Cabotegravir (GSK744, GSK1265744)

China [CN]

Core Mechanism of Action and Resistance

Mechanism of Action

It specifically binds to the catalytic core of HIV integrase, inhibiting the strand transfer reaction (a key step in HIV replication), preventing viral DNA integration into the host cell genome, and blocking viral replication at its source. It is a bactericidal antiretroviral drug.

Resistance Characteristics

It maintains high activity against mutant strains resistant to traditional INSTIs (such as raltegravir and dolutegravir) (e.g., Y143R, Q148K, N155H) (resistance fold change FC < 6.1), with a low risk of cross-resistance.

High-level resistance mutations are rare in clinical practice, and it has a high resistance barrier with long-term use, making it one of the preferred drugs for multidrug-resistant HIV infection.

III. Clinical Applications (Free Base/Sodium Salt are interchangeable)

Indications | Dosage and Administration

Treatment of HIV-1 infection | 1. Oral initiation: 30mg (film-coated tablets) once daily for 1 month to assess tolerability;

2. Long-acting maintenance: 600mg (suspension for injection) deep intramuscular injection once a month, can be used in combination with rilpivirine long-acting injection.

HIV Pre-exposure Prophylaxis (PrEP) | Long-acting injection: 600mg deep intramuscular injection every 2 months, suitable for high-risk populations (such as men who have sex with men, and high-risk heterosexual individuals), with better preventive effects than daily oral PrEP medication. Dosage Form and Specifications: Oral tablets: 30 mg (calculated as free base); Long-acting injectable suspension: 600 mg/3 mL (calculated as sodium salt)

IV. Pharmacokinetics (Key Parameters of Free Base)

Pharmacokinetic Parameters Data (Oral) Data (Long-acting Injection)

Bioavailability Approximately 64% (no difference between fasting and fed states) - (Directly enters the bloodstream, no first-pass effect)

Time to Peak Concentration (Tmax) 2-3 hours Steady-state plasma concentration reached 7-10 days after injection

Elimination Half-life (t₁/₂) Approximately 40 hours 5-7 days (long-acting sustained release, stable blood concentration)

Plasma Protein Binding Rate >99% (mainly binds to albumin) >99%

Metabolic Pathway Mainly metabolized by UGT1A1 glucuronidation, no CYP450-mediated metabolism Same as oral administration, metabolites have no anti-HIV activity

Excretion Pathway Feces (61%); Urine (32%, mainly metabolites) Same as oral administration

V. Safety and Drug Interactions

Common Adverse Reactions

Oral dosage form: Headache (15%), nausea (12%), diarrhea (10%), mostly mild to moderate, no need to discontinue the drug.

Injectable dosage form: Injection site reactions (redness, swelling, pain, induration, incidence approximately 70%), gradually decrease with increased frequency of use.

Serious adverse reactions: Rare liver damage, allergic reactions, mental abnormalities; liver function needs to be monitored regularly.