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Pharmacology: Pharmacodynamics: Mechanism of action: Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration, which is essential for the HIV replication cycle.
Pharmacodynamic effects: Antiviral Activity in cell culture: Cabotegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean concentration of cabotegravir necessary to reduce viral replication by 50 percent (EC50) values of 0.22 nM in peripheral blood mononuclear cells (PBMCs), 0.74 nM in 293T cells and 0.57 nM in MT-4 cells. Cabotegravir demonstrated antiviral activity in cell culture against a panel of 24 HIV-1 clinical isolates (three in each group of M clades A, B, C, D, E, F, and G, and 3 in group O) with EC50 values ranging from 0.02 nM to 1.06 nM for HIV-1. Cabotegravir EC50 values against three HIV-2 clinical isolates ranged from 0.10 nM to 0.14 nM. No clinical data is available in patients with HIV-2.
Antiviral Activity in combination with other antiviral agents: No drugs with inherent anti-HIV activity were antagonistic to cabotegravir's antiretroviral activity (in vitro assessments were conducted in combination with rilpivirine, lamivudine, tenofovir and emtricitabine).
Effect of Human Serum and Serum Proteins: In vitro studies suggested a 408-fold shift in IC50 of cabotegravir in the presence of 100% human serum (by method of extrapolation), and the protein adjusted IC50 (PA-IC50) was estimated to be 102 nM in MT4 cells.
Resistance in vitro: Isolation from wild-type HIV-1 and activity against resistant strains: Viruses with >10-fold increase in cabotegravir EC50 were not observed during the 112-day passage of strain IIIB. The following integrase (IN) mutations emerged after passaging wild-type HIV-1 (with T124A polymorphism) in the presence of cabotegravir: Q146L (fold-change range 1.3-4.6), S153Y (fold-change range 2.8-8.4) and I162M (fold-change=2.8). As noted previously, the detection of T124A is selection of a pre-existing minority variant that does not have differential susceptibility to cabotegravir. No amino acid substitutions in the integrase region were selected when passaging the wild-type HIV-1 NL-432 in the presence of 6.4 nM of cabotegravir through Day 56.
Among the multiple mutants, the highest fold-change was observed with mutants containing Q148K or Q148R. E138K/Q148H resulted in a 0.92-fold decrease in susceptibility to cabotegravir, but E138K/Q148K resulted in an 81-fold decrease in susceptibility to cabotegravir. G140C/Q148R and G140S/Q148R resulted in a 22- and 12-fold decrease in susceptibility to cabotegravir, respectively. While N155H did not alter susceptibility to cabotegravir, N155H/Q148R resulted in a 61-fold decrease in susceptibility to cabotegravir.
Resistance in vivo: HPTN 083: In the primary analysis of the HPTN 083 study, there were 13 incident infections on the cabotegravir arm and 39 incident infections on the tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) arm. In the cabotegravir arm, 5 incident infections occurred when receiving cabotegravir PrEP injections, of which 4 participants received on-time injections and 1 participant had one injection off-schedule. Five incident infections occurred ≥6 months after the last dose of cabotegravir PrEP. Three incident infections occurred during the oral lead-in period.
HIV genotyping and phenotyping were attempted at the first visit where HIV viral load was >500 copies/mL. Of the 13 incident infections in the cabotegravir arm, 4 participants had INSTI resistance mutations. In the TDF/FTC arm, the 4 participants with NRTI resistance (including 3 who had multi-class resistance) included 3 with M184V/I and one with K65R.
None of the 5 participants who were infected after prolonged interruption from cabotegravir administration had INSTI resistance mutations. Neither genotype nor phenotype could be generated for one of the 5 participants, with just 770 copies/mL HIV-1 RNA. Integrase phenotype could not be generated for one of the remaining 4 participants. The remaining 3 participants retained susceptibility to all INSTIs.
Three participants became infected during the oral lead-in phase, prior to receiving cabotegravir injections. One participant with undetectable plasma cabotegravir levels had no INSTI resistance mutations and was susceptible to all INSTIs. Two participants with detectable plasma cabotegravir concentrations had INSTI resistance mutations. The first participant had INSTI resistant mutations E138E/K, G140G/S, Q148R and E157Q.
Integrase phenotype could not be generated. The second participant had INSTI resistance mutations E138A and Q148R. This virus was resistant to cabotegravir (fold-change=5.92) but susceptible to dolutegravir (fold-change=1.69).
