HIVADA (IC50 = 2.5 nM); OAT3 (IC50 = 0.41 μM); OAT1 (IC50 = 0.81 μM)

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].

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1. Cabotegravir (CAB; GSK1265744) is a potent HIV integrase inhibitor in clinical development as an oral lead-in tablet and long-acting injectable for the treatment and prevention of HIV infection. 2. This work investigated if CAB was a substrate for efflux transporters, the potential for CAB to interact with drug-metabolizing enzymes and transporters to cause clinical drug interactions, and the effect of CAB on the pharmacokinetics of midazolam, a CYP3A4 probe substrate, in humans. 3. CAB is a substrate for Pgp and BCRP; however, its high intrinsic membrane permeability limits the impact of these transporters on its intestinal absorption. 4. At clinically relevant concentrations, CAB did not inhibit or induce any of the CYP or UGT enzymes evaluated in vitro and had no effect on the clinical pharmacokinetics of midazolam. 5. CAB is an inhibitor of OAT1 (IC50 0.81 µM) and OAT3 (IC50 0.41 µM) but did not or only weakly inhibited Pgp, BCRP, MRP2, MRP4, MATE1, MATE2-K, OATP1B1, OATP1B3, OCT1, OCT2 or BSEP. 6. Based on regulatory guidelines and quantitative extrapolations, CAB has a low propensity to cause clinically significant drug interactions, except for coadministration with OAT1 or OAT3 substrates. [2]

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The in vitro antiviral profile and mechanism of action of GSK1265744 were established through integrase enzyme assays, resistance passage experiments, and cellular assays with site-directed molecular (SDM) HIV clones resistant to other classes of anti-HIV-1 agents and earlier INSTIs. GSK1265744 inhibited HIV replication with low or subnanomolar efficacy and with a selectivity index of at least 22,000 under the same culture conditions. The protein-adjusted half-maximal inhibitory concentration (PA-EC50) extrapolated to 100% human serum was 102 nM. When the virus was passaged in the presence of GSK1265744, highly resistant mutants with more than a 10-fold change (FC) in EC50 relative to that of the wild-type were not observed for up to 112 days of culture. GSK1265744 demonstrated activity against SDM clones containing the raltegravir (RAL)-resistant Y143R, Q148K, N155H, and G140S/Q148H signature variants (FC less than 6.1), while these mutants had a high FC in the EC50 for RAL (11 to >130). Either additive or synergistic effects were observed when GSK1265744 was tested in combination with representative anti-HIV agents, and no antagonistic effects were seen[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].

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Long-acting parenteral (LAP) antiretroviral drugs have generated considerable interest for treatment and prevention of HIV-1 infection. One new LAP is cabotegravir (CAB), a highly potent integrase inhibitor, with a half-life of up to 54 days, allowing for every other month parenteral administrations. Despite this excellent profile, high volume dosing, injection site reactions and low body fluid drug concentrations affect broad use for virus infected and susceptible people. To improve the drug delivery profile, we created a myristoylated CAB prodrug (MCAB). MCAB formed crystals that were formulated into nanoparticles (NMCAB) of stable size and shape facilitating avid monocyte-macrophage entry, retention and reticuloendothelial system depot formulation. Drug release kinetics paralleled sustained protection against HIV-1 challenge. After a single 45 mg/kg intramuscular injection to BALB/cJ mice, the NMCAB pharmacokinetic profiles was 4-times greater than that recorded for CAB LAP. These observations paralleled replicate measurements in rhesus macaques. The results coupled with improved viral restriction in human adult lymphocyte reconstituted NOD/SCID/IL2Rγc-/- mice led us to conclude that NMCAB can improve biodistribution and viral clearance profiles upon current CAB LAP formulations. [1]

