Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939--an oral, direct Factor Xa inhibitor--after multiple dosing in healthy male subjects.
OBJECTIVE
There is a clinical need for safe new oral anticoagulants. The safety, tolerability, pharmacodynamics, and pharmacokinetics of BAY 59-7939--a novel, oral, direct Factor Xa (FXa) inhibitor--were investigated in this single-center, placebo-controlled, single-blind, parallel-group, multiple-dose escalation study.


METHODS
Healthy male subjects (aged 20-45 years, body mass index 18.6-31.4 kg/m(2)) received oral BAY 59-7939 (n=8 per dose regimen) or placebo (n=4 per dose regimen) on days 0 and 3-7. Dosing regimens were 5 mg once, twice (bid), or three times daily, and 10 mg, 20 mg, or 30 mg bid.


RESULTS
There were no clinically relevant changes in bleeding time or other safety variables across all doses and regimens. There was no dose-related increase in the frequency or severity of adverse events with BAY 59-7939. Maximum inhibition of FXa activity occurred after approximately 3 h, and inhibition was maintained for at least 12 h for all doses. Prothrombin time, activated partial thromboplastin time, and HepTest were prolonged to a similar extent to inhibition of FXa activity for all doses. Dose-proportional pharmacokinetics (AUC(tau, norm) and C(max, norm)) were observed at steady state (day 7). Maximum plasma concentrations were achieved after 3-4 h. The terminal half-life of BAY 59-7939 was 5.7-9.2 h at steady state. There was no relevant accumulation at any dose.


CONCLUSIONS
BAY 59-7939 was safe and well tolerated across the wide dose range studied, with predictable, dose-proportional pharmacokinetics and pharmacodynamics and no relevant accumulation beyond steady state. These results support further investigation of BAY 59-7939 in phase II clinical trials.
Kubitza
Dagmar
D
Institute of Clinical Pharmacology, Bayer HealthCare AG, 42096 Wuppertal, Germany. dagmar.kubitza@bayerhealthcare.com
Becka
Michael
M
Wensing
Georg
G
Voith
Barbara
B
Zuehlsdorf
Michael
M
D000284:Administration, Oral; D000328:Adult; D000990:Antithrombin III / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069552:Rivaroxaban; D016037:Single-Blind Method; D013876:Thiophenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D009025:Morpholines; D013876:Thiophenes; D000990:Antithrombin III; D000069552:Rivaroxaban