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Population pharmacokinetic analyses of pozelimab in patients with CD55-deficient protein-losing enteropathy (CHAPLE
Kuan-Ju Lin1, Jeanne Mendell2, John D Davis2
1Regeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Road, Tarrytown, NY, 10591-6707, USA. kuanju.lin@regeneron.com.
Insights
Pozelimab is the first treatment for CHAPLE disease. Pharmacokinetic modeling supported the 10 mg/kg weight-based dose regimen for pozelimab in these patients.
Area of Science:
- Pharmacology
- Immunology
- Genetics
Background:
- CD55-deficient protein-losing enteropathy (CHAPLE) disease is a rare condition.
- Pozelimab is a novel monoclonal antibody targeting C5, approved for CHAPLE disease.
Purpose of the Study:
- To characterize the pharmacokinetics (PK) of pozelimab and C5 in patients with CHAPLE disease.
- To develop a population pharmacokinetic (PopPK) model to support pozelimab dosing.
- To simulate drug exposure and inform the optimal dose regimen.
Main Methods:
- A target-mediated drug disposition (TMDD) PopPK model was developed using data from Phase 1-3 studies.
- The model incorporated data from healthy volunteers, paroxysmal nocturnal hemoglobinuria (PNH) patients, and CHAPLE disease patients.
- Stochastic simulations were used to predict drug concentrations and exposures.
Main Results:
- A two-compartment TMDD model with two binding sites accurately described pozelimab and C5 pharmacokinetics.
- Body weight was the primary source of variability in pozelimab PK.
- The model supported a 10 mg/kg weight-based dose regimen for pozelimab in CHAPLE disease patients.
Conclusions:
- A robust TMDD PopPK model was successfully developed for pozelimab in CHAPLE disease.
- The model enables reliable prediction of individual drug exposures.
- The findings support the established weight-based dosing regimen for pozelimab.
Abstract:
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.
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