Sotrovimab and Its Use in Children

Introduction

Sotrovimab is a monoclonal antibody therapy developed for the treatment of COVID-19. As the COVID-19 pandemic continues to evolve, with new variants emerging and vaccination efforts ongoing, therapeutic options for treating active infections remain crucial, especially in vulnerable populations such as children. This clinical note aims to provide pediatricians with a comprehensive overview of sotrovimab, its mechanism of action, efficacy, safety profile, and specific considerations for use in pediatric patients.

Mechanism of Action

Sotrovimab is a recombinant human IgG1κ monoclonal antibody that binds to a highly conserved epitope on the spike protein receptor binding domain of SARS-CoV-2. The antibody was derived from a SARS-CoV-1 survivor and has been engineered to have extended half-life and reduced effector functions.

Key points about sotrovimab's mechanism of action include:

High-affinity binding to the SARS-CoV-2 spike protein
Neutralization of the virus by blocking its entry into host cells
Potential for antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP)
Activity against multiple variants of concern due to targeting of a conserved epitope

The unique epitope targeted by sotrovimab is thought to contribute to its broader efficacy against variants compared to some other monoclonal antibody therapies. This characteristic is particularly important in the context of an evolving virus and the emergence of new variants.

Clinical Efficacy in Adults

Before discussing pediatric use, it is important to understand the efficacy data in adults, as this forms the basis for extrapolation to pediatric populations. The primary evidence for sotrovimab's efficacy comes from the COMET-ICE trial, a phase 3, randomized, double-blind, placebo-controlled study in non-hospitalized adults with mild-to-moderate COVID-19 and at least one risk factor for progression.

Key findings from the COMET-ICE trial:

85% reduction in hospitalization or death compared to placebo
Absolute risk reduction of 6% (1% in sotrovimab group vs. 7% in placebo group)
Number needed to treat (NNT) of 17 to prevent one hospitalization or death
Efficacy maintained across various subgroups, including age, BMI, and presence of comorbidities

These results led to the Emergency Use Authorization (EUA) of sotrovimab by the FDA for the treatment of mild-to-moderate COVID-19 in patients aged 12 years and older weighing at least 40 kg who are at high risk for progression to severe disease.

Pediatric Considerations

The use of sotrovimab in pediatric patients requires careful consideration of several factors:

Extrapolation of Adult Data

The FDA's decision to include adolescents ≥12 years and weighing ≥40 kg in the EUA was based on extrapolation of adult efficacy data. This approach is supported by:

Similar disease pathophysiology in adolescents and adults
Comparable pharmacokinetics expected in this age/weight group
The established safety profile in adults

However, it is important to note that direct efficacy data in pediatric populations is limited, and ongoing studies are needed to confirm these extrapolations.

Dosing in Pediatrics

The recommended dose of sotrovimab for both adults and pediatric patients (≥12 years, ≥40 kg) is:

500 mg administered as a single intravenous infusion
Infusion should be given over 30 minutes
Treatment should be initiated as soon as possible after positive SARS-CoV-2 test and within 10 days of symptom onset

There is currently no data to support dose adjustments based on age or weight within the approved pediatric population.

Pharmacokinetics in Pediatrics

While specific pharmacokinetic studies in pediatric patients are limited, the following assumptions are made based on known monoclonal antibody characteristics:

Similar distribution and elimination processes as in adults
Extended half-life (approximately 49 days) due to Fc region modifications
No significant differences expected in adolescents meeting the weight criteria

Pediatricians should be aware that these assumptions may need to be revised as more pediatric-specific data becomes available.

Safety Profile in Pediatrics

The safety profile of sotrovimab in pediatric patients is primarily extrapolated from adult data. Key safety considerations include:

Most common adverse events: infusion-related reactions (including fever, chills, dizziness, dyspnea, pruritus, and rash)
Potential for serious hypersensitivity reactions, including anaphylaxis
Theoretical risk of antibody-dependent enhancement (ADE) of disease, though not observed in clinical trials

Pediatricians should monitor patients closely during and after infusion, with particular attention to infusion-related reactions in younger patients who may have difficulty communicating symptoms.

Efficacy Against Variants

The efficacy of sotrovimab against SARS-CoV-2 variants is of particular importance in pediatric populations, as children may be vectors for transmission and new variant emergence. Current data suggests:

Maintained neutralization activity against Alpha, Beta, Gamma, Delta, and Omicron BA.1 variants
Reduced activity against Omicron BA.2 and subsequent subvariants
Ongoing surveillance and in vitro testing to monitor efficacy against emerging variants

Pediatricians should stay informed about local variant prevalence and updated guidance on sotrovimab's efficacy against circulating strains.