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Objective: Researchers evaluated the effectiveness of cabotegravir (CAB; GSK1265744 or GSK744) long-acting (LA) as pre-exposure prophylaxis (PrEP) against intravenous SIV challenge in a model that mimics blood transfusions based on the per-act probability of infection.
Design: CAB LA is an InSTI formulated as a 200 mg/mL injectable nanoparticle suspension that is an effective pre-exposure prophylaxis (PrEP) agent against rectal and vaginal SHIV transmission in macaques.
Methods: Three groups of rhesus macaques (n=8/group) were injected intramuscularly with CAB LA and challenged intravenously with 17 AID50 SIVmac251 on week 2. Group 1 was injected with 50 mg/kg on week 0 and 4 to evaluate the protective efficacy of the CAB LA dose used in macaque studies mimicking sexual transmission. Group 2 was injected with 50 mg/kg on week 0 to evaluate the necessity of the second injection of CAB LA for protection against intravenous challenge. Group 3 was injected with 25 mg/kg on week 0 and 50 mg/kg on week 4 to correlate CAB plasma concentrations at the time of challenge with protection. Five additional macaques remained untreated as controls.
Results: CAB LA was highly protective with 21 of the 24 CAB LA-treated macaques remaining aviremic, resulting in 88% protection. The plasma CAB concentration at the time of virus challenge appeared to be more important for protection than sustaining therapeutic plasma concentrations with the second CAB LA injection.
Conclusions: These results support the clinical investigation of CAB LA as PrEP in people who inject drugs [4].

In vitro strand transfer assay. [3]
The inhibitory concentrations of cabotegravir (GSK1265744) and other INSTIs were measured in a strand transfer assay using recombinant HIV IN as previously described. A complex of integrase and biotinylated donor DNA-streptavidin-coated scintillation proximity assay (SPA) beads was formed by incubating 2 μM purified recombinant integrase with 0.66 μM biotinylated donor DNA–4 mg/ml streptavidin-coated SPA beads in 25 mM sodium morpholinepropanesulfonic acid (MOPS) (pH 7.2), 23 mM NaCl, and 10 mM MgCl2 for 5 min at 37°C. These beads were spun down and preincubated with diluted INSTIs for 60 min at 37°C. Next, 3H-labeled target DNA substrate was added to give a final concentration of 7 nM substrate, and the strand transfer reaction mixture was incubated at 37°C for 25 to 45 min, which allowed for a linear increase in strand transfer of donor DNA to radiolabeled target DNA. The signal was read using a Wallac MicroBeta scintillation plate reader.

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PHIV assay. [3]
The antiviral activities of compounds were measured in a single-round assay using a self-inactivating PHIV lentiviral vector. CIP4 cells (2 × 104 cells/well) were infected with PHIV sufficient to produce approximately 50,000 relative light units in the assay. The infected cells were added to 96-well, black, clear-bottom plates with various concentrations of cabotegravir (GSK1265744) and incubated for 2 days. Luciferase activity was measured in a luminometer using the Steady-Glo reagent.

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Effect of human serum and serum proteins. [3]
The effect of the presence of human serum albumin (HSA) (20 or 40 mg/ml), α1-acid glycoprotein (AAG) (2 mg/ml), and human serum (HS) (using up to 30% or 50% and extrapolated to 100%) on the antiviral activity of cabotegravir (GSK1265744) was evaluated in PHIV and MT-4 assay systems. To estimate the effects of protein binding, antiviral activity was tested with the addition of various concentrations of human serum to an HIV replication assay in MT-4 cells as previously described. The protein-adjusted half-maximal effective concentration (PA-EC50) was estimated by multiplying the EC50 in PBMCs by the fold-shift value.

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.

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Cell models to assess antiretroviral activity [1]
Monocyte-derived macrophages (MDM) were utilized. Human peripheral blood monocytes were obtained and cultured as previously described. Briefly, monocytes were obtained by leukapheresis of HIV-1/2 and hepatitis B seronegative donor blood cells, followed by purification via countercurrent centrifugal elutriation. Elutriated monocytes were cultured as adherent cells in DMEM supplemented with 10% heat-inactivated pooled human serum, 10 µg/mL ciprofloxacin, 50 µg/mL gentamicin, and 1000 U/mL recombinant macrophage colony stimulating factor. Cells were maintained at 37 °C in a 5% CO2 incubator. Seven days later, differentiated macrophages were treated with various concentrations (0.06–1000 nM) of native cabotegravir (GSK1265744)/CAB or MCAB for 30 min, followed by HIV-1ADA challenge at a multiplicity of infection (MOI) of 0.1 infectious viral particles/cell. Four hrs after challenge, cells were washed three times with sterile phosphate-buffered saline (PBS) followed by incubation with the same concentration of each compound used before infection. Cells were cultured for additional 7 days with half-media changes every other day with DMEM media containing the same drug concentrations. Supernatants were collected 7 days after the challenge for HIV reverse transcriptase (RT) activity determination as previously described. To determine the antiretroviral activity of nanoformulations, MDM were treated with NMCAB, CAB LAP, or NCAB containing 100 µM drug for 8 h, followed by 3 PBS washes to remove any extracellular drug. At predetermined time points (days 0, 2, 5, 10, and 15), MDM were challenged with HIV-1ADA at an MOI of 0.1 for 4 h. Seven days after the virus challenge, culture media were analyzed for RT activity, while adherent MDM were fixed with 4% PFA and HIV-1p24 protein expression was assessed by immunocytochemistry.

