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

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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. 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. 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. 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. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disease that causes hemolysis, or destruction of red blood cells. People with PNH are lacking in red blood cells, which can lead to symptoms such as fatigue, as well as blood clots and organ damage. People with PNH may receive medicines called complement inhibitors, which act to block hemolysis. Pegcetacoplan is a complement inhibitor for adults with PNH. As PNH is a rare disease, most clinical trials include a limited number of patients. This study used two models based on clinical trial data to predict how pegcetacoplan might act in the body once it is administered in a wide range of patient types that had differing clinical characteristics such as weight or previous treatments. The recommended dosage was included (1080 mg twice weekly, subcutaneous administration). A population pharmacokinetic model looked at how pegcetacoplan moved through the body. After administration, pegcetacoplan remained in the bloodstream at a steady consistent level, with a reduction in concentration by half at a median of 8.6 days (n = 284). Pharmacodynamic analyses looked at how pegcetacoplan would affect the body’s biochemical processes. It was predicted that pegcetacoplan would lead to robust responses in biomarkers indicative of disease improvement (hemoglobin and lactate dehydrogenase) in adult patients with PNH, with no need to adjust the dose based on clinical characteristics such as weight or previous treatments (n = 165). The approved pegcetacoplan dose was predicted to produce rapid and sustained exposure and robust hemoglobin and lactate dehydrogenase responses in a range of adult patients with PNH.

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