Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: ViiV Healthcare BV, Van Asch van Wijckstraat 55H, 3811 LP Amersfoort, Netherlands
Pharmacotherapeutic group: Antiviral for systemic use, integrase inhibitor
ATC code: J05AJ04
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.
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 medicinal products 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).
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 above, 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/Q148R resulted in a 12-fold decrease in susceptibility and 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. Other multiple mutants, which resulted in a FC between 5 and 10, are: T66K/L74M (FC=6.3), G140S/Q148K (FC=5.6), G140S/Q148H (FC=6.1) and E92Q/N155H (FC=5.3).
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 multiclass 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.
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 nonadherent 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 E138K alone).
Following the primary analysis, extended retrospective virologic testing was performed to better characterise 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.
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 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).
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 medicinal products up to Week 153.
At baseline, the median age of participants was 26 years, 12% were transgender women, 72% were non-white, 67% were <30 years and <1% were over 60 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 5).
Table 5. Primary Efficacy Endpoint: Comparison of Rates of Incident HIV Infections during Randomised Phase in HPTN 083 (mITT, extended retrospective virologic testing):
| Cabotegravir (N=2278) | TDF/FTC (N=2281) | Superiority P-Value | |
|---|---|---|---|
| Person years | 3211 | 3193 | |
| HIV-1 incident infections (incidence rate per 100 person years) | 121 (0.37) | 39 (1.22) | |
| Hazard ratio (95% CI) | 0.31 (0.16, 0.58) | p=0.0003 | |
1 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 on cabotegravir was determined to be a prevalent infection. The original hazard ratio (95% CI) from the primary analysis is 0.34 (0.18, 0.62).
Findings 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 6).
Table 6. Rate of incident HIV-1 infection by subgroup in HPTN 083 (mITT, extended retrospective virologic testing):
| Subgroup | Cabotegravir incidence per 100 person years | Cabotegravir person years | TDF/FTC incidence per 100 person years | TDF/FTC person years) | HR (95% CI) |
|---|---|---|---|---|---|
| Age | |||||
| <30 years | 0.47 | 2110 | 1.66 | 1987 | 0.29 (0.15, 0.59) |
| ≥30 years | 0.18 | 1101 | 0.50 | 1206 | 0.39 (0.08, 1.84) |
| Gender | |||||
| MSM | 0.35 | 2836 | 1.14 | 2803 | 0.32 (0.16, 0.64) |
| TGW | 0.54 | 371 | 1.80 | 389 | 0.34 (0.08, 1.56) |
| Race (US) | |||||
| Black | 0.58 | 691 | 2.28 | 703 | 0.26 (0.09, 0.76) |
| Non-Black | 0.00 | 836 | 0.50 | 801 | 0.11 (0.00, 2.80) |
| Region | |||||
| US | 0.26 | 1528 | 1.33 | 1504 | 0.21 (0.07, 0.60) |
| Latin America | 0.49 | 1020 | 1.09 | 1011 | 0.47 (0.17, 1.35) |
| Asia | 0.35 | 570 | 1.03 | 581 | 0.39 (0.08, 1.82) |
| Africa | 1.08 | 93 | 2.07 | 97 | 0.63 (0.06, 6.50) |
MSM = cisgender men who have sex with men
TGW = Transgender women who have sex with men
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 medicinal product 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, with a maximum age of 45 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 (p< 0.0001) 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 7).
Table 7. Primary Efficacy Endpoint in HPTN 084: Comparison of Rates of Incident HIV Infections during Randomised Phase (mITT, extended retrospective virologic testing):
| Cabotegravir (N=1613) | TDF/FTC (N=1610) | Superiority P-Value | |
|---|---|---|---|
| Person years | 1960 | 1946 | |
| HIV-1 incident infections (incidence rate per 100 person years) | 31 (0.15) | 36 (1.85) | |
| Hazard ratio (95% CI) | 0.10 (0.04, 0.27) | p<0.0001 | |
1 Following the primary analysis, extended retrospective virologic testing was performed to better characterise 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. The original hazard ratio corrected for early stopping (95% CI) from the primary analysis is 0.12 (0.05, 0.31).
Findings 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 8).