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Cytotoxicity assays. [3]
In vitro growth inhibition (cytotoxicity) studies were conducted with cabotegravir (GSK1265744) in proliferating human leukemia and lymphoma cell lines (IM-9, U-937, MT-4, and Molt-4) as well as stimulated and unstimulated human PBMCs. As a surrogate of cell growth, ATP levels were quantified using the CellTiter-Glo luciferase reagent.

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Mechanistic cellular studies. [3]
To determine if cabotegravir (GSK1265744) was inhibiting HIV replication in cellular assays through an integrase inhibition mechanism, the effect on the synthesis of HIV NL432 DNA species in MT-4 cells was measured in a single-round infection assay using quantitative PCR methods in the presence of INSTI or nonnucleoside reverse transcriptase inhibitor (NNRTI) as described previously with minor modifications. Briefly, 293T cells were transfected with the NL432 plasmid to generate infectious virus, and the supernatant was filtered through 0.45-μm-pore-size filters and treated with DNase I. MT-4 cells were infected with HIV-1 NL432 virus for 1 h with diluted compound and collected after 6 or 18 h of incubation. All cells were incubated with a 0.5 μM concentration of the protease inhibitor (PI) ritonavir to limit HIV replication to a single cycle. Total-DNA PCR to detect late RT products was performed with the samples after 6 h of incubation. Nested Alu-PCR to detect integrated provirus and two-LTR PCR to detect two-LTR circles were performed with the samples taken at 18 h of incubation. Reactions were analyzed using the ABI Prism 7900HT-3 sequence detection system.

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Cross-resistance profiling of cabotegravir (GSK1265744). [3]
cabotegravir (GSK1265744) was evaluated against molecular clones with mutations in the IN-, RT-, and protease (PR)-coding regions. INSTI-, nucleoside reverse transcriptase inhibitor (NRTI)-, and NNRTI-resistant mutants were analyzed by the reporter assay based on HeLa-CD4 cells, while PI-resistant mutants were analyzed by infectivity in MT-4 cells, monitoring RT activity as described previously. The HIV-1 wild-type infectious molecular clone pNL432 was used for site-directed mutagenesis to generate HIV clones containing mutations. Fifty INSTI-resistant mutants were constructed. The molecular clones with K101E, K103N, E138K, Y181C, M184I, M184V, Y188L, K101E/M184I, E138K/M184I D67/K70R/T215Y, and R4 (V75I/F77L/F116Y/Q151M) substitutions within the RT coding region were used as NRTI or NNRTI-resistant viruses, and PI-resistant mutants carrying the M46I/I47V/I50V and L24I/M46I/L63P/A71V/G73S/V82T mutations with the protease coding region were used. 293T cells were subsequently transfected with the plasmids to generate infectious virus using Lipofectamine 2000. Supernatants were harvested 2 to 3 days after transfection, stored as cell-free culture supernatants at −80°C, and used for each assay.

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Combination antiviral activity assay in MT-4 cells. [3]
The in vitro combination activity relationships of cabotegravir (GSK1265744) were determined as previously described. Multiple concentrations of cabotegravir (GSK1265744) were tested in a checkerboard dilution fashion in the presence and absence of dilutions of approved representative anti-HIV drugs, adefovir or ribavirin. The interaction of compounds was analyzed by dosewise additivity-based calculations. Wells containing the top concentration of compounds by themselves were compared to wells with the top concentration of both compounds to show that combination effects were due to the drugs used and not to toxicity. Assays with the MT-4 system format were run as described previously. Fractional inhibitory concentration (FIC) values in the range of −0.1 to −0.2 indicated weak synergy, values that approached −0.5 indicated strong synergy, and positive values of 0.1 to 0.2 indicated weak antagonism. The effects of the anti-hepatitis B virus (HBV) and anti-hepatitis C virus (HCV) agents adefovir and ribavirin on the cabotegravir (GSK1265744) EC50 were examined using linear regression as described previously (30). Since the HIV-1 IIIB MT-4 system is CXCR4 based, the CCR5 inhibitor Maraviroc was evaluated in a checkerboard dilution format using HIV-1 Ba-L-infected MAGI-CCR5 cells with Gal-Screen reagent for the chemiluminescent endpoint. Data were analyzed as described by Prichard using the MacSynergy II program. Synergy volumes in the range of −50 to 50 defined additivity, <−50 defined antagonism, and >50 defined synergy.