Five participants acquired HIV-1, despite on time cabotegravir injections for 4 participants and one off-schedule injection for one participant. Two participants had viral loads too low to analyse. The third participant had no INSTI resistance mutations at the first viraemic visit (Week 17) but had R263K at 112 and 117 days later. While phenotype could not be determined 112 days later, day 117 phenotype showed this virus to be susceptible to both cabotegravir (fold-change=2.32) and dolutegravir (fold-change=2.29). The fourth participant had INSTI resistance mutations G140A and Q148R. Phenotype showed resistance to cabotegravir (fold-change=13) but susceptibility to dolutegravir (fold-change=2.09). The fifth participant had no INSTI resistance mutations.
In addition to the 13 incident infections, one further participant was HIV-1 infected at enrolment and had no INSTI resistance mutations at that time, however, 60 days later, INSTI resistance mutation E138K and Q148K were detected. Phenotype could not be generated.
Following the primary analysis, extended retrospective virologic testing was performed to better characterise the timing of HIV infections. As a result, one of the 13 incident infections in a participant receiving on time cabotegravir injections was determined to be a prevalent infection.
HPTN 084: In the primary analysis of the HPTN 084 study, there were 4 incident infections on the cabotegravir arm and 36 incident infections on the TDF/FTC arm.
In the cabotegravir arm, 2 incident infections occurred while receiving injections; one participant had 3 delayed cabotegravir injections, and both had been non-adherent to oral cabotegravir.
Two incident infections occurred after the last dose of oral cabotegravir; both participants were non-adherent to oral cabotegravir. The first HIV positive visit occurred approx. 11 weeks after enrolment for one participant and 57 weeks after enrolment for the other.
HIV genotyping was attempted at the first visit where HIV viral load was >500 c/mL (first viraemic visit). HIV genotyping results were available for 3 of the 4 cabotegravir arm participants. No major INSTI resistance mutations were detected.
HIV genotyping results were available for 33 of the 36 incident infections in the TDF/FTC group. One participant had a major NRTI mutation (M184V); this participant also had NNRTI resistance with the mutation K103N. Nine other participants had NNRTI resistance (7 had K103N, alone or with E138A or P225H; 1 had K101E alone; 1 had E138A alone).
Following the primary analysis, extended retrospective virologic testing was performed to better characterize the timing of HIV-1 infections. As a result, 1 of the 4 HIV-1 incident infections in participants receiving cabotegravir was determined to be a prevalent infection.
HPTN 083-01 and HPTN 084-01: In studies HPTN 083-01 and HPTN 084-01, there were no incident infections observed among 64 at-risk adolescents (weighing 35 kg or more) receiving cabotegravir for HIV-1 PrEP.
Effects on Electrocardiogram: In a randomised, placebo-controlled, three-period cross-over trial, 42 healthy subjects were randomized into 6 random sequences and received three doses of oral administration of placebo, cabotegravir 150 mg every 12 hours (mean steady-state Cmax was approximately 2.8-fold and 5.6-fold above the 30 mg oral once-daily dose and the 600 mg cabotegravir injection every 2 month dose, respectively), or single dose of moxifloxacin 400 mg (active control). After baseline and placebo adjustment, the maximum time-matched mean QTc change based on Fridericia's correction method (QTcF) for cabotegravir was 2.62 msec (1-side 90% upper CI:5.26 msec). Cabotegravir did not prolong the QTc interval over 24 hours post-dose.
Clinical studies: Clinical efficacy and safety: The efficacy of cabotegravir for PrEP has been evaluated in two randomised (1:1), double blind, multi-site, two-arm, controlled studies. The efficacy of cabotegravir was compared with daily oral tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC).
Participants randomised to receive cabotegravir initiated oral lead-in dosing with one 30 mg cabotegravir tablet and a placebo daily, for up to 5 weeks, followed by cabotegravir intramuscular (IM) injection (single 600 mg [3 mL] injection, at months 1, 2 and every 2 months thereafter and a daily placebo tablet. Participants randomised to receive TDF/FTC initiated oral TDF 300 mg/FTC 200 mg and placebo for up to 5 weeks, followed by oral TDF 300 mg/FTC 200 mg daily and placebo (IM) injection (3 mL, 20% lipid injectable emulsion at months 1, 2 and every 2 months thereafter).