Table 8. Rate of incident HIV-1 infection by subgroup in HPTN 084 (mITT, extended retrospective virologic testing):
| Subgroup | Cabotegravir incidence per 100 person years | Cabotegravir person years | TDF/FTC incidence per 100 person years | TDF/FTC person years) | HR (95% CI) |
|---|---|---|---|---|---|
| Age | |||||
| <25 years | 0.23 | 868 | 2.34 | 853 | 0.12 (0.03, 0.46) |
| ≥25 years | 0.09 | 1093 | 1.46 | 1093 | 0.09 (0.02, 0.49) |
| BMI | |||||
| <30 | 0.22 | 1385 | 1.88 | 1435 | 0.12 (0.04, 0.38) |
| ≥30 | 0.00 | 575 | 1.76 | 511 | 0.04 (0.00, 0.93) |
The European Medicines Agency has waived the obligation to submit the results of studies with Apretude injections in children under the age of 12 years, in the prevention of HIV-1 infection.
Cabotegravir pharmacokinetics is similar between healthy and HIV-infected subjects. The pharmacokinetic 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.
Table 9. Pharmacokinetic parameters following cabotegravir orally once daily, and initiation and every 2 month continuation intramuscular injections in adults:
| Dosing Phase | Dose Regimen | Geometric Mean (5th, 95th Percentile)1 | ||
|---|---|---|---|---|
| AUC(0-tau)2 (µg•h/mL) | Cmax (µg/mL) | Ctau (µg/mL) | ||
| Oral lead-in3 (Optional) | 30 mg once daily | 145 (93.5, 224) | 8.0 (5.3, 11.9) | 4.6 (2.8, 7.5) |
| Initial injection4 | 600 mg IM Initial Dose | 1591 (714, 3245) | 8.0 (5.3, 11.9) | 1.5 (0.65, 2.9) |
| Every 2-month injection5 | 600 mg IM Every 2-month | 3764 (2431, 5857) | 4.0 (2.3, 6.8) | 1.6 (0.8, 3.0) |
1 Pharmacokinetic (PK) parameter values were based on individual post-hoc estimates from population PK models for subjects in Phase III treatment studies. 2 tau is dosing interval: 24 hours for oral administration; 1 month for the initial injection and 2 months for every
2 months for IM injections of extended-release injectable suspension.
3 Oral lead-in pharmacokinetic parameter values represent steady-state.
4 Initial injection Cmax values primarily reflect oral dosing because the initial injection was administered on the same day as the last oral dose; however, the AUC(0-tau) and Ctau values reflect the initial injection. When administered without oral lead-in to HIV infected recipients (n=110), the observed cabotegravir geometric mean (5th, 956th^ percentile) Cmax (1 week post-initial injection) was 1.89 mcg/mL (0.438, 5.69) and Ctau was 1.43 mcg/mL (0.403, 3.90).
5 Pharmacokinetic parameter values represent steady state.
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 intramuscular (IM) injection (see Table 9). Cabotegravir has been detected in plasma up to 52 weeks or longer after administration of a single injection.
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 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.
In vitro, cabotegravir was not a substrate of organic anion transporting polypeptide (OATP) 1B1, OATP2B1, OATP1B3 or organic cation transporter (OCT1).
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 medicinal product or biliary excretion of the glucuronide 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 glucuronide 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).
Cabotegravir is not a clinically relevant inhibitor of the following enzymes and transporters: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B15, and UGT2B17, P-gp, BCRP, Bile salt export pump (BSEP), OCT1, OCT2, OATP1B1, OATP1B3, multidrug and toxin extrusion transporter (MATE) 1, MATE 2-K, multidrug resistance protein (MRP) 2 or MRP4.
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 reflects elimination from the injection site into the systemic circulation. The apparent CL/F was 0.151 L/h.
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.
In a meta-analysis of healthy and HIV-infected participant trials, HIV-infected participants with UGT1A1 genotypes conferring poor cabotegravir metabolism had a 1.2-fold mean increase in steadystate cabotegravir AUC, Cmax, and Ctau following long-acting injection administration compared with participants with genotypes associated with normal metabolism via UGT1A1. These differences are not considered clinically relevant. No dose adjustment is required in individuals with UGT1A1 polymorphisms.
