Palivizumab

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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)

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.[2][3] It is recommended for infants that are high-risk because of prematurity or other medical problems such as congenital heart disease.[2][3]

The most common side effects include fever and rash.[2][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%. Palivizumab is dosed once a month via intramuscular (IM) injection, to be administered throughout the duration of the RSV season, which usually starts in November or December in the US.[2][4]

Palivizumab targets the fusion protein of RSV,[5] inhibiting its entry into the cell and thereby preventing infection. Palivizumab was approved for medical use in 1998.[6]

Medical use[edit]

Palivizumab is indicated for the prevention of serious lower respiratory tract disease requiring hospitalization caused by respiratory syncytial virus (RSV) in children at high risk for RSV disease:[2][3]

  • 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.[7]

RSV Prophylaxis[edit]

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.[7] A Cochrane review shows evidence that palivizumab RSV prophylaxis is effective at reducing the frequency of hospitalization in children with RSV infection. [8]

Since the risk of RSV decreases after the first year of birth, use of palivizumab after 12 months of age is generally not recommended with the exception of premature infants born who need supplemental oxygen, bronchodilator therapy, or steroid therapy at the time of their second RSV season.[9]

RSV Prophylaxis Target Groups:[edit]

Decisions regarding palivizumab prophylaxis for children in these groups should be made on a case-by-case basis.[7]

RSV Treatment[edit]

Because palivizumab is a passive antibody, it is ineffective in treatment of RSV infection, and its administration is not recommended for this indication.[11] A recent 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. [12] Larger RCTs will be required before palivizumab can be recommended as a treatment option. [13] If an infant has an RSV infection despite use of palivizumab during the RSV season, monthly doses of palivizumab may be discontinued for the rest of the RSV season due to low risk of rehospitalization.[7]

Mechanism of Action[edit]

Palivizumab is a monoclonal antibody that targets the fusion (F) glycoprotein on the surface of RSV, and deactivates it.[14] 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.[14][15]

Pharmacodynamics[edit]

Palivizumab has demonstrated significantly higher affinity and potency in neutralizing both A and B subtypes of RSV when compared with RSV-IGIV.[16] 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.[17]

Pharmacokinetics[edit]

Absorption[edit]

Based on a recent meta analysis, palivizumab absorption is quicker in pediatrics compared to adult populations (ka = 1.01/day vs. ka = 0.373/day). The intramuscular bioavailability of this drug is approximately 70% in healthy young adults.[18] Current recommendation for RSV immunoprophylaxis is administration of 5 x 15 mg/kg doses of palivizumab to maintain body concentrations above 40 μg/mL.[19]

Distribution[edit]

The volume of distribution is approximately 4.1 liters.[18]

Clearance[edit]

Palivizumab has a relatively low 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 recent meta analysis estimated clearance in pediatric population by considering maturation of CL and body weight which showed a significant reduction compared to adult populations.[18]

Side effects[edit]

Palivizumab use may cause side effects, which include, but are not limited to:[20]

Some more serious side effects include:

Contraindications[edit]

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.[21]

Cost[edit]

Palivizumab is a relatively expensive medication. Multiple studies have been done by both the manufacturer and by independent researchers to determine the cost-effectiveness of palivizumab but have concluded with conflicting results. However, the heterogeneity between the studies makes them difficult to compare. Since there is no consensus about the cost effectiveness of palivizumab, usage largely depends on location of care and individual risk factors for each case.[22][23][24]

One meta analysis shows palivizumab prophylaxis being a dominant strategy that has an incremental cost-effectiveness ratio of $2,526,203 per quality-adjusted life-year (QALY). It also showed incremental cost-effectiveness ratio for preterm infants between $5188 and $791 265 per QALY, from the payer perspective. [25]

History[edit]

The disease burden of RSV in young infants and its global prevalence has prompted attempts for vaccine development. To this day, however, there is no approved vaccine for RSV prevention. A formalin-inactivated RSV vaccine (FIRSV) was studied in the 1960's. 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 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.[26] Subsequent attempts to develop an attenuated live virus vaccine with an optimal immune response and minimal reactogenicity have been unsuccessful.[27] Further research on animal subjects suggested that intravenously administered immunoglobulin with high RSV neutralizing activity can protect against RSV infection.[28] 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.[29]

Palivizumab, originally known as MEDI-493, was developed an RSV immune prophylaxis tool that was easier to administer and more effective than the current tools of that time (1990's). 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 Mab. Overall, the Mab is 95% to other human antibodies with the other 5% having DNA origins from the original mouse. [30]

References[edit]

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  2. ^ a b c d e f "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.
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  24. ^ Barr, Rachael; Green, Christopher A.; Sande, Charles J.; Drysdale, Simon B. (2019-07-29). "Respiratory syncytial virus: diagnosis, prevention and management". Therapeutic Advances in Infectious Disease. 6. doi:10.1177/2049936119865798. ISSN 2049-9361. PMC 6664627. PMID 31384456. line feed character in |title= at position 55 (help)
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  26. ^ Kim, Hyun Wha; Canchola, Jose G.; Brandt, Carl D.; Pyles, Gloria; Chanock, Robert M.; Jensen, Keith; Parrott, Robert H. (1969). "RESPIRATORY SYNCYTIAL VIRUS DISEASE IN INFANTS DESPITE PRIOR ADMINISTRATION OF ANTIGENIC INACTIVATED VACCINE12". American Journal of Epidemiology. 89 (4): 422–434. doi:10.1093/oxfordjournals.aje.a120955. ISSN 1476-6256.
  27. ^ Karron, Ruth A.; Buchholz, Ursula J.; Collins, Peter L. (2013), Anderson, Larry J.; Graham, Barney S. (eds.), "Live-Attenuated Respiratory Syncytial Virus Vaccines", Challenges and Opportunities for Respiratory Syncytial Virus Vaccines, Berlin, Heidelberg: Springer Berlin Heidelberg, 372, pp. 259–284, doi:10.1007/978-3-642-38919-1_13, ISBN 978-3-642-38918-4, PMC 4794267, PMID 24362694, retrieved 2021-07-30CS1 maint: PMC format (link)
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  30. ^ Resch, Bernhard (2017-06-12). "Product review on the monoclonal antibody palivizumab for prevention of respiratory syncytial virus infection". Human Vaccines & Immunotherapeutics. 13 (9): 2138–2149. doi:10.1080/21645515.2017.1337614. ISSN 2164-5515. PMC 5612471. PMID 28605249.

External links[edit]

  • "Palivizumab". Drug Information Portal. U.S. National Library of Medicine.