Cabotegravir (GSK744, GSK1265744)

Absorption

Oral cabotegravir has a Tmax of 3 hours, reaches a Cmax of 8.0 μg/mL, and has an AUC of 145 μg*h/mL. Intramuscular extended-release cabotegravir has a Tmax of 7 days, reaches a Cmax of 8.0 μg/mL, and has an AUC of 1591 μg*h/mL.

Toxicity

Data regarding the toxicity of cabotegravir is not readily available. In the event of overdose, patients should have their vital signs monitored, including an ECG to monitor the QT interval. Treat patients symptomatically and supportively. As cabotegravir is highly protein bound, dialysis is not expected to remove a significant amount of the drug from plasma.

The Uses of Cabotegravir (GSK744, GSK1265744)

Cabotegravir is a long acting HIV-1 integrase inhibitor with action against a broad range of HIV subtypes.

Definition

ChEBI: Cabotegravir is a monocarboxylic acid amide obtained by formal condensation of the carboxy group of (3S,11aR)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid with the amino group of 2,4-difluorobenzylamine. Used (as its sodium salt) for treatment of HIV-1. It has a role as a HIV-1 integrase inhibitor. It is a difluorobenzene, a secondary carboxamide, a monocarboxylic acid amide and an organic heterotricyclic compound. It is a conjugate acid of a cabotegravir(1-).

Indications

Oral cabotegravir is indicated in combination with rilpivirine for the short-term treatment of HIV-1 in virologically suppressed adults with no history of treatment failure to assess tolerability of cabotegravir or who have missed an injected dose of cabotegravir. Intramuscular extended-release cabotegravir in combination with rilpivirine is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents 12 years of age and older weighing at least 35 kg to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine.
An extended-release injectable suspension formulation of cabotegravir is also indicated for the prevention of sexually-acquired HIV-1 infection (i.e. for pre-exposure prophylaxis, PrEP) in at-risk adults and adolescents weighing at least 35kg.

Background

Cabotegravir, or GSK1265744, is an HIV-1 integrase inhibitor that is prescribed with the non-nucleoside reverse transcriptase inhibitor, rilpivirine. Early research into cabotegravir showed it had lower oral bioavailability than dolutegravir, which resulted in the development of long acting monthly intramuscular injection formulation for cabotegravir.
Cabotegravir was granted FDA approval on 21 January 2021 in combination with rilpivirine to treat HIV-1 infection in virologically suppressed individuals. While previously administered once monthly only, this combination product was granted FDA approval for dosing every two months on February 01, 2022 and without the need for an oral lead-in period prior.

Biological Activity

Cabotegravir (GSK744, GSK1265744) is a long-acting HIV integrase inhibitor against a broad range of HIV subtypes, inhibiting HIV-1 integrase-catalyzed strand transfer with IC50 of 3 nM. Phase 2.

Mechanism of action

Caboggravir is a potent inhibitor of HIV integrase, which prevents the HIV virus from infecting human cells, while rilpivirine prevents the virus from replicating itself.

Pharmacokinetics

Cabotegravir is an inhibitor of HIV integrase, which reduces viral replication. It has a long duration of action as the oral tablet is given daily and the intramuscular suspension is given monthly. Patients should be counselled regarding the risk of hypersensitivity, hepatotoxicity, and depression.

Metabolism

Cabotegravir is O-glucuronidated to the M1 and M2 metabolites, with 67% of glucuronidation performed by UGT1A1, and 33% by UGT1A9.