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Palivizumab

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Palivizumab, sold under the brand name Synagis, is a monoclonal antibody produced by recombinant DNA technology used to prevent severe disease caused by respiratory syncytial virus (RSV) infections.[4][3] It is recommended for infants at high-risk for RSV due to conditions such as prematurity or other medical problems including heart or lung diseases.[4][3]

Palivizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetRSV protein F
Clinical data
Trade namesSynagis
AHFS/Drugs.comMonograph
MedlinePlusa698034
License data
Pregnancy
category
  • AU: N
Routes of
administration		Intramuscular
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)[1]
  • US: ℞-only[2]
  • EU: Rx-only[3]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life18-20 days
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC6470H10056N1700O2008S50
Molar mass145388.51 g·mol−1
 ☒NcheckY (what is this?)  (verify)

The most common side effects include fever and rash.[4][3]

Palivizumab is a humanized monoclonal antibody (IgG) directed against an epitope in the A antigenic site of the F protein of RSV. In two phase III clinical trials in the pediatric population, palivizumab reduced the risk of hospitalization due to RSV infection by 55% and 45%.[5] Palivizumab is dosed once a month via intramuscular (IM) injection, to be administered throughout the duration of the RSV season, which in based on past trends has started in Mid-September to Mid-November.[4][6][7]

Palivizumab targets the fusion protein of RSV,[8] inhibiting its entry into the cell and thereby preventing infection. Palivizumab was approved for medical use in 1998.[9]

Medical use

Palivizumab is indicated for the prevention of serious lower respiratory tract disease requiring hospitalization caused by the respiratory syncytial virus (RSV) in children at high risk for RSV disease:[4][3][10]

  • children born at 35 weeks of gestation or less and less than six months of age at the onset of the RSV season;[3]
  • children less than two years of age and requiring treatment for bronchopulmonary dysplasia within the last six months;[3]
  • children less than two years of age and with hemodynamically significant congenital heart disease.[3]

The American Academy of Pediatrics has published guidelines for the use of palivizumab. The most recent updates to these recommendations are based on new information regarding RSV seasonality, palivizumab pharmacokinetics, the incidence of bronchiolitis hospitalizations, the effect of gestational age and other risk factors on RSV hospitalization rates, the mortality of children hospitalized with RSV infection, the effect of prophylaxis on wheezing, and palivizumab-resistant RSV isolates.[11]

RSV Prophylaxis

All infants younger than one year who were born at <29 weeks (i.e. ≤28 weeks, 6 days) of gestation are recommended to use palivizumab. Infants younger than one year with bronchopulmonary dysplasia (i.e. who were born at <32 weeks gestation and required supplemental oxygen for the first 28 days after birth) and infants younger than two years with bronchopulmonary dysplasia who require medical therapy (e.g. supplemental oxygen, glucocorticoids, diuretics) within six months of the anticipated RSV season are recommended to use palivizumab as prophylaxis.[11] A Cochrane review shows evidence that palivizumab RSV prophylaxis is effective at reducing the frequency of hospitalization in children with RSV infection.[12]

Since the risk of RSV decreases after the first year following birth, the use of palivizumab for children more than 12 months of age is generally not recommended with the exception of premature infants who need supplemental oxygen, bronchodilator therapy, or steroid therapy at the time of their second RSV season.[11]

RSV Prophylaxis Target Groups

Decisions regarding palivizumab prophylaxis for children in these groups should be made on a case-by-case basis.[11]

RSV Treatment

Because palivizumab is a passive antibody, it is ineffective in the treatment of RSV infection, and its administration is not recommended for this indication.[11] A 2019 Cochrane review found no differences in palivizumab and placebo on outcomes of mortality, length of hospital stay, and adverse events in infants and children aged up to 3 years old with RSV.[13] Larger RCTs will be required before palivizumab can be recommended as a treatment option.[14] If an infant has an RSV infection despite the use of palivizumab during the RSV season, monthly doses of palivizumab may be discontinued for the rest of the RSV season due to the low risk of re-hospitalization.[11] Current studies are in progress to determine new treatments for RSV rather than solely prophylaxis. [15]

Mechanism of Action

Palivizumab is a monoclonal antibody that targets the fusion (F) glycoprotein on the surface of RSV, and deactivates it.[16] The F protein is a membrane protein responsible for fusing the virus with its target cell and is highly conserved among subgroups of RSV. Deactivating the F protein prevents the virus from fusing with its target's cell membrane and prevents the virus from entering the host cell.[16][17]

Pharmacodynamics

Palivizumab has demonstrated a significantly higher affinity and potency in neutralizing both A and B subtypes of RSV when compared with RSV-IGIV.[18] Treatment with 2.5 mg/kg of palivizumab led to a serum concentration of 25-30 μg/mL in cotton rats and reduced RSV titers by 99% in their lungs.[19]

