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

In vitro, cabotegravir (GSK-1265744) blocks the strand transfer reaction that HIV-1 integrase catalyzes at an IC50 of 3.0 nM. The antiviral EC50 for NL432 and HIV-1 Ba-L in PBMCs was 0.34 nM and 0.22 nM, respectively. With an EC50 of 0.5 nM in a PHIV experiment employing type A self-inactivating virus, the EC50 in MT-4 cells was determined to be 0.57 nM using CellTiter-Glo and 1.3 nM using MTT [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].

The half-phase drop of Cabotegravir in mice is as long as 54 days [1]. Cabotegravir (25 or 50 mg/kg; iv; single or twice dosage) protects against SIVmac251 infection in macaques (Macaques) [4].

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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.

Viability assay[3]
Cell Types: MT-4 Cell
Tested Concentrations: 0-32 nM
Incubation Duration: 4 or 5 days
Experimental Results: Displayed antiviral activity with 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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\n\n Pharmacokinetics (PK) and biodistribution (BD) of NMCAB in BALB/cJ mice [1]
\nMale 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.\n

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\n\nNMCAB PK in rhesus macaques [1]
\nTwo 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. \n

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\n\nStudies of viral restriction in humanized adult lymphocyte mice [1]
\nMale 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.\n

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\nEfficacy of cabotegravir (GSK1265744)/CAB LA in preventing SIV intravenous transmission [4]
\nThe 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
The time to peak concentration (Tmax) of orally administered cabobotevir was 3 hours, with a peak plasma concentration (Cmax) of 8.0 µg/mL and an AUC of 145 µgh/mL. The time to peak concentration (Tmax) of intramuscularly administered sustained-release cabobotevir was 7 days, with a peak plasma concentration (Cmax) of 8.0 µg/mL and an AUC of 1591 µgh/mL. 58.5% of orally administered radiolabeled cabobotevir was recovered from feces, and 26.8% from urine. Data on the volume of distribution of cabobotevir are currently unavailable. Data on cabobotevir clearance are currently unavailable. The clearance rate in dogs was 0.34 mL/min/kg, and in cynomolgus monkeys it was 0.32 mL/min/kg.

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Metabolites/Metabolites
Cabotabvir is converted to M1 and M2 metabolites via O-glucuronidation, with 67% of glucuronidation occurring via UGT1A1 and 33% via UGT1A9.Biological Half-Life
The mean half-life of orally administered cabobotevir is 41 hours. The mean half-life of intramuscularly administered extended-release cabobotevir is 5.6–11.5 weeks.
Background: GSK1265744 is an HIV integrase strand transfer inhibitor that has been selected for clinical development. Objective: This first-in-human, Phase IIa study evaluated the antiviral activity, pharmacokinetics, safety, and tolerability of GSK1265744 in healthy subjects and individuals infected with HIV-1.
Methods: This double-blind, placebo-controlled study included single-dose (Part A) and multiple-dose (Part B) oral dose escalation trials in 48 healthy subjects, and oral dose escalation trials in 11 HIV-1 infected individuals (Part C). In Part A, nine subjects in each of the two groups received doses of 5 mg and 25 mg, or 10 mg and 50 mg, respectively. In Part B, ten subjects in each of the three groups received doses of 5 mg, 10 mg, or 25 mg once daily for 14 days. In Part C and the Phase IIa study, subjects received doses of 5 mg or 30 mg once daily for 10 days. Results: A dose-proportional increase in drug exposure was observed in both healthy subjects and HIV-1 infected individuals. Pharmacokinetic variability was low in healthy subjects after single or repeated dosing (coefficients of variation were 13%–34% and 15%–23%, respectively). The mean plasma half-life was 31.5 hours. In HIV-1 infected individuals, those receiving 5 mg or 30 mg GSK1265744 monotherapy showed a significant reduction in plasma HIV-1 RNA levels from baseline up to day 11 (P < .001 compared to the placebo group); the mean reduction ranged from 2.2 to 2.3 log10 copies/mL. The study drug was generally well-tolerated, with no clinically significant trends observed in laboratory values, vital signs, or electrocardiograms. Conclusion: GSK1265744 was well-tolerated in both healthy subjects and HIV-1 infected individuals. The results indicate that once-daily doses of 5 mg or 30 mg exceeded the minimum target therapeutic concentration and significantly reduced plasma HIV-1 RNA viral load. https://www.tandfonline.com/doi/abs/10.1310/hct1405-192?src=recsys

