Key result
Multiple oral doses of R1663 were safe, well tolerated, and inhibited thrombin generation in a concentration-dependent manner without increasing bleeding time.
Why the study?
Does multiple ascending doses of R1663 demonstrate safety, predictable pharmacokinetics, and pharmacodynamics in healthy volunteers?
RCT (n=64)
Single-blind
Randomised
Does multiple ascending doses of R1663 demonstrate safety, predictable pharmacokinetics, and pharmacodynamics in healthy volunteers?
R1663, a novel oral factor Xa inhibitor, demonstrated a favorable safety profile, linear pharmacokinetics, and predictable pharmacodynamics in healthy volunteers, with no substantial influence of age or gender.
Supports progression to patient trials; extends early pharmacokinetic and pharmacodynamic data for oral factor Xa inhibitors.
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.
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Charoin-Pannier et al. (2012) conducted an RCT in Healthy volunteers (n=64). R1663 vs. Placebo was evaluated on Safety, pharmacokinetics and pharmacodynamics. Multiple oral doses of R1663 were safe, well tolerated, and inhibited thrombin generation in a concentration-dependent manner without increasing bleeding time.
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