Cabenuva
cabotegravir and rilpivirine
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and monkey (cabotegravir)
“Pivotal repeat-dose toxicology evaluations for CAB included GLP studies of up to 26 weeks duration in rats and 39 weeks duration in monkeys.”
Why that species
Rodent and non-rodent species with highest systemic exposure; relevant metabolite profile
“The test species were justified as the rodent and non-rodent species with the highest systemic exposure. All selected species are considered relevant from a metabolite perspective.”
Surrogate molecule
No surrogate; the clinical compound was tested
“All studies were conducted using the oral formulation of CAB, with the exception of a 3-month bridging study in rats using the subcutaneous and IM routes.”
Species: general tox
Cabotegravir: rat (up to 26 weeks) and monkey (up to 39 weeks); mouse up to 13 weeks
“Pivotal repeat-dose toxicology evaluations for CAB included GLP studies of up to 26 weeks duration in rats and 39 weeks duration in monkeys. Additional GLP studies of up to 13 weeks duration were conducted in mice to support the 2-year mouse carcinogenicity study.”
Species: DART
Cabotegravir: rat (male fertility, female fertility/EFD, PPND) and rabbit (EFD)
“Reproductive toxicology studies with CAB consist of a male fertility study in rats, a combined female fertility and embryo-fetal development study in rats, an embryo-fetal development study in rabbits, and PPND studies in rats.”
Species: carcinogenicity
Cabotegravir: mouse and rat (2-year)
“Two-year carcinogenicity studies in mice and rats were conducted with cabotegravir.”
Surrogate used in
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“Pivotal repeat-dose toxicology evaluations for CAB included GLP studies of up to 26 weeks duration in rats and 39 weeks duration in monkeys.”
Pivotal GLP studies
GLP studies up to 26 weeks in rats and 39 weeks in monkeys
“Pivotal repeat-dose toxicology evaluations for CAB included GLP studies of up to 26 weeks duration in rats and 39 weeks duration in monkeys.”
Route in tox
Oral; plus a 3-month subcutaneous/IM bridging study in rats
“All studies were conducted using the oral formulation of CAB, with the exception of a 3-month bridging study in rats using the subcutaneous and IM routes.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and in vivo rat micronucleus assays
“CAB was negative for mutagenesis and clastogenicity in the in vitro bacterial reverse mutation assay and the in vivo micronucleus assay in rats.”
Carcinogenicity
2-year oral mouse and rat studies: no carcinogenic potential
“CAB has demonstrated a lack of carcinogenic potential in conventional oral 2-year studies in mouse and rats at doses corresponding 7 and 19-fold the clinical AUC exposure in patients.”
Reproductive & developmental
Rat PPND: increased F1 stillbirths and early postnatal deaths at 1,000 mg/kg/dose
“In the pivotal rat PPND study, an increase in the number of F1 stillbirths and early postnatal deaths by PND 4 was observed at 1,000 mg/kg/dose (27.9× higher than human exposure at the proposed human dose).”
Safety pharmacology
No hERG IC50 identified; transient heart rate and arterial pressure increases at 1,000 mg/kg only
“An IC50 was not identified in the hERG assay. Increases in heart rate and mean arterial pressure were observed at 1,000 mg/kg up to 2 hours postdose in the cardiovascular function study, but no drug-related effects on these parameters were observed in the general toxicology studies up to the highest doses tested.”
Genotox: Ames
Negative (cabotegravir and rilpivirine)
“CAB was negative for mutagenesis and clastogenicity in the in vitro bacterial reverse mutation assay and the in vivo micronucleus assay in rats.”
Genotox: in vitro mammalian
Mouse lymphoma assay: negative (3-fold increase in a non-GLP assay without S9 not reproduced in the GLP assay)
“A 3-fold increase in mutant frequency was noted in a non-GLP in vitro mouse lymphoma assay in the absence of S9 only, but no drug-related changes were observed in a subsequent GLP in vitro mouse lymphoma assay. As a result, CAB was also considered negative in this assay.”
Genotox: in vivo
Rat micronucleus (cabotegravir): negative
“CAB was negative for mutagenesis and clastogenicity in the in vitro bacterial reverse mutation assay and the in vivo micronucleus assay in rats.”
Carcinogenicity model
Cabotegravir 2-year mouse and rat: no tumor increase in mice up to 8x (males) and 7x (females) human exposure
“Two-year carcinogenicity studies were conducted in mice and rats. In mice, no drug-related increases in tumor incidence were observed up to 75 mg/kg/dose in males and 35 mg/kg/dose in females (8× [males] and 7× [females] higher than human exposure at the proposed human dose).”