Clinical Use in Pediatric Patients

Patient Selection

Appropriate patient selection is crucial for the effective use of sotrovimab in pediatric populations. Candidates for treatment should meet the following criteria:

Age ≥12 years and weight ≥40 kg
Positive SARS-CoV-2 test (PCR or antigen)
Mild to moderate COVID-19 symptoms
Within 10 days of symptom onset
At high risk for progression to severe disease

High-risk factors in pediatric patients may include:

Obesity or being overweight (BMI ≥85th percentile for age)
Chronic lung disease (e.g., asthma, cystic fibrosis)
Congenital heart disease
Neurodevelopmental disorders
Medical-related technological dependence
Immunocompromised state or immunosuppressive treatment
Sickle cell disease
Chronic kidney disease
Diabetes

Pediatricians should carefully assess each patient's individual risk factors and potential benefit from sotrovimab treatment.

Administration and Monitoring

The administration of sotrovimab in pediatric patients requires careful attention to detail:

Preparation:
- Sotrovimab should be diluted in 0.9% Sodium Chloride for infusion
- Use aseptic technique to prepare the infusion solution
- Gently invert the bag to mix; do not shake
Administration:
- Administer via intravenous infusion pump over 30 minutes
- Use a sterile, in-line or add-on 0.2 micron polyethersulfone (PES) filter
- Do not administer as an intravenous push or bolus
Monitoring:
- Observe patients during the infusion and for at least 1 hour after completion
- Monitor for signs and symptoms of infusion-related reactions
- Have appropriate medications and equipment for managing potential reactions readily available

Pediatricians should ensure that staff administering sotrovimab are trained in infusion techniques and the management of potential adverse reactions in pediatric patients.

Post-Treatment Considerations

After administering sotrovimab to pediatric patients, several follow-up considerations are important:

Continued monitoring for delayed adverse reactions
Assessment of clinical response and disease progression
Counseling on continued infection control measures
Guidance on COVID-19 vaccination (typically recommended to defer vaccination for 90 days post-treatment)
Reporting of any adverse events to the FDA and the manufacturer

Pediatricians should establish a follow-up plan tailored to each patient's individual circumstances and risk factors.

Comparative Efficacy and Treatment Selection

When considering sotrovimab for pediatric patients, it is important to evaluate its efficacy in comparison to other available treatments:

Other Monoclonal Antibodies

Several other monoclonal antibody therapies have been developed for COVID-19 treatment, including:

Casirivimab/Imdevimab (REGEN-COV)
Bamlanivimab/Etesevimab
Tixagevimab/Cilgavimab (Evusheld)

The choice between these options should be based on:

Current variant susceptibility
Local availability and supply
Patient-specific factors (e.g., renal function, drug interactions)
Route of administration (IV vs. IM)

Antiviral Medications

Oral antiviral medications, such as nirmatrelvir/ritonavir (Paxlovid) and molnupiravir, have also been authorized for COVID-19 treatment. Considerations when comparing these to sotrovimab include:

Age restrictions (e.g., Paxlovid authorized for ≥12 years, molnupiravir for ≥18 years)
Ease of administration (oral vs. IV)
Drug interactions (particularly with nirmatrelvir/ritonavir)
Efficacy against current variants

Pediatricians should stay informed about the latest guidelines and recommendations for treatment selection in pediatric patients.

Research Gaps and Future Directions

While sotrovimab has shown promise in the treatment of COVID-19, several areas require further research, particularly in pediatric populations:

Direct efficacy data in children and adolescents
Long-term safety and immunogenicity in pediatric patients
Optimal timing of treatment initiation in pediatric COVID-19
Efficacy in preventing multisystem inflammatory syndrome in children (MIS-C)
Potential role in post-exposure prophylaxis for high-risk pediatric patients
Combination therapy approaches (e.g., with antivirals)
Impact on long COVID symptoms in pediatric patients

Ongoing clinical trials and real-world evidence studies will be crucial in addressing these knowledge gaps and refining the use of sotrovimab in pediatric practice.

Practical Considerations for Pediatricians

When implementing sotrovimab treatment in pediatric practice, several practical aspects should be considered:

Establishing protocols for rapid identification of eligible patients
Ensuring adequate infrastructure for safe administration and monitoring
Developing clear communication strategies for patients and families
Coordinating with local health authorities and hospital systems
Staying updated on evolving guidelines and variant susceptibility
Managing potential supply constraints and prioritizing high-risk patients
Integrating sotrovimab treatment into overall COVID-19 management strategies

Pediatricians should work collaboratively with infectious disease specialists, pharmacists, and other healthcare professionals to optimize the use of sotrovimab in their practice settings.