Effects of Single-Dose BAY 59-7939 - An Oral, Direct Factor Xa Inhibitor - in Subjects with Extreme Body Weight.

Currently, agents used for the prevention of venous thromboembolism, such as low molecular weight heparins and pentasaccharides, require dose adjustments for patients in extreme weight categories. BAY 59-7939 is a novel, oral, direct Factor Xa (FXa) inhibitor currently undergoing clinical development for the prevention and treatment of thromboembolic disorders. In this single-center, randomized, single-blind, placebo-controlled, parallel-group study, the influence of extremely low and high body weight on the safety, tolerability, pharmacodynamics and pharmacokinetics of a single 10 mg dose of BAY 59-7939 administered with food was investigated. In total, 48 healthy male and female subjects aged 20–54 years and in three different weight groups (≤ 50, 70–80, and >120 kg) were evaluated; 12 received placebo and 36 received BAY 59-7939. The 70–80 kg and >120 kg groups were gender-balanced (six men and six women in each group); the ≤ 50 kg group comprised of 12 women. Overall, BAY 59-7939 was well tolerated. No serious adverse events were reported; all events were of mild to moderate intensity and resolved 7 days after drug administration. The occurrence of adverse events was similar among the weight groups. No adverse events were reported in the placebo group. FXa was inhibited by BAY 59-7939 in all three weight groups, with a maximum inhibition (E_max) of 46.8%, 45.8%, and 41.7% in the ≤ 50, 70–80, and >120 kg groups, respectively; maximum inhibition was observed about 2–3 hours after BAY 59-7939 administration in all three weight groups. AUC for inhibition of Factor Xa activity was comparable for all volunteer groups regardless of the body weight. BAY 59-7939 prolonged prothrombin time (PT), which was less pronounced in the higher weight groups: 1.7 times baseline (tb), 1.6 tb, and 1.5 tb in subjects ≤ 50, 70–80, and >120 kg, respectively. The pharmacodynamic parameters have returned to baseline within 24 hours in all weight groups. Placebo treatment had no effect on PT. The clotting tests activated partial thromboplastin time and HepTest were also distinctly prolonged after drug administration in all weight groups; the prolongation was slightly more pronounced in subjects in the ≤ 50 kg group than in the other weight groups. The bioavailability of BAY 59-7939 as a 10 mg single dose, in terms of AUC of plasma concentrations, was similar in all three weight groups (P=0.205). However, peak plasma concentrations (C_max) were 24% higher in subjects with ≤ 50 kg body weight compared with normal-weight subjects. For subjects >120 kg, C_max was similar to normal-weight subjects. No pharmacokinetic differences between men and women were detected in the normal-weight and >120 kg groups. In conclusion, these data demonstrate that only small influences of body weight on pharmacodynamic or pharmacokinetic parameters are observed which require no dose adjustment of BAY 59-7936 in subjects with extreme body weight.