With an IC50 of 3.0 nM, capetreavir (GSK-1265744) blocks the strand transfer reaction that HIV-1 integrase catalyzes in vitro. In PBMCs, the antiviral EC50 against NL432 and HIV-1 Ba-L was 0.34 nM and 0.22 nM, respectively. The EC50 in MT-4 cells was found to be 0.57 nM using CellTiter-Glo, 1.3 nM using MTT, and 0.5 nM in the pseudotyped self-inactivating virus (PHIV) test [3].

In mice, capetreavir can have a half-life of up to 54 days [1]. When macaques (Macaques) are infected with SIVmac251, they are protected by capetregravir (iv; single dose or twice; 25 or 50 mg/kg) [4].

Cell Viability Assay[3]
Cell Types: MT-4 cells
Tested Concentrations: 0-32 nM
Incubation Duration: 4 or 5 days
Experimental Results: demonstrated antiviral activity with an EC50 of 1.3 nM.

Absorption, Distribution and Excretion
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.
An oral radiolabelled dose of cabotegravir is 58.5% recovered in the feces and 26.8% recovered in the urine.
Data regarding the volume of distribution of cabotegravir is not readily available.
Data regarding the clearance of cabotegravir is not readily available. Clearance in dogs was 0.34 mL/min/kg and in cynomolgus monkeys was 0.32 mL/min/kg.

---

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

---

Biological Half-Life
The mean half life of oral cabotegravir is 41 hours. The mean half life of intramuscular extended-release cabotegravir is 5.6-11.5 weeks.

Hepatotoxicity
In large clinical trials, switching antiretroviral therapy of HIV infection to the combination of parenteral injections of long acting cabotegravir and rilpivirine was associated with alanine aminotransferase (ALT) elevations in up to 7% of patients, but levels above 5 times the upper limit of normal (ULN) arose in only 1% to 2% of subjects. The elevations were typically transient, asymptomatic, and rarely required dose modification or discontinuation. While clinically apparent liver injury with jaundice was reported to occur in early studies, there were no such cases in the large, preregistration trials of long acting, parenteral cabotegravir and rilpivirine used for treatment of HIV infection or in the large trials of long acting cabotegravir used as prophylaxis against acquiring HIV infection. The use of injections every 4 or 8 weeks has been found to improve compliance and to be preferable to daily oral therapy by many patients requiring long term antiretroviral therapy. Since approval of cabotegravir for use as maintenance therapy and for prophylaxis against HIV infection, there have been no case reports of clinically apparent hepatotoxicity associated with its use.
Interestingly, in the large preregistration trials of parenteral cabotegravir and rilpivirine as replacement therapy of HIV infection, cases of acute hepatitis A, B and C were reported as adverse events, occurring largely in patients who had been switched to the parenteral regimen compared to control subjects who were continued on oral agents. The reasons for these differences were unclear. Importantly, neither cabotegravir or rilpivirine have activity against hepatitis B virus (HBV), and one possibility has been that reactivation of hepatitis B may occur after withdrawal of oral antiretroviral agents that have activity against HBV, such as tenofovir, emtricitabine, and lamivudine. For this reason, patients starting long- acting parenteral regimens of cabotegravir and rilpivirine should be screened for hepatitis B virus markers and potential risks of stopping agents with activity against HBV should be considered. In addition, persons with HIV without protective antibodies to HAV and HBV should be offered hepatitis A and B virus vaccination.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No published information is available on the use of cabotegravir during breastfeeding. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
Cabotegravir is >99.8% bound to proteins in plasma, usually alubmin.

[1]. Zhou T, et al. Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials. 2018 Jan;151:53-65.
[2]. Reese MJ, et al. Drug interaction profile of the HIV integrase inhibitor cabotegravir: assessment from in vitro studies and a clinical investigation with midazolam. Xenobiotica. 2015 Sep 4:1-12.
[3]. Yoshinaga T, et al. Antiviral characteristics of GSK1265744, an HIV integrase inhibitor dosed orally or by long-acting injection. Antimicrob Agents Chemother. 2015 Jan;59(1):397-406.
[4]. Andrews CD, et al. Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251. AIDS. 2017 Feb 20;31(4):461-467.

