Pegnisatide an update

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  • 1. DR.JITENDRA AGRAWALSECOND YEAR RESIDENT

2. Synthetic Pegylated Erythropoesis Stimulating Agent Dimeric Peptide having two identical 21-amino acid chainscovalently bonded to a linker derived from iminodiacetic acidand -alanine. The dimeric peptide is covalently linked to a single lysine-branched bis-(methoxypoly(ethylene glycol)) (PEG) Amino acid sequence is defferent from Erythropoetine 3. Recently approved as treatment of anemia associated with chronic kidney disease (CKD) in adult patients on dialysis by US FDA on 27th March 2012 4. Binds to human erythropoietin receptor Activates receptorStimulates erythropoesis in human red cell precursor 5. Following IV / SC route: Maximal plasma concentration (Cmax) and area under theplasma concentration versus time curve (AUC) increasewith dose Following SC injection Maximum plasma concentration reach within 48 hrs Bioavailability approximately 46% Not metabolized Excreted predominantly through kidney 6. Half life: RouteHealthyCKD individual(hrs) (hrs)IV 25.0 7.647.9 16.5SC 53.0 17.7 53.0 17.7 7. No accumulation every 4 weeks following intravenous or subcutaneous administration The pharmacokinetics of patients with CKD on dialysis are not altered by age, gender or race 8. Increases the reticulocyte count followed by increases inhemoglobin The rate of hemoglobin increase varies among patients and isdependent on the dose. No effect on QTc Interval 9. No formal drug/drug interaction studies have been performed. Peginesatide does not bind to serum albumin or lipoproteins asdemonstrated in in vitro protein binding studies in rat, monkeyand human sera. In vitro studies conducted with human hepatocytes ormicrosomes have shown no potential for peginesatide to induceor inhibit CYP450 enzymes. 10. Treatment of anaemia due to chronic kidney disease (CKD) inadult patients on dialysis. Not indicated : Who are not on dialysis Receiving treatment for cancer Substitute for red blood cell (RBC) transfusions in patients who require immediate correction of anemia. 11. Uncontrolled hypertension 12. First evaluate iron store and nutritional factor Individualize dosing and use the lowest dosesufficient to reduce the need for RBC transfusions Initiate treatment when the hemoglobin level is lessthan 10 g/dL 13. If patient not received any ESA previously Initial dose 0.04 mg/kg body weight, IV or SCOnce monthly 14. If the patient is previously on :Epoetin alfaDarbepoetin alfa1st dose should be 1st dose should beadministered oneadministeredatweek after the last the next scheduledepoetin alfa dose dose in place ofwas administereddarbepoetin alfa. 15. Replaced Dose? Previous Total Weekly Previous Weekly PEGNISATIDE Dose Epoetin Alfa Dose Darbepoetin Alfa Dose Once Monthly (mg/month) (U/week) (mcg/week)Less than 2,500Less than 1222,500 to 4,300 12 to 1834,300 to 6,500 18 to 254 6,500 to 8,90025 to 3558,900 to 13,00035 to 45613,000 to 19,000 45 to 60819,000 to 33,000 60 to 951033,000 to 68,000 95 to 175 15 greater than or equal to greater than or equal to 175 2068,000 16. Monitor Hb levels at least every 2 weeks until stable, thenmonitor at least monthly. Do not increase the dose more frequently than once every 4weeks. If the Hb rises rapidly (e.g., more than 1 g/dL in the 2 weeksprior to the dose or more than 2 g/dL in 4 weeks), reduce thedose 25% or more as needed to reduce rapid responses. 17. If the Hb level approaches or exceeds 11 g/dL, reduce orinterrupt the dose. After a dose has been withheld and once the hemoglobin beginsto decrease, restart at a dose approximately 25% below thepreviously administered dose. Patients who do not respond adequately, if the hemoglobin hasnot increased by more than 1 g/dL after 4 weeks of therapy,increase the dose by 25%. If a dose of is missed, administer the missed dose as soon aspossible 18. Serious Adverse Drug Reactions Myocardial Infarction Stroke Thromboembolism Hypertension 19. Gastrointestinal MusculoskeletalDiarrhoea (18.4%)Muscle Spasms(15.3%)Nausea (17.4%) Pain in Extremity (10.9%)Vomitting (15.3%)Back Pain(10.9%) Arthralgia(10.7%) RespiratoryDyspnea (18.4%)Cough (15.9%) Metabolic Hyperkalemia (11.4%0 CNSHeadache (15.4%) Procedural Arteriovenous Fistula Site Complication (16.1%) CVSHypotension (10.9%)Hypotension (14.2%)Hypertension (13.2%) 20. Immunogenicity Only 1.2% patients developed detectable levels ofpeginesatide-specific binding antibodies More incidence in SC administered patients presence of antibodies associated with declining hemoglobinlevels The requirement of dose increases to maintain Hb level 21. Novel ESAwhich is synthetic and unrelated toErythropoietin No added advantage over Epoetin alfa and Darbepoetin alfain adverse drug reactions Administered once a month rather than once a Weekly thatof Epoetin alfa and Darbepoetin alfa Does not cause Pure Red Cell Aplasia 22. 1. Kenneth Kaushansky , Thomas Kipps.Hematopoietic Agents: Growth factors, Minerals and Vitamins. In: Brunton L, editor.Goodman & Gillmans The Pharmacological Basis of Therapeutics, 12th ed. New York: Mcgraw Hill; 2011.p.1068-73.2. Andrew Wagner, Ramy Arnaout, George Demetri. Pharmacology of Hematopoiesis and Immunomodulation. In: David Golan, editor. Principles of Pharmacology, The Pathophysiological Basis of Drug Therapy, 3rd ed. Philadelphia: Lippincott Williams and Wilkins Publications; 2012.p.779-83.3. OMONTYS (Peginasatide) for Injection. US Prescribing Information. April 2012.[ cited April 30, 2012]. Available from: www.accessdata.fda.gov/drugsatfda_docs/label/.../202799s000lbl.pdf4. Richard B Stead et al.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, 15 September 2006, Vol. 108, No. 6, pp. 1830-1834.5. FDA approves Omontys to treat anemia in adult patients on dialysis, Press Announcement. [cited April 29, 2012]. Available From: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm297 464.htm?utm_campaign=Google2&utm_source=fdaSearch&utm_medium=w ebsite&utm_term=peginesatide&utm_content=6