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Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria. | LitMetric

AI Article Synopsis

  • Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder that can cause severe hemolysis and blood clots, and the new therapy pegcetacoplan aims to improve patient outcomes by targeting both types of hemolysis.
  • The analysis of data from clinical studies showed that administering pegcetacoplan at a dose of 1080 mg twice weekly resulted in effective and stable levels in the body, along with significant improvements in blood biomarkers related to hemolysis within four weeks.
  • Factors such as body weight and previous treatments influenced drug exposure and responses, but these effects were not significant enough to alter treatment effectiveness, supporting the approved dosage for optimal patient care.

Article Abstract

Background And Objective: Paroxysmal nocturnal hemoglobinuria is a rare blood disorder characterized by life-threatening hemolysis and thrombosis. Complement C5 inhibitor therapy improves symptoms and life prognosis; however, it can result in insufficient hemolysis control, with residual intravascular hemolysis and extravascular hemolysis in some patients. Pegcetacoplan, the first complement C3 inhibitor approved for patients with paroxysmal nocturnal hemoglobinuria, targets both intravascular and extravascular hemolysis. This analysis evaluated population pharmacokinetic/pharmacodynamic profiles of pegcetacoplan.

Methods: Pooled clinical study data were used to predict pegcetacoplan concentrations and biomarker responses indicative of hemolysis (hemoglobin and lactate dehydrogenase) over time, including the impact of patient characteristics and prior or concurrent complement C5 inhibitor treatment, to support the approved dose of subcutaneous pegcetacoplan 1080 mg twice weekly.

Results: The population pharmacokinetoc analysis included 284 subjects, and the pharmacokinetic/pharmacodynamic analysis included 165 subjects. Subcutaneous pegcetacoplan 1080 mg twice weekly resulted in rapid serum exposures and robust biomarker response within 4 weeks after treatment initiation. Steady-state serum concentrations demonstrated consistent exposure (median ≥ 600 µg/mL) with minimal peak-to-trough variation. The median effective half-life was 8.6 days in patients with paroxysmal nocturnal hemoglobinuria. Body weight significantly impacted pegcetacoplan exposure, and other covariates impacted hemoglobin (sex and creatinine clearance) or lactate dehydrogenase (prior or concurrent complement C5 inhibitor treatment); however, effects were not clinically meaningful.

Conclusions: The approved dose of pegcetacoplan is predicted to produce rapid and sustained exposure and robust hemoglobin and lactate dehydrogenase responses in adult patients with paroxysmal nocturnal hemoglobinuria, with no initial dose adjustments required for any specific patient population.

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Source
http://dx.doi.org/10.1007/s40268-024-00500-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652457PMC

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