Pb2053: population pharmacokinetics of pegcetacoplan in healthy subjects and patients with paroxysmal nocturnal hemoglobinuria

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Pegcetacoplan is a PEGylated peptide that targets complement protein C3 and C3b. Aims: A population pharmacokinetic (PK) analysis was performed to describe the serum concentration-time profile of pegcetacoplan and quantify the impact of intrinsic and extrinsic subject factors on its exposure. Methods: Data from 11 clinical studies were used, including 2 phase 3 studies. Pegcetacoplan was administered via subcutaneous (SC) bolus injection, SC delivery devices, or intravenous infusion to healthy adult subjects, adult subjects with renal impairment, or adult patients with paroxysmal nocturnal hemoglobinuria (PNH). Doses ranged from a single 25-mg SC injection to 2600 mg-SC once-weekly infusion; the dosing regimen for phase 3 studies was 1080 mg SC twice weekly (which could be adjusted to every 3 days depending on clinical response) for up to 48 weeks. The final model consisted of 1-compartment systemic disposition, first-order elimination, and transit compartment absorption following SC dose administration. Results: Pegcetacoplan displays linear PKs over the range of doses evaluated in clinical studies. The predicted geometric mean (coefficient of variation %) of clearance is 0.36 L/day (30%) and median (interquartile range) effective elimination half-life is 8.6 (6.9–11.0) days in patients with PNH. Concomitant administration of eculizumab, age, sex, Asian race, Japanese ethnicity, renal function, and hepatic function (as evaluated by total bilirubin, albumin, aspartate aminotransferase, or alanine aminotransferase) had no meaningful effect on the PK profile of pegcetacoplan. Body weight did influence pegcetacoplan kinetics with 1.20-fold (90% CI, 1.16–1.23) higher and 0.827-fold (90% CI, 0.800–0.853) lower average exposure at the 5th (53 kg) and 95th (94 kg) percentiles of body weight compared with a 70-kg reference. Summary/Conclusion: The population PK model adequately described the observed concentration data. Predictions from the model further suggest that no adjustment to initial dosing is needed for the specific populations represented by the intrinsic or extrinsic factors evaluated in this analysis. Keywords: Complement, Population, Paroxysmal nocturnal hemoglobinuria (PNH), Pharmacokinetic