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Thromb Haemost 2012; 108(01): 54-64
DOI: 10.1160/TH12-01-0023
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

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

Christophe Schmitt
1   F. Hoffmann-La Roche AG, Basel, Switzerland
,
Anne Charoin-Pannier
1   F. Hoffmann-La Roche AG, Basel, Switzerland
,
Christine McIntyre
1   F. Hoffmann-La Roche AG, Basel, Switzerland
,
Hagen Zandt
1   F. Hoffmann-La Roche AG, Basel, Switzerland
,
Cornelia Ciorciaro
1   F. Hoffmann-La Roche AG, Basel, Switzerland
,
Katie Winters
2   Roche Products Ltd., Welwyn Garden City, UK
,
Tom Pepper
2   Roche Products Ltd., Welwyn Garden City, UK
› Author Affiliations Financial support: This study was sponsored by Roche.
Further Information

Publication History

Received: 17 January 2012

Accepted after minor revision: 09 April 2012

Publication Date:
22 November 2017 (online)

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Summary

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.

Keywords

Factor Xa inhibitor - multiple ascending dose study - healthy volunteers - gender and age effect
 

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