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no publicly available information regarding the use of Cabotegravir during lactation. Achieving and maintaining viral suppression through antiretroviral therapy can reduce the risk of transmission through breastfeeding to below 1%, but not zero. For HIV-infected individuals receiving antiretroviral therapy with a persistently low viral load, breastfeeding should be supported if they choose to do so. If viral load is not suppressed, pasteurized donor breast milk or formula is recommended.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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Hepatotoxicity
In large clinical trials, up to 7% of patients experienced elevated alanine aminotransferase (ALT) levels after switching from antiretroviral therapy for HIV infection to a combination of long-acting cabozantvir and rilpivirine. However, only 1% to 2% of subjects experienced ALT levels exceeding five times the upper limit of normal (ULN). These elevations were usually transient and asymptomatic, rarely requiring dose adjustments or discontinuation. Although clinically significant liver injury with jaundice had been reported in earlier studies, no such cases were observed in large pre-registration trials of long-acting injectable cabozantvir and rilpivirine for the treatment of HIV infection, or in large trials of long-acting cabozantvir for HIV prophylaxis. Studies have found that injections every 4 or 8 weeks improve patient adherence, and for many patients requiring long-term antiretroviral therapy, injections are superior to daily oral therapy. Since cabozantvir was approved for maintenance therapy and HIV prophylaxis, no clinically significant cases of hepatotoxicity associated with its use have been reported. It is noteworthy that in large pre-registration trials of injectable cabozantvir and rilpivirine as alternative therapies for HIV infection, cases of acute hepatitis A, B, and C were reported as adverse events. These cases primarily occurred in patients switching to injectable regimens, while control groups continued oral medication. The reasons for these differences are unclear. Importantly, neither cabozantvir nor rilpivirine possesses anti-hepatitis B virus (HBV) activity. One possibility is that HBV reactivation may occur after discontinuation of oral antiretroviral agents with anti-HBV activity (such as tenofovir, emtricitabine, and lamivudine). Therefore, patients starting long-acting parenteral regimens of cabozantvir and rilpivirine should undergo HBV biomarker screening, and the potential risks of discontinuing anti-HBV drugs should be considered. In addition, hepatitis A and hepatitis B vaccination should be provided to HIV-infected individuals who have not developed protective antibodies against hepatitis A virus (HAV) and hepatitis B virus (HBV). Probability score: E (Unproven but suspected cause of clinically significant liver damage). Pregnancy and Lactation Effects ◉ Overview of Lactation Use There is currently no published information on the use of Cabotegravir during lactation. Achieving and maintaining viral suppression with antiretroviral therapy can reduce the risk of transmission through breastfeeding to below 1%, but not zero. Breastfeeding should be supported for HIV-infected individuals receiving antiretroviral therapy with a persistently low viral load if they choose to breastfeed. If the viral load is not suppressed, pasteurized donor breast milk or formula is recommended. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
Cabotvir binds to plasma proteins (usually albumin) at a rate >99.8%.

[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.

Cabotegravir sodium is an organic sodium salt, the monosodium salt of Cabotegravir. It is used to treat HIV-1 infection. It is an HIV-1 integrase inhibitor. It contains the Cabotegravir (1-) molecule. Cabotegravir is a prescription drug approved by the U.S. Food and Drug Administration (FDA). It is approved in two different dosage forms and under two different brand names for the following uses: Cabotegravir oral tablets (brand name: Vocabulia) for short-term treatment of HIV infection in adults and adolescents aged 12 years and older who weigh at least 77 pounds (35 kg) and meet specific requirements determined by a healthcare provider. When used to treat HIV, Cabotegravir must be used in combination with the HIV drug rilpivirine (brand name: Edurant). Short-term pre-exposure prophylaxis (PrEP) for reducing the risk of HIV infection in adults and adolescents who weigh at least 77 pounds (35 kg), have tested negative for HIV, and are at risk of HIV infection. When used orally for pre-exposure prophylaxis (PrEP), cabozantvir should always be used in conjunction with safe sexual practices (such as condom use) to reduce the risk of infection with other sexually transmitted infections (STIs). Long-acting injectable cabozantvir (brand name: Apretude) is used to reduce the risk of HIV infection in adults and adolescents who weigh at least 35 kg (77 lbs), have a negative HIV test, and are at risk of HIV infection. When used for pre-exposure prophylaxis (PrEP), long-acting injectable cabozantvir should always be used in conjunction with safe sexual practices (such as condom use) to reduce the risk of infection with other STIs.

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Drug Indications
Vocabria tablets, used in combination with rilpivirine tablets, are indicated for short-term treatment of HIV-1 infection in virologically suppressed adults (HIV-1 infected individuals). (RNA)

