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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