Population pharmacokinetic analyses of pozelimab in patients with CD55-deficient protein-losing enteropathy (CHAPLE disease).

Autor: Lin KJ; Regeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Road, Tarrytown, NY, 10591-6707, USA. kuanju.lin@regeneron.com., Mendell J; Regeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Road, Tarrytown, NY, 10591-6707, USA., Davis JD; Regeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Road, Tarrytown, NY, 10591-6707, USA., Harnisch LO; Regeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Road, Tarrytown, NY, 10591-6707, USA.
Jazyk: angličtina
Zdroj: Journal of pharmacokinetics and pharmacodynamics [J Pharmacokinet Pharmacodyn] 2024 Dec; Vol. 51 (6), pp. 905-917. Date of Electronic Publication: 2024 Sep 30.
DOI: 10.1007/s10928-024-09941-8
Abstrakt: Pozelimab, a monoclonal antibody directed against C5, is the first and only treatment for adult and pediatric patients (≥ 1 year) with CD55-deficient protein-losing enteropathy (CHAPLE) disease. A target-mediated drug disposition (TMDD) population pharmacokinetic (PopPK) model was developed using pooled data from four phase 1-3 studies to characterize the pharmacokinetics (PK) of total pozelimab and total C5, and to simulate free pozelimab and free C5 to support the dose regimen in patients with CHAPLE disease. A TMDD PopPK model was developed using total pozelimab and total C5 concentration-time data from 106 participants (82 healthy volunteers; 24 patients with paroxysmal nocturnal hemoglobinuria [PNH]). This model was refined and updated to include PK data from 10 patients with CHAPLE disease from a phase 2/3 study. Stochastic simulations predicted concentration-time profiles for total pozelimab, free pozelimab, and free C5, to obtain pozelimab exposure metrics for patients with CHAPLE disease. A two-compartment TMDD model with two binding sites based on the quasi-equilibrium approximation adequately described the concentration-time profiles of total pozelimab and total C5. Body weight was identified as the most important source of pozelimab PK variability; therefore, the dose was adjusted based on body weight for the predominantly pediatric patients with CHAPLE disease. A robust TMDD PopPK model was developed to describe the PK of total pozelimab and total C5 following pozelimab administration. Reliable predictions for individual exposures of total pozelimab and free C5 were possible and supported the 10 mg/kg weight-based dose regimen in patients with CHAPLE disease.
Competing Interests: Declarations. Ethical approval: All studies were conducted in accordance with ethical principles of the Declaration of Helsinki, and were consistent with International Conference on Harmonisation, Good Clinical Practices, and applicable regulatory requirements. Consent to participate: All participants provided consent prior to enrolling in these studies. Competing interests: Kuan-Ju Lin, Jeanne Mendell, John D. Davis, and Lutz Harnisch are all employees of and stockholders in Regeneron Pharmaceuticals, Inc.
(© 2024. The Author(s).)
Databáze: MEDLINE
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