Function of peginesatide in anemia

2018-09-24

Introduction 

Peginesatide sold under the brand name Omontys, formerly Hematide, is a synthetic peptide consisting of two 21 amino acids chains linked to polyethylene glycol and an erythropoietic agent. Erythropoietic agents bind to the erythropoietin receptors and act as EPO, thus promoting the red blood cell development and improving the anemia. Compared with the older drugs for treatment of anemia such as epogen and aranesp, peginesatide has an advantage that patients can be injected only once a month while patients using epogen have to be administrated 12 times a month. Peginesatide provides a better therapeutic method for anemic patients on dialysis.

Pharmacologic action

Peginesatide, as an erythropoietic agent, mimics the structure of the human hormone, erythropoietin generated by kidney. Thus, it's able to bind to and activate the erythropoietin receptors and stimulate erythropoiesis in red cell precursors of human. Once binding to the receptors, a conformational change occurs, which brings erythropoietin-receptor-associated Janus family tyrosine protein kinase 2 molecules into close proximity. After JAK2 molecules being activated by phosphorylation, the phosphorylate tyrosine residues in the intracellular domain of the receptors act as the docking sites for the intracellular signaling proteins. Once phosphorylated by JAK2, one of the signaling proteins named STAT5 will dissociate from the erythropoietin receptor, dimerize and translocate to the nucleus where it acts as transcription factors to activate target genes associated with cell proliferation and cell apoptosis inhibition. Eventually, as an endogenous erythropoietin, peginesatide increases the number of reticulocytes, hemoglobin and hematocrit.

Function

Peginesatide is indicated for the treatment of anemia in adult patients with chronic kidney disease. Peginesatide consists of a synthetic peptide that mimics the structure of endogenous human erythropoietin and the polyethylene glycol moiety, which makes the drug less immunogenic and prolongs its plasmatic half-life in vivo. Therefore, peginesatide has a longer period of validity than the older drugs for anemia and has a better patient compliance. Not only can peginesatide increase the number of reticulocytes and the level of hemoglobin, but also increase the RBC count, hematocrit and soluble transferrin receptor proteins.

Pharmacokinetics and metabolism

After a IV dose administration of peginesatide, the plasma concentration achieved its maximum within 48 hours. Peginesatide does not accumulate in vivo when administered via intravenous or subcutaneous administration every 4 weeks. After the IV dose injection of peginesatide, the volume of distribution was 34.9±13.8 mL/kg and the mean clearance is 0.5±0.2 mL/hr·kg in patients on dialysis. Peginesatide is shown not to be metabolized in preclinical radiolabeled study. Peginesatide is mostly excreted via urine in the form of unchanged drug. Its mean elimination half-life is 25.0±7.6 hours in healthy subjects and 47.9±16.5 hours in patients on dialysis.

References:

1. Schmid, H. (2013). Peginesatide for the treatment of renal disease-induced anemia. Expert opinion on pharmacotherapy, 14(7), 937-948.

2. Woodburn, K. W., Holmes, C. P., Wilson, S. D., Fong, K. L., Press, R. J., Moriya, Y., & Tagawa, Y. (2012). Absorption, distribution, metabolism and excretion of peginesatide, a novel erythropoiesis-stimulating agent, in rats. Xenobiotica, 42(7), 660-670.

3. Woodburn, K. W., Fong, K. L., Wilson, S. D., Sloneker, S., Strzemienski, P., Solon, E., ... & Tagawa, Y. (2013). Peginesatide clearance, distribution, metabolism, and excretion in monkeys following intravenous administration. Drug Metabolism and Disposition, dmd-112.

4. Fishbane, S., Schiller, B., Locatelli, F., Covic, A. C., Provenzano, R., Wiecek, A., ... & Mayo, M. R. (2013). Peginesatide in patients with anemia undergoing hemodialysis. New England Journal of Medicine, 368(4), 307-319.

5. Macdougall, I. C., Provenzano, R., Sharma, A., Spinowitz, B. S., Schmidt, R. J., Pergola, P. E., ... & Polu, K. R. (2013). Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis. New England Journal of Medicine, 368(4), 320-332.

6. Stead, R. B., Lambert, J., Wessels, D., Iwashita, J. S., Leuther, K. K., Woodburn, K. W. & Duliege, A. M. (2006). Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers. Blood, 108(6), 1830-1834.

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