DR.JITENDRA AGRAWALSECOND YEAR RESIDENT
PEGINESATIDE
Synthetic Pegylated Erythropoesis Stimulating Agent
Dimeric Peptide having two identical 21-amino acid chains
covalently bonded to a linker derived from iminodiacetic acid
and β-alanine.
The dimeric peptide is covalently linked to a single lysine-
branched bis-(methoxypoly(ethylene glycol)) (PEG)
Amino acid sequence is defferent from Erythropoetine
PEGINESATIDE - INTRODUCTON
Recently approved as treatment of anemia associated
with chronic kidney disease (CKD) in adult patients on
dialysis by US FDA on 27th March 2012
APPROVAL STATUS
Binds to human erythropoietin receptor
Activates receptor
Stimulates erythropoesis in human red cell precursor
MECHANISM OF ACTION
Following IV / SC route: Maximal plasma concentration (Cmax) and area under the
plasma concentration versus time curve (AUC) increase with dose
Following SC injection Maximum plasma concentration reach within 48 hrs Bioavailability – approximately 46%
Not metabolized
Excreted predominantly through kidney
PHARMACOKINETICS
Half life:
PHARMACOKINETICS (CONT.)
Route Healthy individual(hrs)
CKD(hrs)
IV 25.0 ± 7.6 47.9 ± 16.5
SC 53.0 ± 17.7 53.0 ± 17.7
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
PHARMACOKINETICS (CONT.)
Increases the reticulocyte count followed by increases in
hemoglobin
The rate of hemoglobin increase varies among patients and is
dependent on the dose.
No effect on QTc Interval
PHARMACODYNAMICS
No formal drug/drug interaction studies have been performed.
Peginesatide does not bind to serum albumin or lipoproteins
as demonstrated in in vitro protein binding studies in rat,
monkey and human sera.
In vitro studies conducted with human hepatocytes or
microsomes have shown no potential for peginesatide to
induce or inhibit CYP450 enzymes.
DRUG INTERACTIONS
Treatment of anaemia due to chronic kidney disease (CKD)
in adult 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.
INDICATION AND LIMITATION OF USE
Uncontrolled hypertension
CONTRAINDICATION
First evaluate iron store and nutritional factor
Individualize dosing and use the lowest dose
sufficient to reduce the need for RBC transfusions
Initiate treatment when the hemoglobin level is less
than 10 g/dL
DOSAGE AND ADMINISTRATION
If patient not received any ESA previously
Initial dose
0.04 mg/kg body weight, IV or SC
Once monthly
DOSAGE AND ADMINISTRATION (cont)
If the patient is previously on :
DOSAGE AND ADMINISTRATION (cont)
Epoetin alfa
1st dose should be administered one week after the last epoetin
alfa dose was administered
Replaced Dose?
DOSAGE AND ADMINISTRATION (cont)
Previous Total Weekly Epoetin Alfa Dose
(U/week)
Previous Weekly Darbepoetin Alfa Dose
(mcg/week)
PEGNISATIDE Dose Once Monthly (mg/month)
Less than 2,500 Less than 12 2
2,500 to 4,300 12 to 18 3
4,300 to 6,500 18 to 25 4
6,500 to 8,900 25 to 35 5
8,900 to 13,000 35 to 45 6
13,000 to 19,000 45 to 60 8
19,000 to 33,000 60 to 95 10
33,000 to 68,000 95 to 175 15
greater than or equal to 68,000
greater than or equal to 175 20
Monitor Hb levels at least every 2 weeks until stable, then
monitor at least monthly.
Do not increase the dose more frequently than once every 4
weeks.
If the Hb rises rapidly (e.g., more than 1 g/dL in the 2 weeks
prior to the dose or more than 2 g/dL in 4 weeks), reduce the
dose 25% or more as needed to reduce rapid responses.
MONITORING
If the Hb level approaches or exceeds 11 g/dL, reduce or
interrupt the dose.
After a dose has been withheld and once the hemoglobin
begins to decrease, restart at a dose approximately 25% below
the previously administered dose.
Patients who do not respond adequately, if the hemoglobin has
not 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 as
possible
MONITORING (cont..)
Serious Adverse Drug Reactions
Myocardial Infarction
Stroke
Thromboembolism
Hypertension
ADVERSE DRUG REACTION
ADVERSE DRUG REACTION (cont.)
Gastrointestinal Diarrhoea (18.4%)Nausea (17.4%)Vomitting (15.3%)
Respiratory Dyspnea (18.4%) Cough (15.9%)
CNSHeadache (15.4%)
CVSHypotension (14.2%)Hypertension (13.2%)
Musculoskeletal Muscle Spasms (15.3%)
Pain in Extremity (10.9%)
Back Pain (10.9%)
Arthralgia (10.7%)
MetabolicHyperkalemia (11.4%0
ProceduralArteriovenous Fistula Site
Complication (16.1%) Hypotension (10.9%)
Immunogenicity
Only 1.2% patients developed detectable levels of
peginesatide-specific binding antibodies
More incidence in SC administered patients
presence of antibodies associated with declining hemoglobin
levels
The requirement of dose increases to maintain Hb level
ADVERSE DRUG REACTION (cont.)
Novel ESA which is synthetic and unrelated to
Erythropoietin
No added advantage over Epoetin alfa and Darbepoetin
alfa in adverse drug reactions
Administered once a month rather than once a Weekly that
of Epoetin alfa and Darbepoetin alfa
Does not cause Pure Red Cell Aplasia
CONCLUSION
1. Kenneth Kaushansky , Thomas Kipps.Hematopoietic Agents: Growth factors, Minerals and Vitamins. In: Brunton L, editor.Goodman & Gillman’s 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.pdf
4. 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/ucm297464.htm?utm_campaign=Google2&utm_source=fdaSearch&utm_medium=website&utm_term=peginesatide&utm_content=6
REFERENCES
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