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.
Population pharmacokinetic analyses revealed no clinically relevant effect of race on the exposure of cabotegravir, therefore no dose adjustment is required on the basis of race.
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.
Population pharmacokinetic analyses revealed no clinically relevant differences in exposure between the HIV-1 infected adolescent and HIV-1 infected and uninfected adult participants from the cabotegravir development programme, therefore, no dose adjustment is needed for adolescents weighing ≥35 kg.
Table 10. Predicted pharmacokinetic parameters following cabotegravir orally once daily, and initiation and every 2 month continuation intramuscular injections in adolescents Participants aged 12 to less than 18 years (≥35 kg):
| Dosing Phase | Dose Regimen | Geometric Mean (5th, 95th Percentile)1 | ||
|---|---|---|---|---|
| AUC(0-tau)2 (µg•h/mL) | Cmax (µg/mL) | Ctau (µg/mL) | ||
| Oral leadin3 (Optional) | 30 mg once daily | 193 (106, 346) | 14.4 (8.02,25.5) | 5.79 (2.48,12.6) |
| Initial injection4 | 600 mg IM Initial Dose | 2123 (881, 4938) | 11.2 (5.63,21.5) | 1.84 (0.64,4.52) |
| Every 2-month injection5 | 600 mg IM Every 2-month | 4871 (2827, 8232) | 7.23 (3.76,14.1) | 2.01 (0.64,4.73) |
1 Pharmacokinetic (PK) parameter values were based on population PK model simulations in a virtual HIV-1 infected adolescent population weighing 35-156 kg.
2 tau is dosing interval: 24 hours for oral administration; 1 month for the initial injection, 2 months for every 2 months for IM injections of extended-release injectable suspension.
3 Oral lead-in pharmacokinetic parameter values represent steady-state.
4 Initial injection Cmax values primarily reflect oral dosing because the initial injection was administered on the same day as the last oral dose; however, the AUC(0-tau) and Ctau values reflect the initial injection.
5 Pharmacokinetic parameter values represent steady state.
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.
No clinically important pharmacokinetic differences between subjects with severe renal impairment (CrCL <30 mL/min and not on dialysis) and matching healthy subjects were observed. No dose adjustment is necessary for individuals with mild to severe renal impairment (not on dialysis). Cabotegravir has not been studied in individuals on dialysis.
No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. No dose 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.
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.
No effect on male or female fertility was observed in rats treated with cabotegravir at oral doses up to 1000 mg/kg/day (>20 times the exposure in humans at the maximum recommended dose (MRHD) of 30 mg/day orally).
In an embryo-foetal development study there were no adverse developmental outcomes following oral administration of cabotegravir to pregnant rabbits up to a maternal toxic dose of 2,000 mg/kg/day (0.66 times the exposure in humans at the oral MRHD) or to pregnant rats at doses up to 1000 mg/kg/day (>30 times the exposure in humans at the oral MRHD). In rats, alterations in foetal growth (decreased body weights) were observed at oral dose of 1,000 mg/kg/day. Studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in foetal tissue.
In rat pre- and post-natal (PPN) studies cabotegravir reproducibly induced a delayed onset of parturition, and an increase in the number of stillbirths and neonatal mortalities at oral dose of 1,000 mg/kg/day (>30 times the exposure in humans at the oral MRHD). At a lower dose of 5 mg/kg/day (approximately 10 times the exposure in humans at the oral MRHD) cabotegravir was not associated with delayed parturition or neonatal mortality. In rabbit and rat studies there was no effect on survival when foetuses were delivered by caesarean section. Given the exposure ratio, the relevance to humans is unknown.
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 reactions in rats or monkeys given cabotegravir orally at doses up to 1,000 mg/kg/day or 500 mg/kg/day, respectively.
In a 14 day and 28 day monkey toxicity study, gastro-intestinal (GI) effects (body weight loss, emesis, loose/watery faeces, and moderate to severe dehydration) were observed and were the result of local medicinal product administration (oral) 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 reactions noted and no new target organ toxicities (at exposures >49 times the exposure in humans at the MRHD of 600 mg IM dose).
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