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-).
Cabotegravir is a prescription medicine approved by the U.S. Food and Drug Administration (FDA). It is approved as two different dosage forms under two different brand names for the following uses:
Cabotegravir oral tablet (brand name: Vocabria)
For the short-term treatment of HIV infection in adults and adolescents 12 years of age and older who weigh at least 77 lb (35 kg) and who meet certain requirements, as determined by a health care provider. When used for HIV treatment, cabotegravir is always used with the HIV medicine rilpivirine (brand name: Edurant).
For short-term PrEP to reduce the risk of HIV infection in adults and adolescents who weigh at least 77 lb (35 kg), are HIV negative, and are at risk of getting HIV. Oral cabotegravir for PrEP should always be used in combination with safer sex practices, such as using condoms, to reduce the risk of getting other sexually transmitted infections. 
Long-acting injectable cabotegravir (brand name: Apretude)
For HIV PrEP to reduce the risk of HIV infection in adults and adolescents who weigh at least 77 lb (35 kg), are HIV negative, and are at risk of getting HIV. Long-acting injectable cabotegravir for PrEP should always be used in combination with safer sex practices, such as using condoms, to reduce the risk of getting other sexually transmitted infections.
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.
Cabotegravir is a Human Immunodeficiency Virus Integrase Strand Transfer Inhibitor. The mechanism of action of cabotegravir is as a HIV Integrase Inhibitor, and Organic Anion Transporter 1 Inhibitor, and Organic Anion Transporter 3 Inhibitor.
Cabotegravir is an antiviral agent that inhibits the human immunodeficiency virus (HIV) integrase and is used in combination with rilpivirine, a non-nucleoside HIV reverse transcription inhibitor, in the treatment of HIV infection and the acquired immunodeficiency syndrome (AIDS). The fixed combination of cabotegravir and rilpivirine is typically given intramuscularly once monthly and has been linked to a low rate of serum aminotransferase elevations during therapy and to rare episodes of acute, clinically apparent liver injury.
Cabotegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), that is used for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Upon gluteal intramuscular administration, cabotegravir binds to the active site of HIV integrase and inhibits the activity of HIV integrase, an HIV-1 coded enzyme that is necessary for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA.
See also: Cabotegravir Sodium (annotation moved to).

---

Drug Indication
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.
Apretude is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in high-risk adults and adolescents, weighing at least 35 kg (see sections 4. 2, 4. 4 and 5. 1).
Treatment of human immunodeficiency virus (HIV-1) infection
Prevention of human immunodeficiency virus (HIV-1) infection
Treatment of human immunodeficiency virus (HIV-1) infection
Treatment of human immunodeficiency virus (HIV-1) infection

---

Mechanism of Action
Cabotegravir binds to the active site of HIV integrase, preventing strand transfer of the viral genome into the host genome, and preventing replication of the virus.

C19H17F2N3O5

405.35

405.113

C, 56.30; H, 4.23; F, 9.37; N, 10.37; O, 19.73

1051375-10-0

Dolutegravir;1051375-16-6;Cabotegravir sodium;1051375-13-3;Cabotegravir-d5;2750534-77-9

54713659

Solid powder

1.6±0.1 g/cm3

664.0±55.0 °C at 760 mmHg

355.4±31.5 °C

0.0±2.1 mmHg at 25°C

1.661

-1.7

2

8

3

29

814

2

C[C@H]1CO[C@H]2N1C(=O)C3=C(C(=O)C(=CN3C2)C(=O)NCC4=C(C=C(C=C4)F)F)O

WCWSTNLSLKSJPK-LKFCYVNXSA-N

InChI=1S/C19H17F2N3O5/c1-9-8-29-14-7-23-6-12(16(25)17(26)15(23)19(28)24(9)14)18(27)22-5-10-2-3-11(20)4-13(10)21/h2-4,6,9,14,26H,5,7-8H2,1H3,(H,22,27)/t9-,14+/m0/s1

(3S,11aR)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

GSK744; S/GSK 1265744; GSK-744; S/GSK1265744; GSK 744; S/GSK-1265744; Cabotegravir; Cabenuva.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 1.67 mg/mL (4.12 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)