Direct comparison of two extended-half-life recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A.

BAY 94-9027 is an extended-half-life, recombinant factor VIII (rFVIII) product conjugated with a 60-kDa branched polyethylene glycol (PEG) molecule indicated for use in previously treated patients (aged ≥ 12 years) with hemophilia A. This randomized, open-label, two-way crossover study compared the pharmacokinetics (PK) of BAY 94-9027 and rFVIII Fc fusion protein (rFVIIIFc) in patients with hemophilia A. Patients aged 18-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII were randomized to receive intravenous single-dose BAY 94-9027 60 IU/kg followed by rFVIIIFc 60 IU/kg or vice versa, with ≥ 7-day wash-out between doses. FVIII activity was measured by one-stage assay. PK parameters, including area under the curve from time 0 to the last data point (AUClast, primary parameter), half-life, and clearance were calculated. Eighteen patients were randomized and treated. No adverse events were observed. In the analysis set excluding one outlier, geometric mean (coefficient of variation [%CV, 95% confidence interval {CI}]) AUClast was significantly higher for BAY 94-9027 versus rFVIIIFc (2940 [37.8, 2440-3550] IU h/dL versus 2360 [31.8, 2010-2770] IU h/dL, p = 0.0001). A population PK model was developed to simulate time to reach FVIII threshold levels; median time to 1 IU/dL was approximately 13 h longer for BAY 94-9027 versus rFVIIIFc after a single infusion of 60 IU/kg. In conclusion, BAY 94-9027 had a superior PK profile versus rFVIIIFc. ClinicalTrials.gov : NCT03364998.

H(C)Ag: a triple resonance NMR experiment for (109) Ag detection in labile silver-carbene complexes.

In silver complexes, indirect detection of (109) Ag resonances via (1) H,(109) Ag-HMQC frequently suffers from small or absent JHAg couplings or rapid ligand dissociation. In these cases, it would be favourable to employ H(X)Ag triple resonance spectroscopy that uses the large one-bond JXAg coupling (where the donor atom of the ligand X is the relay nucleus). We have applied an HMQC-based version of the H(C)Ag experiment to a labile silver-NHC complex (NHC=N-heterocyclic carbene) at natural (13) C isotopic abundance and variable temperature. In agreement with simulations, H(C)Ag detection became superior to (1) H,(109) Ag-HMQC detection above -20 °C.

First randomized evaluation of safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, an antibody targeting coagulation factor XI and factor XIa, in healthy men.

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.