Pharmacokinetics

Absorption

A 2008 meta-analysis found that palivizumab absorption was quicker in the pediatric population compared to adults (ka = 1.01/day vs. ka = 0.373/day). The intramuscular bioavailability of this drug is approximately 70% in healthy young adults.[20] Current recommendation for RSV immunoprophylaxis is administration of 5 x 15 mg/kg doses of palivizumab to maintain body concentrations above 40 μg/mL.[21]

Distribution

The volume of distribution is approximately 4.1 liters.[20]

Clearance

Palivizumab has a drug clearance (CL) of approximately 198 ml/day. The half-life of this drug is approximately 20 days with three doses sustaining body concentrations that will last the entire RSV season (5 to 6 months). A 2008 meta-analysis estimated clearance in the pediatric population by considering maturation of CL and body weight which showed a significant reduction compared to adults.[20]

Side effects

Palivizumab use may cause side effects, which include, but are not limited to:[22]

Some more serious side effects include:

Contraindications

Contraindications for the use of palivizumab include hypersensitivity reactions upon exposure to palivizumab. Serious cases of anaphylaxis have been reported after exposure to palivizumab. Signs of hypersensitivity include hives, shortness of breath, hypotension, and unresponsiveness. No other contraindications for palivizumab have been reported.[23] Further studies are needed to determine if any drug-drug interactions exist as none have been conducted as of yet.

Cost

Palivizumab is a relatively expensive medication, with a 100-mg vial ranging from $904 to $1866.[24] Multiple studies done by both the manufacturer and independent researchers to determine the cost-effectiveness of palivizumab have found conflicting results. The heterogeneity between these studies makes them difficult to compare. Given that there is no consensus about the cost-effectiveness of palivizumab, usage largely depends on the location of care and individual risk factors.[25][16][26]

A 2013 meta-analysis reported that palivizumab prophylaxis was a dominant strategy with an incremental cost-effectiveness ratio of $2,526,203 per quality-adjusted life-year (QALY). It also showed an incremental cost-effectiveness ratio for preterm infants between $5188 and $791,265 per QALY, from the payer perspective.[27] However, as previously stated, the cost-effectiveness of palivizumab is undecided, and this meta-analysis is only one example of society can benefit from palivizumab prophylaxis.

History

The disease burden of RSV in young infants and its global prevalence have prompted attempts for vaccine development. As of 2019, there was no approved vaccine for RSV prevention.[28] A formalin-inactivated RSV vaccine (FIRSV) was studied in the 1960s. The immunized children who were exposed to the virus in the community developed an enhanced form of RSV disease presented by wheezing, fever, and bronchopneumonia. This enhanced form of the disease led to 80% hospitalization in the recipients of FIRSV compared to 5% in the control group. Additionally, 2 fatalities occurred among the vaccine recipients upon reinfection in subsequent years.[29] Subsequent attempts to develop an attenuated live virus vaccine with optimal immune response and minimal reactogenicity have been unsuccessful.[30] Further research on animal subjects suggested that intravenously administered immunoglobulin with high RSV neutralizing activity can protect against RSV infection.[31] In 1995, the U.S. Food and Drug Administration (FDA) approved the use of RespiGam (RSV-IGIV) for the prevention of serious lower respiratory tract infection caused by RSV in children younger than 24 months of age with bronchopulmonary dysplasia or a history of premature birth.[32] The success of the RSV-IGIV demonstrated efficacy in immunoprophylaxis and prompted research into further technologies. Thus, Palivizumab was developed as an antibody that was found to be fifty times more potent than its predecessor. This antibody has been widely used for RSV since 1998 when it was approved. [33]

Palivizumab, originally known as MEDI-493, was developed as an RSV immune prophylaxis tool that was easier to administer and more effective than the current tools of that time (the 1990s).[34] It was developed over a 10-year period by MedImmune Inc. by combining human and mouse DNA. Specifically, antibody production was stimulated in a mouse model following immunization with RSV. The antibody-producing B cells were isolated from the mouse's spleen and fused with mouse myeloma cell lines. The antibodies were then humanized by cloning and sequencing the DNA from both the heavy and light chains of the monoclonal antibody. Overall, the monoclonal antibody is 95% similar to other human antibodies with the other 5% having DNA origins from the original mouse.[19]

