Abstract
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.
Highlights
Chronic kidney disease (CKD) is a major public health problem affecting 50 million people worldwide, with recent United States (US) adult prevalence estimates of .13% (.25 million) [1,2,3]
A total of 2,665 peginesatide plasma samples collected from 672 CKD patients on or not on dialysis enrolled in five clinical trials were used in the population PK analysis
Pharmacokinetic Model of Peginesatide Peginesatide PK administered either as an SC or IV dose in CKD patients on and not on dialysis is best described by a twocompartment model with first-order absorption and saturable MM elimination, where inter-compartmental clearance was fixed to improve model stability (Figure 1)
Summary
Chronic kidney disease (CKD) is a major public health problem affecting 50 million people worldwide, with recent United States (US) adult prevalence estimates of .13% (.25 million) [1,2,3]. CKD often progresses and may result in end-stage renal disease (ESRD), where the kidneys are no longer functioning and dialysis or kidney transplantation is needed. Erythropoiesis-stimulating agents (ESAs) are considered standard treatment for CKD-related anemia. Peginesatide (OMONTYSH) is a once-monthly ESA that was recently approved in the US for the treatment of anemia due to CKD in adult patients on dialysis. The compound is a novel, synthetic peptide-based ESA designed and engineered to stimulate the erythropoietin receptor dimer that governs erythropoiesis [4]. It is composed of a dimeric peptide that is linked to a polyethylene glycol (PEG) moiety [4]. Peginesatide was voluntarily withdrawn from the market in February 2013 due to the post-marketing reports of serious hypersensitivity reactions, including anaphylaxis observed in some subjects (0.02% after the first intravenous dose)
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