Palivizumab

Palivizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetRSV protein F
Names
Trade namesSynagis
Clinical data
Drug classMonoclonal antibody[1]
Main usesPrevention of RSV[2]
Side effectsFever, rash[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: N
  • US: C (Risk not ruled out)
    Routes of
    use
    Intramuscular
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa698034
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only) [3]
    • US: ℞-only [4]
    • EU: Rx-only [2]
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Elimination half-life18-20 days
    Chemical and physical data
    FormulaC6470H10056N1700O2008S50
    Molar mass145388.51 g·mol−1

    Palivizumab, sold under the brand name Synagis, is a medication used to prevent severe respiratory syncytial virus (RSV) infections in those at high risk.[1][2] This includes those under 6 months who were born premature and those under two years with certain heart or lung diseases.[2] It is given once a month by intramuscular (IM) injection, during the RSV season.[2][5]

    The most common side effects are fever and rash.[2] Severe side effects may include anaphylaxis and low platelets.[1][6] It is not used in adults.[1] It is a monoclonal antibody directed against fusion protein A of RSV, blocking its entry into cells of the lungs.[2]

    Palivizumab was approved for medical use in the United States in 1998 and Europe in 1999.[1][2] In Canada it costs about 7,000 CAD per year in 2017.[7] In the the United Kingdome it costs about £560 and in the United States it costs about 3,200 USD for 100 mg as of 2021.[6][8]

    Medical use

    Chest CT three months after admission with resolved ground glass infiltrates revealing the initial atelectasis of the left lower lobe present two months prior to admission (arrow).

    Palivizumab is used to prevent serious lower respiratory tract disease requiring hospitalization caused by the respiratory syncytial virus (RSV) in children at high risk for RSV disease:[9][2][10]

    • children born at 35 weeks of gestation or less and less than six months of age at the onset of the RSV season;[2]
    • children less than two years of age and requiring treatment for bronchopulmonary dysplasia within the last six months;[2]
    • children less than two years of age and with hemodynamically significant congenital heart disease.[2]

    The American Academy of Pediatrics published guidelines on its use in 2014.[11]

    It decreases the risk of hospitalization due to RSV from about 11% to 5% (an approximately 50% decrease).[2]

    RSV prevention

    All babies 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]

    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]

    Dosage

    It is given at a dose of 15 mg/kg.[5] It is given once a month for 5 months during RSV season.[1]

    Side effects

    Palivizumab use may cause side effects, which include, but are not limited to:[16]

    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.[17] Further studies are needed to determine if any drug-drug interactions exist as none have been conducted as of yet.

    Mechanism of action

    Palivizumab is a monoclonal antibody that targets the fusion (F) glycoprotein on the surface of RSV, and deactivates it.[18] 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.[18][19]

    Pharmacodynamics

    Palivizumab has demonstrated a significantly higher affinity and potency in neutralizing both A and B subtypes of RSV when compared with RSV-IGIV.[20] 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.[21]

    Pharmacokinetics

    Absorption

    A 2008 meta-analysis found that palivizumab absorption was quicker in children 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.[22] Current recommendation for RSV immunoprophylaxis is administration of 5 x 15 mg/kg doses of palivizumab to maintain body concentrations above 40 μg/mL.[23]

    Distribution

    The volume of distribution is approximately 4.1 liters.[22]

    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.[22]

    History

    The disease burden of RSV in babies and its global prevalence have prompted attempts for vaccine development. As of 2019, there was no approved vaccine for RSV prevention.[24] 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.[25] Subsequent attempts to develop an attenuated live virus vaccine with optimal immune response and minimal reactogenicity have been unsuccessful.[26] Further research on animal subjects suggested that intravenously administered immunoglobulin with high RSV neutralizing activity can protect against RSV infection.[27] 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.[28] 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. [29]

    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).[30] It was developed over a 10-year period by MedImmune Inc. by combining human and mouse DNA.[31] 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.[21]

    Society and culture

    Cost

    Palivizumab is a relatively expensive medication, with a 100-mg vial ranging from $904 to $1866.[32] 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.[33][18][34]

    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.[35] 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.

    References

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