A Population Pharmacokinetic and Pharmacodynamic Analysis of Peginesatide in Patients with Chronic Kidney Disease on Dialysis

• Published in: PloS one Vol. 8; no. 6; p. e66422
• Main Authors: Naik, Himanshu, Tsai, Max C., Fiedler-Kelly, Jill, Qiu, Ping, Vakilynejad, Majid
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.06.2013; Public Library of Science (PLoS)
• Subjects: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anemia; Anemia - prevention & control; Care and treatment; Cells (biology); Chronic kidney failure; Computer simulation; Dialysis; Dose-Response Relationship, Drug; Erythropoiesis; Female; Glycosylated hemoglobin; Health care; Hemodialysis; Hemoglobin; Humans; Injections, Subcutaneous; Intravenous administration; Kidney diseases; Kidney transplantation; Kidneys; Life span; Male; Medical laboratories; Medical treatment; Medicine; Middle Aged; Patients; Peptides - administration & dosage; Peptides - pharmacokinetics; Peptides - pharmacology; Pharmacodynamics; Pharmacokinetics; Pharmacology; Polyethylene glycol; Population; R&D; Renal Dialysis; Renal Insufficiency, Chronic - blood; Renal Insufficiency, Chronic - therapy; Research & development; Standard deviation; Stem cells; Studies; Transplants & implants; United States; Young Adult; United States > US; Illinois
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0066422

Peginesatide (OMONTYS®) is an erythropoiesis-stimulating agent that was indicated in the United States for the treatment of anemia due to chronic kidney disease in adult patients on dialysis prior to its recent marketing withdrawal by the manufacturer. The objective of this analysis was to develop a population pharmacokinetic and pharmacodynamic model to characterize the time-course of peginesatide plasma and hemoglobin concentrations following intravenous and subcutaneous administration. Plasma samples (n = 2,665) from 672 patients with chronic kidney disease (on or not on dialysis) and hemoglobin samples (n = 18,857) from 517 hemodialysis patients (subset of the 672 patients), were used for pharmacokinetic-pharmacodynamic model development in NONMEM VI. The pharmacokinetic profile of peginesatide was best described by a two-compartment model with first-order absorption and saturable elimination. The relationship between peginesatide and hemoglobin plasma concentrations was best characterized by a modified precursor-dependent lifespan indirect response model. The estimate of maximal stimulatory effect of peginesatide on the endogenous production rate of progenitor cells (Emax) was 0.54. The estimate of peginesatide drug concentration required for 50% of maximal response (EC50) estimates was 0.4 µg/mL. Several significant (P<0.005) covariates affected simulated peginesatide exposure by ≤36%. Based upon ≤0.2 g/dL effects on simulated hemoglobin levels, none were considered clinically relevant.