic modeling of drug interactions at the P2Y₁₂ receptor between selatogrel and oral P2Y₁₂ antagonists

Henrich

Claussen²,

Dingemanse

et al. 2021

CPT Pharmacom & Syst Pharma

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

Abstract: 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.

Cited by 33 publications

References 33 publications

Clinical Pharmacology of the Reversible and Potent P2Y₁₂ Receptor Antagonist ACT‐246475 After Single Subcutaneous Administration in Healthy Male Subjects

Clinical Pharmacology of the Reversible and Potent P2Y₁₂ Receptor Antagonist ACT‐246475 After Single Subcutaneous Administration in Healthy Male Subjects

The Case for an Unblinded Modeler in Early Clinical Development

Pharmacokinetic/pharmacodynamic modeling of drug interactions at the P2Y₁₂ receptor between selatogrel and oral P2Y₁₂ antagonists

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

Abstract: 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.

Cited by 33 publications

References 33 publications

Clinical Pharmacology of the Reversible and Potent P2Y12 Receptor Antagonist ACT‐246475 After Single Subcutaneous Administration in Healthy Male Subjects

Clinical Pharmacology of the Reversible and Potent P2Y12 Receptor Antagonist ACT‐246475 After Single Subcutaneous Administration in Healthy Male Subjects

The Case for an Unblinded Modeler in Early Clinical Development

Pharmacokinetic/pharmacodynamic modeling of drug interactions at the P2Y12 receptor between selatogrel and oral P2Y12 antagonists

Contact Info

Product

Resources

About

Clinical Pharmacology of the Reversible and Potent P2Y₁₂ Receptor Antagonist ACT‐246475 After Single Subcutaneous Administration in Healthy Male Subjects

Clinical Pharmacology of the Reversible and Potent P2Y₁₂ Receptor Antagonist ACT‐246475 After Single Subcutaneous Administration in Healthy Male Subjects

Pharmacokinetic/pharmacodynamic modeling of drug interactions at the P2Y₁₂ receptor between selatogrel and oral P2Y₁₂ antagonists