Background
Coagulation factor
XI
(
FXI
) contributes to the development of thrombosis but appears to play only a minor role in hemostasis and is therefore an attractive anticoagulant drug target.
Objectives
To evaluate the safety, pharmacodynamic, and pharmacokinetic properties of
BAY
1213790, a fully human immunoglobulin (Ig) G1 antibody targeting activated coagulation
FXI
(
FXI
a), in healthy men.
Methods
In this phase 1, single‐blind, parallel‐group, placebo‐controlled, dose‐escalation study, 83 healthy Caucasian men were randomized 4:1 to receive a single 60‐minute intravenous infusion of
BAY
1213790 (0.015‐10 mg/kg) or placebo. Adverse events, pharmacodynamic parameters (including activated partial thromboplastin time [
aPTT
]) and pharmacokinetic parameters were determined. Volunteers were followed up for 150 days.
Results
BAY
1213790 demonstrated favorable safety and tolerability; there were no observed cases of bleeding or clinically relevant antidrug antibody formation. One volunteer (1.2%) experienced an infusion reaction. Following intravenous administration of
BAY
1213790, dose‐dependent increases in
aPTT
(maximal mean increase relative to baseline: 1.85 [conventional method] and 2.17 [kaolin‐triggered method]) and rotational thromboelastometry whole blood clotting time were observed, as well as dose‐dependent reductions in
FXI
activity. Bleeding times did not increase following administration of
BAY
1213790 and were similar for all dose cohorts, including placebo. Measurable and dose‐dependent increases in systemic exposure were detected for all doses of
BAY
1213790 of 0.06 mg/kg or higher.
Conclusions
Based on these safety, pharmacodynamic, and pharmacokinetic results, further evaluation of
BAY
1213790 in patients with, or at risk of, thrombosis is warranted.
Paclitaxel is a commonly used cytotoxic anticancer drug with potentially life-threatening toxicity at therapeutic doses and high interindividual pharmacokinetic variability. Thus, drug and effect monitoring is indicated to control dose-limiting neutropenia. Joerger et al. (2016) developed a dose individualization algorithm based on a pharmacokinetic (PK)/pharmacodynamic (PD) model describing paclitaxel and neutrophil concentrations. Furthermore, the algorithm was prospectively compared in a clinical trial against standard dosing (Central European Society for Anticancer Drug Research Study of Paclitaxel Therapeutic Drug Monitoring; 365 patients, 720 cycles) but did not substantially improve neutropenia. This might be caused by misspecifications in the PK/PD model underlying the algorithm, especially without consideration of the observed cumulative pattern of neutropenia or the platinum-based combination therapy, both impacting neutropenia. This work aimed to externally evaluate the original PK/PD model for potential misspecifications and to refine the PK/PD model while considering the cumulative neutropenia pattern and the combination therapy. An underprediction was observed for the PK (658 samples), the PK parameters, and these parameters were re-estimated using the original estimates as prior information. Neutrophil concentrations (3274 samples) were overpredicted by the PK/PD model, especially for later treatment cycles when the cumulative pattern aggravated neutropenia. Three different modeling approaches (two from the literature and one newly developed) were investigated. The newly developed model, which implemented the bone marrow hypothesis semiphysiologically, was superior. This model further included an additive effect for toxicity of carboplatin combination therapy. Overall, a physiologically plausible PK/PD model was developed that can be used for dose adaptation simulations and prospective studies to further improve paclitaxel/carboplatin combination therapy.
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