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Pharmacodynamics
Cabostatin is an HIV integrase inhibitor that reduces viral replication. Because the oral tablets are taken daily and the intramuscular suspension is injected monthly, its duration of action is relatively long. Patients should be informed of the risks of hypersensitivity, hepatotoxicity, and depression. Cabotegravir is a monocarboxylic acid amide formed by the condensation of the carboxyl 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]pyrazin-8-carboxylic acid with the amino group of 2,4-difluorobenzylamine. It (in its sodium salt form) is used to treat HIV-1 infection. It is an HIV-1 integrase inhibitor. It is a difluorobenzene compound, a secondary amide, and Cabotegravir is a monocarboxylic acid amide and an organic heterocyclic tricyclic compound. It is the conjugate acid of Cabotegravir (1-). Cabotegravir is a prescription drug approved by the U.S. Food and Drug Administration (FDA). It is approved in two different dosage forms and under two different brand names for the following uses:
Cabotabvir oral tablets (brand name: Vocabria)
For short-term treatment of HIV infection in adults and adolescents aged 12 years and older who weigh at least 77 pounds (35 kg) and meet specific requirements determined by a healthcare provider. When used for HIV treatment, cabobetavir must be used in combination with the HIV drug rilpivirine (brand name: Edurant).
For short-term pre-exposure prophylaxis (PrEP) to reduce the risk of HIV infection in adults and adolescents who weigh at least 77 pounds (35 kg), are HIV-negative, and are at risk of HIV infection. Oral cabobetavir for PrEP should always be used in conjunction with safe sex practices. Take measures such as condom use to reduce the risk of contracting other sexually transmitted infections.
Long-acting injectable cabozantvir (trade name: Apretude)
Cabostatin (GSK1265744) is an HIV-1 integrase inhibitor, usually used in combination with the non-nucleoside reverse transcriptase inhibitor rilpivirine. Early studies showed that cabozantvir's oral bioavailability was lower than dolutegravir, therefore a long-acting once-monthly intramuscular formulation of cabozantvir was developed. On January 21, 2021, cabozantvir, in combination with rilpivirine, received FDA approval for the treatment of virologically suppressed HIV-1 infected individuals. Previously, this combination formulation was only administered once a month, but on February 1, 2022, the FDA approved it to be administered every two months without a prior oral lead-in period.
Cabostatin is a human drug immunodeficiency virus integrase chain transfer inhibitor. Cabozantvir's mechanism of action is as an HIV integrase inhibitor, an organic anion transporter 1 inhibitor, and an organic anion transporter 3 inhibitor. Cabotegravir is an antiviral drug that inhibits the human immunodeficiency virus (HIV) integrase and is used in combination with the non-nucleoside HIV reverse transcription inhibitor rilpivirine to treat HIV infection and acquired immunodeficiency syndrome (AIDS). The fixed-dose combination of Cabotegravir and rilpivirine is typically administered intramuscularly once monthly and is associated with a low incidence of elevated serum transaminases during treatment and rare, acute, clinically significant liver injury events. Cabotegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) used for pre-exposure prophylaxis (PrEP). It reduces the risk of sexually transmitted HIV-1 infection. After intramuscular injection of Cabotegravir in the buttock, Cabotegravir binds to the active site of HIV integrase, inhibiting its activity. HIV integrase is an enzyme encoded by HIV-1 and is essential for viral replication. Inhibition of integrase prevents HIV-1 DNA from integrating into the host genomic DNA. Cabozantvir is a small molecule drug that has reached Phase IV clinical trials (covering all indications). It was first approved in 2021 and currently has three approved indications and one investigational indication.

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Drug Indications
Oral cabozantvir in combination with rilpivirine is used for short-term treatment of HIV-1 in virologically suppressed adult patients who have no history of treatment failure, cannot be assessed for cabozantvir tolerance, or have missed a dose of cabozantvir injection. Intramuscular extended-release cabozantvir in combination with rilpivirine can be used as a complete HIV-1 treatment regimen. For adults and adolescents aged 12 years and older weighing at least 35 kg, if virological levels are suppressed (HIV-1 RNA <50 copies/mL), and their current antiretroviral therapy is stable with no history of treatment failure and no known or suspected resistance to either cabozantvir or rilpivirine, cabozantvir can be used as an alternative to their current antiretroviral therapy. Cabotegravir extended-release injection suspension is also indicated for the prevention of HIV-1 infection via sexual transmission in high-risk adults and adolescents weighing at least 35 kg (i.e., pre-exposure prophylaxis, PrEP). Apretude can be used in combination with safe sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection via sexual transmission in high-risk adults and adolescents weighing at least 35 kg (see Sections 4.2, 4.4, and 5). 1) Vocabria tablets, in combination with rilpivirine tablets, are indicated for the short-term treatment of HIV-1 infection in virologically suppressed (HIV-1 RNA) adults.

C19H16N3O5F2-.NA+

427.33404

427.095

C, 53.40; H, 3.77; F, 8.89; N, 9.83; Na, 5.38; O, 18.72

1051375-13-3

Cabotegravir;1051375-10-0;Cabotegravir-d3 sodium

46215800

White to off-white solid powder

1

8

3

30

820

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-].[Na+]

AEZBWGMXBKPGFP-KIUAEZIZSA-M

InChI=1S/C19H17F2N3O5.Na/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);/q;+1/p-1/t9-,14+;/m0./s1

sodium;(3R,6S)-12-[(2,4-difluorophenyl)methylcarbamoyl]-6-methyl-8,11-dioxo-4-oxa-1,7-diazatricyclo[7.4.0.03,7]trideca-9,12-dien-10-olate

Cabotegravir sodium; 1051375-13-3; Vocabria; GSK1265744B; GSK-1265744B;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ~6.25 mg/mL (~14.63 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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