In female pigtail macaques model that intravaginal inoculated simian/human immunodeficiency virus twice a week for up to 11 weeks, GSK744 injection prevented the macaques from being infected by virus while placebo controls were infected after a 4 median vaginal challenges with SHIV which reminded that GSK744 may be a potential preexposure prophylaxis drug for prevention via inhibiting HIV integrase

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Pharmacokinetics (PK) and biodistribution (BD) of NMCAB in BALB/cJ mice [1]
Male BALB/cJ mice were dosed intramuscularly with NMCAB or CAB LAP 45 mg cabotegravir (GSK1265744)/CAB equivalents, followed by weekly blood collection in heparinized tubes via cheek bleeding. Plasma was collected via centrifugation at 2000 × g for 5 min for the drug quantitation by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) (see supplementary method). At day 28 and day 58 after nano-formulation injection, 5 mice in each treatment group were sacrificed and tissues including liver, lung, spleen, lymph node were collected for drug quantitation by UPLC-MS/MS (see supplementary method). To identify potential drug depots for NMCAB, PK at early time points was assessed in male BALB/cJ mice after a single intramuscular injection of NMCAB or CAB LAP (45 mg CAB equivalents/kg). At predetermined time points (15 min, 1, 2, 4, and 8 h and 1, 3, 7, 10 and 14 days), 25 mL of whole blood was collected and levels of both cabotegravir (GSK1265744)/CAB and MCAB were determined. Tissues were collected at days 1, 3, 7 and 14 for drug quantitation by UPLC-MS/MS.

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NMCAB PK in rhesus macaques [1]
Two male Chinese rhesus macaques (3 years old; 4.0 and 4.7 kg) were anesthetized with 10 mg/kg ketamine and injected intramuscularly with NMCAB at 45 mg cabotegravir (GSK1265744)/CAB equivalents/kg in 2.1 and 2.5 mL, respectively. Blood was collected into potassium EDTA tubes before drug administration, and at days 4, 7, 11, and 18 after the administration, and biweekly thereafter. Plasma was obtained for CAB and MCAB drug quantitation and metabolic panels, while peripheral blood mononuclear cells (PBMCs) were obtained for complete blood counts.

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Studies of viral restriction in humanized adult lymphocyte mice [1]
Male 6–8-week-old NOD/SCID/IL2Rγc−/− (NSG) mice were injected intramuscularly with NMCAB or cabotegravir (GSK1265744)/CAB LAP at 45 mg CAB equivalents/kg. Eleven days after nanoformulation treatments, mice were reconstituted by intraperitoneal injection with 25 × 106 human peripheral blood lymphocytes (PBL) obtained by leukapheresis and centrifugal elutriation. Eleven days after reconstitution, mice were challenged with 104 50% tissue culture infectious dose (TCID50) HIV-1ADA by intraperitoneal injections. Mice were sacrificed 10 days after viral challenge. The experimental timeline is shown in Fig. 7A. Peripheral blood was collected at days 10 (prior to PBL reconstitution), 21 (prior to HIV-1 challenge), and 32 (10 days post HIV-1 challenge) for flow cytometry analysis of human pan-CD45, CD3, CD4 and CD8 immune markers. Plasma was collected via centrifugation at 2000 × g for 5 min for drug quantitation by UPLC-MS/MS. HIV-1 RNA was analyzed in day 32 plasma samples using the Roche Amplicor and Taqman-48 system with HIV-1 kit V 2.0 according to the manufacturer’s instructions. Tissues were collected for CAB concentrations by UPLC/MS/MS, viral RNA and DNA quantitation by semi-nested real-time PC, and immunohistochemical staining for HIV-1p24 antigen as described previously.