HPTN 083: In HPTN 083, a non-inferiority study, 4566 cisgender men and transgender women who have sex with men were randomised 1:1 and received either cabotegravir (n=2281) or TDF/FTC (n=2285) as blinded study medication up to Week 153.
At baseline, the median age of participants was 26 years, 12% were transgender women, 72% were non-white, and 67% were <30 years.
The primary endpoint was the rate of incident HIV infections among participants randomised to oral cabotegravir and cabotegravir injections compared to oral TDF/FTC (corrected for early stopping). The primary analysis demonstrated the superiority of cabotegravir compared to TDF/FTC with a 66% reduction in the risk of acquiring incident HIV infection, hazard ratio (95% CI) 0.34 (0.18, 0.62); further testing revealed one of the infections on cabotegravir to be prevalent then yielding a 69% reduction in the risk of incident infection relative to TDF/FTC (see Table 1). (See Table and Figure 1.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageFindings from all subgroup analyses were consistent with the overall protective effect, with a lower rate of incident HIV-1 infections observed for participants randomised to the cabotegravir group compared with participants randomised to the TDF/FTC group (see Table 2).
Click on icon to see table/diagram/imageHPTN 084: In HPTN 084, a superiority study, 3224 cisgender women were randomised 1:1 and received either cabotegravir (n=1614) or TDF/FTC (n=1610) as blinded study medication up to Week 153.
At baseline, the median age of participants was 25 years, >99% were non-white, >99% were cisgender women, and 49% were <25 years of age.
The primary endpoint was the rate of incident HIV infections among participants randomised to oral cabotegravir and cabotegravir injections compared to oral TDF/FTC (corrected for early stopping). The primary analysis demonstrated the superiority of cabotegravir compared to TDF/FTC with an 88% reduction in the risk of acquiring incident HIV-1 infection hazard ratio (95% CI) 0.12 (0.05, 0.31); further testing revealed 1 of the infections on cabotegravir to be prevalent then yielding a 90% reduction in the risk of HIV-1 incident infection relative to TDF/FTC (see Table 3). (See Table 3 and Figure 2.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageFindings from pre-planned subgroup analyses were consistent with the overall protective effect, with a lower rate of incident HIV-1 infections observed for participants randomised to the cabotegravir group compared with participants randomised to the TDF/FTC group (see Table 4).
Click on icon to see table/diagram/imageMOCHA (HIV-infected adolescents): The safety, tolerability and pharmacokinetics of oral and injectable cabotegravir were assessed in an ongoing Phase I/II multicentre, open-label, non-comparative study, MOCHA (IMPAACT 2017, Study 208580). 30 HIV-1 infected and virologically supressed adolescents, aged 12 to <18 years, weighing at least 35 kg were enrolled and received one 30 mg cabotegravir tablet, daily, for at least 4 weeks followed by cabotegravir monthly injections for 3 months (month 1: 600 mg injection, months 2 and 3: 400 mg injection), or cabotegravir every 2 month injections for 2 months (months 1 and 2: 600 mg injection), while continuing background cART.
At baseline, the median age of participants was 15.0 years, the median weight was 47.9 kg, 47% were female, 100% were non-white, no participants had a CD4+ cell count less than 350 cells per mm3.
The primary endpoints at Week 16 for cabotegravir participants, which were to confirm the doses, safety and pharmacokinetics for oral and injectable cabotegravir, in HIV-infected, virologically suppressed adolescents, were met (see Adverse Reactions, Pharmacokinetics: Special patient populations as follows).
Pharmacokinetics: Suspension for Injection: Cabotegravir pharmacokinetics is similar between healthy and HIV-infected subjects. The PK variability of cabotegravir is moderate to high. In HIV-infected subjects participating in Phase III studies, between-subject CVb% for Ctau ranged from 39 to 48%. Higher between-subject variability ranging from 65 to 76% was observed with single dose administration of long-acting cabotegravir injection. (See Table 5.)
