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Ibalizumab

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:

  1. Binding to CD4: Ibalizumab binds to domain 2 of the CD4 receptor on host T cells.
  2. Conformational changes: This binding induces conformational changes in CD4.
  3. 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:

  1. Loading dose:
    • 2,000 mg administered as a single intravenous infusion over 30 minutes
  2. 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


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