References

  1. ^ "Synagis 100 mg/ml solution for injection - Summary of Product Characteristics (SmPC)". (emc). 12 August 2020. Retrieved 20 August 2020.
  2. ^ "Synagis- palivizumab injection, solution". DailyMed. 12 May 2017. Retrieved 20 August 2020.
  3. ^ a b c d e f g h "Synagis EPAR". European Medicines Agency (EMA). Retrieved 20 August 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ^ a b c d e "Synagis 100 mg/1 ml solution for injection - Summary of Product Characteristics (SmPC) - (emc)". www.medicines.org.uk. Retrieved 2021-08-03.
  5. ^ "Prospective Study for the Use of Palivizumab (Synagis®) in High-risk Children in Germany". ClinicalTrials.gov. 2021.{{cite web}}: CS1 maint: url-status (link)
  6. ^ Borchers AT, Chang C, Gershwin ME, Gershwin LJ (December 2013). "Respiratory syncytial virus--a comprehensive review". Clinical Reviews in Allergy & Immunology. 45 (3): 331–79. doi:10.1007/s12016-013-8368-9. PMC 7090643. PMID 23575961.
  7. ^ CDC (2020-12-18). "Trends and Surveillance for RSV in the US". Centers for Disease Control and Prevention. Retrieved 2021-08-10.
  8. ^ Levinson W (2004). Medical Microbiology and Immunology (8th ed.). Lange. p. 430.
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  10. ^ Santos da Silva, Gloria N.; Monti Atik, Diana; Antunes Fernandes, Jheini L.; de Freitas do Nascimento, Deise; Fazolo, Tiago; Duarte de Souza, Ana Paula; Baggio Gnoatto, Simone C. (2021). "Synthesis of three triterpene series and their activity against respiratory syncytial virus". Archiv der Pharmazie. 351 (8): 1800108. doi:10.1002/ardp.201800108.
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  21. ^ Reuter SE, Evans AM, Ward MB (January 2019). "Reducing Palivizumab Dose Requirements Through Rational Dose Regimen Design". CPT. 8 (1): 26–33. doi:10.1002/psp4.12364. PMC 6363066. PMID 30426719.
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  23. ^ "Drugs@FDA: FDA-Approved Drugs". www.accessdata.fda.gov. Retrieved 28 July 2021.{{cite web}}: CS1 maint: url-status (link)
  24. ^ Mac, Stephen; Sumner, Amanda; Duchesne-Belanger, Samuel; Stirling, Robert; Tunis, Matthew; Sander, Beate (2021). "Cost-effectiveness of Palivizumab for Respiratory Syncytial Virus: A Systematic Review". Pediatrics. 143 (5): e20184064. doi:10.1542/peds.2018-4064. ISSN 0031-4005.
  25. ^ Andabaka T, Nickerson JW, Rojas-Reyes MX, Rueda JD, Bacic Vrca V, Barsic B (April 2013). "Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children". The Cochrane Database of Systematic Reviews (4): CD006602. doi:10.1002/14651858.cd006602.pub4. PMID 23633336.
  26. ^ Barr R, Green CA, Sande CJ, Drysdale SB (2019-07-29). "Respiratory syncytial virus: diagnosis, prevention and management". Therapeutic Advances in Infectious Disease. 6: 2049936119865798. doi:10.1177/2049936119865798. PMC 6664627. PMID 31384456.
  27. ^ Mac S, Sumner A, Duchesne-Belanger S, Stirling R, Tunis M, Sander B (May 2019). "Cost-effectiveness of Palivizumab for Respiratory Syncytial Virus: A Systematic Review". Pediatrics. 143 (5). doi:10.1542/peds.2018-4064. PMID 31040196.
  28. ^ Shafique, Muhammad; Asif Zahoor, Muhammad; Imran Arshad, Muhammad; Aslam, Bilal; Baker Siddique, Abu; Hidayat Rasool, Muhammad; Usman Qamar, Muhammad; Usman, Muhammad (2019-10-30), Resch, Bernhard (ed.), "Hurdles in Vaccine Development against Respiratory Syncytial Virus", The Burden of Respiratory Syncytial Virus Infection in the Young, IntechOpen, doi:10.5772/intechopen.87126, ISBN 978-1-78984-642-3, retrieved 2021-08-03
  29. ^ Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, Parrott RH (April 1969). "Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine". American Journal of Epidemiology. 89 (4): 422–34. doi:10.1093/oxfordjournals.aje.a120955. PMID 4305198.
  30. ^ Karron RA, Buchholz UJ, Collins PL (2013). Anderson L, Graham BS (eds.). "Live-attenuated respiratory syncytial virus vaccines". Current Topics in Microbiology and Immunology. 372. Berlin, Heidelberg: Springer Berlin Heidelberg: 259–84. doi:10.1007/978-3-642-38919-1_13. ISBN 978-3-642-38918-4. PMC 4794267. PMID 24362694.
  31. ^ Boukhvalova MS, Yim KC, Blanco J (2018-01-01). "Cotton rat model for testing vaccines and antivirals against respiratory syncytial virus". Antiviral Chemistry & Chemotherapy. 26: 2040206618770518. doi:10.1177/2040206618770518. PMC 5987903. PMID 29768937.
  32. ^ Pollack P, Groothuis JR (September 2002). "Development and use of palivizumab (Synagis): a passive immunoprophylactic agent for RSV". Journal of Infection and Chemotherapy. 8 (3): 201–6. doi:10.1007/s10156-002-0178-6. PMID 12373481.
  33. ^ Human antibody therapeutics for viral disease. Scott K. Dessain. Berlin: Springer Verlag. 2021. ISBN 978-3-540-72146-8. OCLC 209988317.{{cite book}}: CS1 maint: others (link)
  34. ^ Dessain, Scott K. (2021). Human antibody therapeutics for viral disease. Berlin: Springer Verlag. ISBN 978-3-540-72146-8. OCLC 209988317.
  • "Palivizumab". Drug Information Portal. U.S. National Library of Medicine.
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