Click on icon to see table/diagram/imageAbsorption: Suspension for Injection: Cabotegravir injection exhibits absorption-limited pharmacokinetics because cabotegravir is slowly absorbed into the systemic circulation from the gluteal muscle, resulting in sustained plasma concentrations. Following a single 600 mg intramuscular dose, plasma cabotegravir concentrations are detectable on the first day with median cabotegravir concentrations at 4 hours post dose of 0.290 μg/mL, which is above in-vitro PA-IC90 of 0.166 μg/mL, and reach maximum plasma concentration with a median Tmax of 7 days. Target concentrations are achieved following the initial IM injection (see Table 5). Cabotegravir has been detected in plasma up to 52 weeks or longer after administration of a single injection.
Plasma cabotegravir exposure increases in proportion or slightly less than in proportion to dose following single and repeat IM injection of doses ranging from 100 to 800 mg.
Distribution: Cabotegravir is highly bound (approximately >99%) to human plasma proteins, based on in vitro data. Following administration of oral tablets, the mean apparent oral volume of distribution (Vz/F) in plasma was 12.3 L. In humans, the estimate of plasma cabotegravir Vc/F was 5.27 L and Vp/F was 2.43 L. These volume estimates, along with the assumption of high F, suggest some distribution of cabotegravir to the extracellular space.
Cabotegravir is present in the female and male genital tract, following a single 3 mL (600 mg) IM injection, as observed in a study in healthy participants (n=15). Median cabotegravir concentrations at Day 3 (the earliest tissue PK sample) were 0.49 μg/mL in cervical tissue, 0.29 μg/mL in cervicovaginal fluid, 0.37 μg/mL in vaginal tissue, 0.32 μg/mL in rectal tissue, and 0.69 μg/mL in rectal fluid, which are above the in vitro PA-IC90.
Metabolism: Cabotegravir is primarily metabolised by UGT1A1 with a minor UGT1A9 component. Cabotegravir is the predominant circulating compound in plasma, representing >90% of plasma total radiocarbon. Following oral administration in humans, cabotegravir is primarily eliminated through metabolism; renal elimination of unchanged cabotegravir is low (<1% of the dose). Forty-seven percent of the total oral dose is excreted as unchanged cabotegravir in the faeces. It is unknown if all or part of this is due to unabsorbed drug or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Cabotegravir was observed to be present in duodenal bile samples. The glucuronic acid metabolite was also present in some but not all of the duodenal bile samples. Twenty-seven percent of the total oral dose is excreted in the urine, primarily as a glucuronide metabolite (75% of urine radioactivity, 20% of total dose).
Elimination: Suspension for Injection: Cabotegravir mean apparent terminal phase half-life is absorption-rate limited and is estimated to be 5.6 to 11.5 weeks after a single dose IM injection. The significantly longer apparent half-life compared to oral administration reflects absorption from the injection site into the systemic circulation. The apparent CL/F was 0.151 L/h.
Special patient populations: Gender: Population pharmacokinetic analyses revealed no clinically relevant effect of gender on the exposure of cabotegravir. In addition, no clinically relevant differences in plasma cabotegravir concentrations were observed in the HPTN 083 study by gender, including in cisgender men and transgender women with or without cross-sex hormone therapy use. Therefore, no dose adjustment is required on the basis of gender.
Race: Population pharmacokinetic analyses revealed no clinically relevant effect of race on the exposure of cabotegravir, therefore, no dosage adjustment is required on the basis of race.
BMI: Population pharmacokinetic analyses revealed no clinically relevant effect of BMI on the exposure of cabotegravir, therefore, no dose adjustment is required on the basis of BMI.
Adolescents: Population pharmacokinetic analyses revealed no clinically relevant differences in exposure between adolescent participants and HIV-1 infected and uninfected adult participants from the cabotegravir development programme, therefore, no dosage adjustment is needed for adolescents weighing ≥35 kg. (See Table 6.)
Click on icon to see table/diagram/imageChildren: The pharmacokinetics and dosing recommendations of cabotegravir in individuals less than 12 years of age or weighing less than 35 kg have not been established.
Elderly: Population pharmacokinetic analysis of cabotegravir revealed no clinically relevant effect of age on cabotegravir exposure.
Pharmacokinetic data for cabotegravir in subjects of >65 years old are limited.
Renal impairment: No clinically important pharmacokinetic differences between subjects with severe renal impairment (creatinine clearance ≥15 to <30 mL/min and not on dialysis) and matching healthy subjects were observed. No dosage adjustment is necessary for individuals with mild, moderate or severe renal impairment (not on dialysis). Cabotegravir has not been studied in individuals on dialysis.
