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.
RCT Entities:
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.
Authors: Sidney C Smith; Jerilyn Allen; Steven N Blair; Robert O Bonow; Lawrence M Brass; Gregg C Fonarow; Scott M Grundy; Loren Hiratzka; Daniel Jones; Harlan M Krumholz; Lori Mosca; Richard C Pasternak; Thomas Pearson; Marc A Pfeffer; Kathryn A Taubert Journal: Circulation Date: 2006-05-16 Impact factor: 29.690
Authors: Thomas Gremmel; Sabine Steiner; Daniela Seidinger; Renate Koppensteiner; Simon Panzer; Christoph W Kopp Journal: Thromb Haemost Date: 2009-02 Impact factor: 5.249
Authors: Jeffrey L Anderson; Cynthia D Adams; Elliott M Antman; Charles R Bridges; Robert M Califf; Donald E Casey; William E Chavey; Francis M Fesmire; Judith S Hochman; Thomas N Levin; A Michael Lincoff; Eric D Peterson; Pierre Theroux; Nanette Kass Wenger; R Scott Wright; Sidney C Smith Journal: Circulation Date: 2011-03-28 Impact factor: 29.690
Authors: Elliott M Antman; Daniel T Anbe; Paul Wayne Armstrong; Eric R Bates; Lee A Green; Mary Hand; Judith S Hochman; Harlan M Krumholz; Frederick G Kushner; Gervasio A Lamas; Charles J Mullany; Joseph P Ornato; David L Pearle; Michael A Sloan; Sidney C Smith; Joseph S Alpert; Jeffrey L Anderson; David P Faxon; Valentin Fuster; Raymond J Gibbons; Gabriel Gregoratos; Jonathan L Halperin; Loren F Hiratzka; Sharon Ann Hunt; Alice K Jacobs Journal: Circulation Date: 2004-08-31 Impact factor: 29.690
Authors: Keith A A Fox; Shamir R Mehta; Ron Peters; Feng Zhao; Nasser Lakkis; Bernard J Gersh; Salim Yusuf Journal: Circulation Date: 2004-08-16 Impact factor: 29.690
Authors: Kenneth A Jacobson; Esmerilda G Delicado; Christian Gachet; Charles Kennedy; Ivar von Kügelgen; Beibei Li; M Teresa Miras-Portugal; Ivana Novak; Torsten Schöneberg; Raquel Perez-Sen; Doreen Thor; Beili Wu; Zhenlin Yang; Christa E Müller Journal: Br J Pharmacol Date: 2020-04-06 Impact factor: 9.473
Authors: Robert F Storey; Paul A Gurbel; Jurrien Ten Berg; Corine Bernaud; George D Dangas; Jean-Marie Frenoux; Diana A Gorog; Abdel Hmissi; Vijay Kunadian; Stefan K James; Jean-Francois Tanguay; Henry Tran; Dietmar Trenk; Mike Ufer; Pim Van der Harst; Arnoud W J Van't Hof; Dominick J Angiolillo Journal: Eur Heart J Date: 2020-09-01 Impact factor: 29.983