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Efficacy of cabotegravir (GSK1265744)/CAB LA in preventing SIV intravenous transmission [4]
The efficacy of CAB LA against intravenous SIV transmission was evaluated in three groups of Indian rhesus macaques (Macaca mulatta) (n=8/group) injected IM with cabotegravir (GSK1265744)/CAB LA and challenged intravenously with 17 AID50 SIVmac251 on week 2. Group 1 was injected with 50 mg/kg CAB LA on week 0 and 4, the same dosing regimen used in previous studies assessing CAB LA prevention efficacy against mucosal transmission. Group 2 was injected with 50 mg/kg of CAB LA on week 0 to understand the relative importance of CAB concentrations at the time of challenge and negating the potential benefit of a second injection that would prevent infection distal to the time of challenge as had been seen in the high-dose challenge experiments in female rhesus macaques. Group 3 was injected with 25 mg/kg CAB LA on week 0 and 50 mg/kg CAB LA on week 4 to determine the importance of CAB concentration at the time of challenge while maintaining the second injection thereby modifying a single variable, peak drug concentrations at the time of intravenous challenge. CAB LA is a 200 mg/mL nanosuspension that was administered based on body weights measured at the time of dosing (5.4 to 11.3 kg) with the dose split into four injections, two per quadriceps. Five additional macaques remained untreated as controls. Systemic infection was monitored weekly for 20 weeks after the last CAB LA administration by detection of SIV RNA in plasma using real-time RT-PCR assay with a sensitivity of 40 SIV RNA copies/mL as previously described. PBMC proviral DNA amplification was performed as previously described. Serology was performed utilizing SIVmac251 gp120-coated plates. cabotegravir (GSK1265744)/CAB plasma concentration analyses were performed as previously described. Integrase sequence analyses from bulk plasma virus was performed as previously described.

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.

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

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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.

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Background: GSK1265744 is an HIV integrase strand transfer inhibitor selected for clinical development. Objective: This first-time-in-human and phase IIa investigation assessed GSK1265744 antiviral activity, pharmacokinetics, safety, and tolerability in healthy and HIV-1–infected subjects. Methods: This double-blind, placebo-controlled study consisted of a dose escalation of single (part A) and multiple (part B) oral doses in 48 healthy subjects and an oral dose (part C) in 11 HIV-1–infected subjects. In part A, 2 cohorts of 9 subjects received either 5 and 25 mg or 10 and 50 mg. In part B, 3 cohorts of 10 subjects received 5, 10, or 25 mg once daily for 14 days. In part C and the phase IIa study, subjects received 5 or 30 mg once daily for 10 days. Results: Dose-proportional increases in drug exposure were observed in healthy and HIV-1–infected subjects. In healthy subjects, pharmacokinetic variability was low following single or repeat dosing (coefficient of variation, 13%-34% and 15%-23%, respectively). Mean plasma half-life was 31.5 hours. GSK1265744 monotherapy significantly reduced plasma HIV-1 RNA from baseline to day 11 in HIV-1–infected subjects receiving 5 or 30 mg versus placebo (P < .001); mean decrease was 2.2 to 2.3 log10 copies/mL, respectively. Study drug was generally well tolerated with no clinically relevant trends in laboratory values, vital signs, or electrocardiograms. Conclusions: GSK1265744 was well tolerated in healthy and HIV-1–infected subjects. Results demonstrate once-daily doses of 5 or 30 mg exceeded minimum target therapeutic concentrations and produced a significant reduction in plasma HIV-1 RNA viral load. https://www.tandfonline.com/doi/abs/10.1310/hct1405-192?src=recsys

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).

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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.

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

[1]. Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials. 2018 Jan;151:53-65.

[2]. Drug interaction profile of the HIV integrase inhibitor cabotegravir: assessment from in vitro studies and a clinical investigation with midazolam. Xenobiotica. 2016;46(5):445-56.

[3]. 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]. Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251. AIDS. 2017 Feb 20;31(4):461-467.

Pharmacodynamics
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.

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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)

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.

CABOTEGRAVIR is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2021 and has 3 approved and 1 investigational indication.

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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).
Vocabria tablets are indicated in combination with rilpivirine tablets for the short-term treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults who are virologically suppressed (HIV-1 RNA

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

White to yellow 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; Cabotegravir; 1051375-10-0; GSK1265,744; GSK744; GSK-1265,744; GSK1265,744A; Apretude; Cabotegravir (GSK744, GSK1265,744); 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.

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