Hepatic impairment: No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. No dosage adjustment is necessary for individuals with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of cabotegravir has not been studied.
HBV and HCV Infected Individuals: There are no data for the use of cabotegravir in subjects with HBV and HCV infection in PrEP studies.
Polymorphisms in Drug Metabolising Enzymes: In a meta-analysis of healthy and HIV-infected subjects, HIV-infected subjects with UGT1A1 genotypes conferring poor cabotegravir metabolism had a 1.2-fold increase in mean steady-state cabotegravir AUC, Cmax, and Ctau following cabotegravir injection vs. 1.38-fold mean increase following oral cabotegravir administration. This was similar to 1.3- to 1.5-fold mean increase in steady-state cabotegravir, cabotegravir AUC, Cmax, and Ctau observed following oral cabotegravir in healthy and HIV infected subjects combined. These differences are not considered clinically relevant. Polymorphisms in UGT1A9 were not associated with differences in the pharmacokinetics of cabotegravir, therefore, no dose adjustment is required in subjects with either UGT1A1 or UGT1A9 polymorphisms.
Toxicology: Non-Clinical Information: Carcinogenesis/mutagenesis: Cabotegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay. Cabotegravir was not carcinogenic in long term studies in the mouse and rat.
Reproductive Toxicology: Fertility: Cabotegravir when administered orally to male and female rats at 1000 mg/kg/day (>30 times the exposure in humans at the Maximum Recommended Human Dose [MHRD] of 30 mg oral or 400 mg IM dose) for up to 26 weeks did not cause adverse effects on male or female reproductive organs or spermatogenesis. No functional effects on male or female mating or fertility were observed in rats given cabotegravir at doses up to 1000 mg/kg/day.
Pregnancy: In an embryo-foetal development study there were no adverse developmental outcomes following oral administration of cabotegravir to pregnant rabbits at doses up to 2000 mg/kg/day (0.66 times the exposure in humans at the MRHD of 30 mg oral or approximately 1 times 400 mg IM dose) or to pregnant rats at doses up to 1000 mg/kg/day (>30 times the exposure in humans at the MRHD of 30 mg oral or 400 mg IM dose). In rats, alterations in foetal growth (decreased body weights) in the absence of maternal toxicity were observed at 1,000 mg/kg/day. Studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in foetal tissue.
Non-clinical data from rat pre- and post-natal (PPN) studies at 1,000 mg/kg/day (>30 times the exposure in humans at the MRHD of 30 mg oral or 400 mg IM dose) cabotegravir delayed the onset of parturition, and in some rats, this delay was associated with an increased number of stillbirths and neonatal mortalities immediately after birth. A lower dose of 5 mg/kg/day cabotegravir (>10 times the exposure in humans at the MRHD of 30 mg oral or 400 mg IM dose) was not associated with delayed parturition or neonatal mortality in rats. In rabbit and rat studies, there was no effect on survival when foetuses were delivered by caesarean section. When rat pups born to cabotegravir-treated dams were cross-fostered at birth and nursed by control mothers, similar incidences of neonatal mortalities were observed.
Animal toxicology and/or pharmacology: The effect of prolonged daily treatment with high doses of cabotegravir has been evaluated in repeat oral dose toxicity studies in rats (26 weeks) and in monkeys (39 weeks). There were no drug-related adverse effects in rats or monkeys given cabotegravir orally at doses up to 1000 mg/kg/day or 500 mg/kg/day, respectively.
In the 14-day monkey toxicity study, a dose of 1000 mg/kg/day was not tolerated and resulted in morbidity associated with gastrointestinal (GI) effects (body weight loss, emesis, loose/watery faeces, and moderate to severe dehydration).
In the 28 day monkey toxicity study, end of study exposure at 500 mg/kg/day was similar to that achieved in the 14-day study at 1000 mg/kg/day. This suggests that GI intolerance observed in the 14-day study was the result of local drug administration and not systemic toxicity.
In a 3 month study in rats, when cabotegravir was administered by monthly sub-cutaneous (SC) injection (up to 100 mg/kg/dose); monthly IM injection (up to 75 mg/kg/dose) or weekly SC injection (100 mg/kg/dose), there were no adverse effects noted and no new target organ toxicities (at exposures >30 times the exposure in humans at the MRHD of 400 mg IM dose).
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