Clinical Pharmacokinetics and Pharmacodynamics of Marstacimab, an Anti-tissue Factor Pathway Inhibitor Monoclonal Antibody, in Adolescent and Adult Participants with Hemophilia.

BACKGROUND AND OBJECTIVES: Marstacimab, a monoclonal antibody that targets tissue factor pathway inhibitor (TFPI), was developed for prophylactic treatment of hemophilia, with or without inhibitors. A nonlinear mixed-effects modeling approach was used to characterize plasma marstacimab and TFPI concentrations and identify covariates impacting marstacimab concentration. METHODS: Population modeling using nonlinear mixed-effects modeling (NONMEM) 7.5.0 software was performed with marstacimab and total TFPI concentration data pooled from 213 participants across 6 clinical trials including healthy volunteers (n = 63) and participants with hemophilia (n = 150). Participants received subcutaneous marstacimab at doses ranging from 30 mg to 450 mg. Plasma samples to determine marstacimab and total TFPI were analyzed using validated assays. An Emax pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to link model-predicted free TFPI concentrations to peak thrombin. RESULTS: Marstacimab and total TFPI concentrations were adequately described with a target mediated drug disposition (TMDD) model with nonlinear clearance. Body weight was the key structural covariate. After adjusting for body weight, no clinically relevant effect of age (adolescent vs adult), race (Asian vs non-Asian), participant status (healthy vs hemophilia) or mild hepatic impairment was seen. There was good agreement between observed and model-predicted peak thrombin levels in adults and adolescents, with no clinically relevant differences between the populations. CONCLUSIONS: A TMDD model with first-order absorption and quasi-steady-state approximation adequately characterized marstacimab PK and total TFPI concentrations. An Emax model adequately described the relationship between model-predicted free TFPI and peak thrombin. The PK/PD simulation indicated that no changes in dosing regimen based on age or body weight were warranted. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT02531815, NCT02974855, NCT03363321, NCT03938792, NCT04832139, NCT04878731.