Chemical formula: C₁₉H₁₇F₂N₃O₅ Molecular mass: 405.358 g/mol PubChem compound: 54713659
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 clinical data is available in patients with HIV-2.
No medicines 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 [FC] range 1.3-4.6), S153Y (FC range 3.6-8.4), and I162M (FC = 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 FC 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).
Cabotegravir pharmacokinetics is similar between healthy and HIV-infected subjects.
IM administration: 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 41% to 89% was observed with single dose administration of long-acting cabotegravir injection.
Oral administration: Cabotegravir pharmacokinetics is similar between healthy and HIV-infected subjects. The PK variability of cabotegravir is moderate. In Phase I studies in healthy subjects, between-subject CVb% for AUC, Cmax, and Ctau ranged from 26 to 34% across healthy subject studies and 28 to 56% across HIV-1 infected subject studies. Within-subject variability (CVw%) is lower than between-subject variability.
Pharmacokinetic parameters following cabotegravir orally once daily, and initiation, monthly and every 2 month continuation intramuscular injections:
| Dosing Phase | Dosage Regimen | Geometric Mean (5th, 95th Percentile)a | ||
|---|---|---|---|---|
| AUC(0-tau)b (μ•h/mL) | Cmax (μ/mL) | Ctau (μ/mL) | ||
| Oral lead-inc | 30 mg once daily | 145 (93.5, 224) | 8.0 (5.3, 11.9) | 4.6 (2.8, 7.5) |
| Initial injectiond | 600 mg IM Initial Dose | 1.591 (714, 3.245) | 8.0 (5.3, 11.9) | 1.5 (0.65, 2.9) |
| Monthly injectione | 400 mg IM monthly | 2.415 (1.494, 3.645) | 4.2 (2.5, 6.5) | 2.8 (1.7, 4.6) |
| Every 2-month injectione | 600 mg IM Every 2-month | 3.764 (2.431, 5.857) | 4.0 (2.3, 6.8) | 1.6 (0.8, 3.0) |
a Pharmacokinetic (PK) parameter values were based on individual post-hoc estimates from population PK models for patients in FLAIR and ATLAS for the monthly regimen and in ATLAS-2M for the every 2 month regimen.
b tau is dosing interval: 24 hours for oral administration; 1 month for IM injections of extended-release injectable suspension.
c Oral lead-in pharmacokinetic parameter values represent steady-state.
d Initial injection AUC(0-tau) and Cmax values primarily reflect values following oral dosing because the initial injection was administered on the same day as the last oral dose; however, the Ctau value at Week 4 reflects the initial injection.
e Monthly and every 2 month injection pharmacokinetic parameter values represent Week-48 data.
Cabotegravir is rapidly absorbed following oral administration, with median Tmax at 3 hours post dose for tablet formulation. With once daily dosing, pharmacokinetic steady-state is achieved by 7 days. Cabotegravir may be administered with or without food. Food increased the extent of absorption of cabotegravir. Bioavailability of cabotegravir is independent of meal content: high fat meals increased cabotegravir AUC(0-∞) by 14% and increased Cmax by 14% relative to fasted conditions. These increases are not clinically significant. The absolute bioavailability of cabotegravir has not been established.
Cabotegravir injection exhibits absorption-limited (flip-flop) kinetics resulting from slow absorption from the gluteal muscle into the systemic circulation resulting in sustained plasma concentrations. Following a single intramuscular dose, plasma cabotegravir concentrations are detectable on the first day and gradually rise to reach maximum plasma concentration with a median Tmax of 7 days.
Cabotegravir has been detected in plasma up to 52 weeks or longer after administration of a single injection. Pharmacokinetic steady-state is achieved by 44 weeks.
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.
Cabotegravir is highly bound (>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 bioavailability, suggest some distribution of cabotegravir to the extracellular space.
Cabotegravir is present in the female and male genital tract. Median cervical and vaginal tissue:plasma ratios ranged from 0.16 to 0.28 and median rectal tissue:plasma ratios were ≤0.08 following a single 400 mg intramuscular injection (IM) at 4, 8, and 12 weeks after dosing.
Cabotegravir is present in cerebrospinal fluid (CSF). In HIV-infected subjects receiving a regimen of cabotegravir injection plus rilpivirine injection, the cabotegravir CSF to plasma concentration ratio [median (range)] (n=16) was 0.003(range: 0.002 to 0.004) one week following a steady-state long acting cabotegravir (Q4W or Q8W) injection. Consistent with therapeutic cabotegravir concentrations in the CSF, CSF HIV-1 RNA (n=16) was <50 c/mL in 100% and <2 c/mL in 15/16 (94%) of subjects. At the same time point, plasma HIV-1 RNA (n=18) was <50 c/mL in 100% and <2 c/mL in 12/18 (66.7%) of subjects.
In vitro, cabotegravir was not a substrate of organic anion transporting polypeptide (OATP) 1B1, 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 drug 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 has a mean terminal half-life of 41 h and an apparent clearance (CL/F) of 0.21 L per hour after oral administration.
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 CAB 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 subject trials, HIV-infected subjects with UGT1A1 genotypes conferring poor cabotegravir metabolism had a 1.2-fold mean increase in steady-state cabotegravir AUC, Cmax, and Ctau following long acting injection administration compared with subjects with genotypes associated with normal metabolism via UGT1A1. These differences are not considered clinically relevant. No dose adjustment is required in subjects with UGT1A1 polymorphisms.
Population pharmacokinetic analyses revealed no clinically relevant effect of gender on the exposure of cabotegravir, 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 dosage 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 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 dosage adjustment is necessary for patients with mild to severe renal impairment (not on dialysis). Cabotegravir has not been studied in patients on dialysis.
No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. No dosage adjustment is necessary for patients 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.
No effect on male or female fertility was observed in rats treated with cabotegravir at oral doses up to 1,000 mg/kg/day (>20 times the exposure in humans at the maximum recommended dose).
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 MRHD) or to pregnant rats at doses up to 1,000 mg/kg/day (>30 times the exposure in humans at the MRHD). In rats, alterations in foetal growth (decreased body weights) 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.
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 1,000 mg/kg/day (>30 times the exposure in humans at the MRHD). A lower dose of 5 mg/kg/day (approximately 10 times the exposure in humans at the 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 effects 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 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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