Ibalizumab (HIV-1 Inhibitor): Applications in Pediatric Medicine
Introduction to Ibalizumab
Ibalizumab (Trogarzo) is a humanized monoclonal antibody and the first HIV-1 inhibitor to target the CD4 receptor, a novel mechanism of action in antiretroviral therapy. Developed by TaiMed Biologics and marketed by Theratechnologies, it was approved by the FDA in 2018 for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced adults.
Key points:
- First-in-class CD4 domain 2 directed post-attachment HIV-1 inhibitor
- Approved for use in combination with other antiretroviral medications
- Administered intravenously
- Offers a new option for patients with limited treatment options due to multidrug resistance
Mechanism of Action
Ibalizumab is a CD4 domain 2-directed post-attachment HIV-1 inhibitor. Its unique mechanism of action involves:
- Binding to CD4: Ibalizumab binds to domain 2 of the CD4 receptor on host T cells.
- Conformational changes: This binding induces conformational changes in CD4.
- Inhibition of viral entry: These changes prevent the HIV-1 viral envelope from interacting with the CD4 receptor, thus blocking viral entry into the host cell.
Important characteristics:
- Does not interfere with CD4's role in immune-cell signaling
- Active against CCR5 and CXCR4 tropic HIV-1
- Maintains activity against HIV-1 resistant to other antiretroviral classes
- Does not require daily dosing due to its long half-life
Indications and Usage
Ibalizumab is indicated for:
- Treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen
Specific criteria for use:
- Patients must have multidrug-resistant HIV-1 infection
- Failing or have failed multiple prior antiretroviral regimens
- Resistance to at least one antiretroviral medication from each of the three main classes (NRTIs, NNRTIs, and PIs)
Important considerations:
- Must be used in combination with other antiretroviral medications
- Not indicated for treatment-naïve patients or those without multidrug resistance
- Resistance testing and treatment history should guide the use of ibalizumab
Clinical Pharmacology
Pharmacokinetics:
- Distribution: Mean volume of distribution of 4.8 L
- Metabolism: As a monoclonal antibody, it is expected to be degraded into small peptides and amino acids
- Elimination: Mean elimination half-life of 72 to 84 hours
- Steady-state: Achieved after the first maintenance dose
Pharmacodynamics:
- Exposure-response relationship observed between ibalizumab trough concentrations and efficacy
- No clear relationship between exposure and incidence of adverse reactions
Microbiology:
- Active against CCR5-tropic, CXCR4-tropic, and dual-tropic HIV-1
- No cross-resistance with other antiretroviral classes
- Potential for HIV-1 to develop reduced susceptibility to ibalizumab
Dosage and Administration
Ibalizumab is administered intravenously. The recommended dosage regimen is:
- Loading dose:
- 2,000 mg administered as a single intravenous infusion over 30 minutes
- Maintenance dose:
- 800 mg administered as an intravenous infusion over 15 minutes every 2 weeks
Important administration details:
- Must be diluted in 250 mL of 0.9% Sodium Chloride Injection, USP
- Administer immediately after dilution
- Do not administer as an intravenous push or bolus
- If a maintenance dose is missed by 3 days or more, a loading dose should be administered as early as possible
Dose modifications:
- No dose adjustments required for renal or hepatic impairment
- No dose adjustments based on age, gender, race, or weight
Clinical Efficacy
The efficacy of ibalizumab was primarily established in the TMB-301 study, a single-arm, multicenter clinical trial:
- Study population: 40 heavily treatment-experienced patients with multidrug-resistant HIV-1
- Design: 24-week study with a 7-day control period, followed by ibalizumab addition to failing regimen, then optimization of background regimen
- Primary endpoint: Proportion of patients achieving ≥ 0.5 log10 decrease in HIV-1 RNA at day 14
Key efficacy results:
- 83% of patients achieved ≥ 0.5 log10 decrease in HIV-1 RNA at day 14
- 55% of patients achieved HIV-1 RNA < 200 copies/mL at week 24
- 43% of patients achieved HIV-1 RNA < 50 copies/mL at week 24
- Mean increase in CD4+ T cell count of 62 cells/mm³ at week 24
Long-term efficacy was further supported by the TMB-311 study, showing sustained viral suppression and immunologic improvement for up to 48 weeks.
Adverse Effects
The most common adverse reactions (incidence ≥ 5%) observed in clinical trials include:
- Diarrhea (8%)
- Dizziness (8%)
- Nausea (5%)
- Rash (5%)
Laboratory abnormalities:
- Increased creatinine (10%)
- Increased bilirubin (5%)
- Increased lipase (5%)
Immunogenicity:
- Anti-ibalizumab antibodies were detected in 7% of patients
- No apparent correlation between anti-ibalizumab antibody formation and efficacy or safety
Precautions and Contraindications
Contraindications:
- No contraindications have been identified
Warnings and Precautions:
- Immune Reconstitution Inflammatory Syndrome (IRIS): May occur in patients receiving combination antiretroviral therapy
- Infusion-Related Reactions: May occur during and after infusion. Monitor patients during administration
Monitoring:
- Regular monitoring of viral load and CD4+ T cell count
- Assess for signs and symptoms of infusion-related reactions
- Monitor for signs of opportunistic infections and IRIS
Drug Interactions
Ibalizumab has a low potential for drug-drug interactions due to its mechanism of action and metabolism:
- No clinically significant drug-drug interactions have been identified
- No formal drug interaction studies have been conducted
Important considerations:
- Ibalizumab does not inhibit or induce cytochrome P450 enzymes
- As a monoclonal antibody, it is not expected to be affected by or affect other medications through common metabolic pathways
- Always review the complete regimen for potential interactions with other antiretroviral medications
Use in Special Populations
Pregnancy:
- Limited human data on use during pregnancy
- Animal reproductive studies have not been conducted
- Placental transfer of human IgG to the fetus is well documented
Lactation:
- No data on presence of ibalizumab in human milk, effects on breastfed infant, or milk production
- Human IgG is known to be present in human milk
Pediatric Use:
- Safety and efficacy in pediatric patients have not been established
Geriatric Use:
- Limited number of patients aged 65 and over have been treated with ibalizumab
- No overall differences in safety or efficacy observed between elderly and younger patients
Renal Impairment:
- No dose adjustment required
Hepatic Impairment:
- No dose adjustment required
Disclaimer
The notes provided on Pediatime are generated from online resources and AI sources and have been carefully checked for accuracy. However, these notes are not intended to replace standard textbooks. They are designed to serve as a quick review and revision tool for medical students and professionals, and to aid in theory exam preparation. For comprehensive learning, please refer to recommended textbooks and guidelines.
