RESUMO
BACKGROUND: Bleeding is a clinically significant issue with all current anticoagulants. Safer antithrombotic strategies are required. OBJECTIVES: To investigate the safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, a humanized, factor XI (FXI)-directed monoclonal antibody, after single intravenous (i.v.) or subcutaneous (s.c.) doses in healthy volunteers. PATIENTS/METHODS: In a first-in-human, phase I study, 70 volunteers were randomly assigned (4:1) to receive single-dose BAY 1831865 (3.5, 7, 17, 35, 75, or 150 mg i.v. or 150 mg s.c.) or placebo. Adverse events, pharmacodynamics, and pharmacokinetics were evaluated. RESULTS: In this study, no hemorrhage, or hypersensitivity or infusion-/injection-related reactions were reported. Drug-related adverse events occurred in 3 (5.4%) of 56 volunteers; all were mild and self-limited. Dose-dependent prolongation of activated partial thromboplastin time (aPTT) and inhibition of FXI clotting activity was observed with BAY 1831865 i.v. (geometric mean maximum ratio-to-baseline: aPTT, range, 1.09-3.11 vs. 1.05 with placebo; FXI, range, 0.70-0.04 vs. 0.91 with placebo). Onset of effect was rapid after i.v. administration, with duration of effect (up to 55 days) determined by dose. BAY 1831865 s.c. had similar pharmacodynamic effects but a slower onset of action. Terminal half-life increased continuously with increasing i.v. dose (range, 28-208 h), leading to strong and continuous increases in systemic exposure to BAY 1831865. Absolute bioavailability of BAY 1831865 s.c. was 47.2% (95% confidence interval, 30.2-73.7). CONCLUSIONS: BAY 1831865 i.v. or s.c. was well tolerated, with no evidence of bleeding in healthy volunteers. BAY 1831865 exhibited pronounced, sustained dose-dependent prolongation of aPTT and duration of FXI inhibition.
Assuntos
Anticoagulantes , Fator XIa , Anticorpos Monoclonais Humanizados/farmacologia , Anticoagulantes/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Humanos , Masculino , Tempo de Tromboplastina ParcialRESUMO
Feeding of margarines containing sitostanol (CAS 19466-47-8), sitostanol acetate (CAS 73052-08-1), sitostanol oleate (CAS 107615-79-2), or placebo (equivalent of 0.5 g of sitostanol t.i.d) on cholesterol absorption and serum lipids were studied in 10 normolipemic volunteers in a randomized double blind cross-over trial. The study was divided into an open one-week run-in phase and four one-week treatment periods. Each treatment week was followed by a two-week washout period. Measurements of cholesterol absorption was performed by the continuous isotope feeding method using stable isotope labeled cholesterol and sitostanol. Cholesterol absorption during placebo, sitostanol, sitostanol acetate and sitostanol oleate feeding averaged 41.6 +/- (SD) 8.0, 10.2 +/- 6.6, 17.0 +/- 6.7, and 20.5 +/- 5.3%, respectively (p < 0.001 for all against placebo). Low density lipoprotein (LDL) cholesterol was proportionally reduced by 22 (p < 0.001), 14 (p < 0.05), and 8% (ns). Absorption efficiency was significantly lower with free sitostanol than with sitostanol acetate or oleate (p < 0.01). Percent reduction in cholesterol absorption with all preparations compared to placebo correlated positively with the percent reduction in LDL cholesterol (r = 0.404; p < 0.03). The results indicate that unesterified sitostanol is more effective in inhibiting cholesterol absorption and reducing LDL cholesterol than the acetate or oleate esters.