title: Safety, pharmacokinetics and pharmacodynamics of multiple ascending doses of R1663, an oral factor Xa inhibitor, in healthy young subjects coupled with exploration of influence of gender and age.
abstract: This study investigated the safety, pharmacokinetics and pharmacodynamics of multiple oral doses of R1663, a factor Xa inhibitor, and explored the influence of age and gender on pharmacokinetics and pharmacodynamics of R1663. This was a single-blind, randomised, placebo-controlled, dose escalation study in 48 healthy male volunteers aged 18 to 44 years. R1663 doses up to 300 mg twice daily or 400 mg once daily were administered for seven days. The exploration of gender and age effect was carried out in separate cohorts of eight male and eight female volunteers aged 45 to 65 years. Multiple oral doses of R1663 were safe and well tolerated. Pharmacokinetics was linear and showed moderate variability. Plasma concentrations peaked at 3 hour. Terminal half-life at steady state was 3-5 hours. Accumulation of R1663 was minimal. R1663 prolonged clotting times, inhibited thrombin generation (peak height and endogenous thrombin potential [ETP]) and anti-factor Xa activity in a concentration-dependent manner without increasing bleeding time. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations. The inhibition was more pronounced on peak height (IC₅₀ = 194 ng/ml) than on ETP (2790 ng/ml). Pharmacokinetics and pharmacodynamics of R1663 appeared not to be substantially affected by age or gender but remained to be confirmed in larger clinical trials including older patients. Meanwhile, dose adjustments based on age and gender are not anticipated.
authors.affiliation: Christophe Schmitt, F. Hoffmann-La Roche AG., Department of Clinical Pharmacology, CH-4070 Basel, Switzerland. christophe.schmitt@roche.com
authors.forename: Christophe
authors.initials: C
authors.lastname: Schmitt
authors.forename: Anne
authors.initials: A
authors.lastname: Charoin-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: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D012737:Sex 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); D065427:Factor Xa Inhibitors; D011728:Pyridones; D011759:Pyrrolidines