title: Crossover dose escalation study to assess safety, pharmacokinetics, and pharmacodynamics of single doses of R1663, an oral factor Xa inhibitor, in healthy male volunteers.
abstract: This study investigated the safety, pharmacokinetics, and pharmacodynamics of single oral doses of R1663, a factor Xa inhibitor, in healthy volunteers. It was a single-blind, randomized, crossover, placebo-controlled, dose escalation study in 33 healthy male volunteers aged 18 to 45 years. Each volunteer was dosed on 3 occasions with R1663 or placebo. Single oral doses of R1663 were safe and well tolerated. R1663 did not affect bleeding time. Pharmacodynamic effects (prothrombin time [PT], activated partial thromboplastin time [aPTT]), parameters of thrombogram, and anti-factor Xa activity) and plasma concentrations of R1663 were dose-dependent and showed low to moderate (<40%) intersubject and intrasubject variability. Maximum factor Xa inhibition was achieved 3 hours post dose (time to maximum concentration of R1663): clotting times were prolonged up to 2.5-fold, whereas endogenous thrombin potential (ETP) and peak height were decreased by 48% and 85% from their baseline values, respectively. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations, with IC50 values of 182 and 2680 ng/mL for peak height and ETP, respectively. Oral doses of R1663 up to 480 mg were well tolerated, with predictable pharmacodynamics and pharmacokinetics. R1663 prolonged clotting times (PT, aPTT) and inhibited thrombin generation without increasing bleeding time.
authors.affiliation: F. Hoffmann-La Roche Ltd, Hochstrasse 16, 4053 Basel, Switzerland. christophe.schmitt@roche.com
authors.forename: Christophe
authors.initials: C
authors.lastname: Schmitt
authors.forename: Anne
authors.initials: A
authors.lastname: Pannier
authors.forename: Christine
authors.initials: C
authors.lastname: McIntyre
authors.forename: Hagen
authors.initials: H
authors.lastname: Zandt
authors.forename: Cornelia
authors.initials: C
authors.lastname: Ciorciaro
authors.forename: Katie
authors.initials: K
authors.lastname: Winters
authors.forename: Tom
authors.initials: T
authors.lastname: Pepper
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011728:Pyridones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D016037:Single-Blind Method; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013997:Time Factors; D055815:Young Adult
chemical_list: C573820:1-(2,2-difluoroethyl)pyrrolidine-3,4-dicarboxylic acid 3-((5-chloropyridin-2-yl)amide) 4-((2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl)amide); D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011728:Pyridones; D011759:Pyrrolidines; D013917:Thrombin