Carcinogenicity timing
Cabotegravir 2-year mouse and rat studies completed before the marketing application
“Two-year carcinogenicity studies were conducted in mice and rats.”
hERG / QT
Cabotegravir: no hERG inhibition up to solubility limit (7.14 µg/mL, ~1-2x clinical concentration); no IC50
“In vitro pharmacology studies showed that CAB did no inhibit of the hERG channel up to the highest concentration tested due to solubility propriety (7.14 µg/mL, ∼ 1x / ∼ 2x the clinical CAB concentration”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Cabenuva don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Monkey: no adverse findings up to 500 mg/kg/dose in 4- and 39-week studies (FDA integrated review, p. 126)
NOAEL / key findings
Monkey: no adverse findings up to 500 mg/kg/dose in 4- and 39-week studies
“In monkeys, no adverse findings were observed up to the highest doses tested (500 mg/kg/dose) in the 4- and 39-week studies.”
Risksopen answer page →
Immune & cytokine safety
Negative rat TDAR; no skin sensitization
“CAB was negative for immunosuppression in a T-cell–dependent antibody response (TDAR) study in rats, and was not associated with skin sensitization, skin irritation, ocular irritation, or phototoxicity.”
Biodistribution & persistence
Low brain penetration; detected in rat fetal tissue
“Very small amounts were also detected in the brain, indicating that low levels of CAB cross the blood–brain barrier. CAB was also detected in fetal tissue in an investigative toxicokinetic (TK) study in pregnant rats.”
Modality-specific risk
Injection-site reactions with the long-acting IM formulation
“The main findings in pivotal local tolerance studies in dogs and minipigs via IM injection of RPV LA were injection site findings, which have been characterized in human subjects and are monitorable.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Hypersensitivity Reactions
- Post-Injection Reactions
- Hepatotoxicity
- Depressive Disorders
- Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
- Long-Acting Properties and Potential Associated Risks with CABENUVA
Hypersensitivity & infusion reactionsHepatotoxicityPsychiatric
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Cabenuva don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Monkey: no adverse findings up to 500 mg/kg/dose in 4- and 39-week studies (FDA integrated review, p. 126)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week oral dog study of rilpivirine (reviewed under NDA 202022); recovery not stated
“Exposure was consistent with that observed in 52-week dog study with 5 mg/kg/day oral administration of TMC278 LA (study reviewed under NDA 202022).”
Pivotal GLP studies
GLP studies up to 26 weeks in rats and 39 weeks in monkeys
“Pivotal repeat-dose toxicology evaluations for CAB included GLP studies of up to 26 weeks duration in rats and 39 weeks duration in monkeys.”
DART package
Species: DART
Cabotegravir: rat (male fertility, female fertility/EFD, PPND) and rabbit (EFD)
“Reproductive toxicology studies with CAB consist of a male fertility study in rats, a combined female fertility and embryo-fetal development study in rats, an embryo-fetal development study in rabbits, and PPND studies in rats.”
Reproductive & developmental
Rat PPND: increased F1 stillbirths and early postnatal deaths at 1,000 mg/kg/dose
“In the pivotal rat PPND study, an increase in the number of F1 stillbirths and early postnatal deaths by PND 4 was observed at 1,000 mg/kg/dose (27.9× higher than human exposure at the proposed human dose).”
PPND / ePPND: when
Cabotegravir rat PPND studies completed before the marketing application
“Reproductive toxicology studies with CAB consist of a male fertility study in rats, a combined female fertility and embryo-fetal development study in rats, an embryo-fetal development study in rabbits, and PPND studies in rats.”
Carcinogenicity
Species: carcinogenicity
Cabotegravir: mouse and rat (2-year)
“Two-year carcinogenicity studies in mice and rats were conducted with cabotegravir.”
Carcinogenicity model
Cabotegravir 2-year mouse and rat: no tumor increase in mice up to 8x (males) and 7x (females) human exposure
“Two-year carcinogenicity studies were conducted in mice and rats. In mice, no drug-related increases in tumor incidence were observed up to 75 mg/kg/dose in males and 35 mg/kg/dose in females (8× [males] and 7× [females] higher than human exposure at the proposed human dose).”
Carcinogenicity timing
Cabotegravir 2-year mouse and rat studies completed before the marketing application
“Two-year carcinogenicity studies were conducted in mice and rats.”
Safety marginopen answer page →
Safety margin at NOAEL
Cabotegravir 39-week monkey NOAEL 3.7x human AUC at the oral dose
“The exposure multiples at the NOAELs in the 2-week, 4-week, and 39-week monkey studies are 1.6, 6.2, and 3.7, respectively.”
NOAEL / key findings
Monkey: no adverse findings up to 500 mg/kg/dose in 4- and 39-week studies
“In monkeys, no adverse findings were observed up to the highest doses tested (500 mg/kg/dose) in the 4- and 39-week studies.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro antiviral activity in human MT4 T-cell line and HIV-1 primary isolates (rilpivirine)
“RPV had antiviral activity against wild-type laboratory strain HIV-1IIIB in the MT4 T-cell line with a median EC50 value of 0.73nM and against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 to 1.01nM”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
EMA: pharmacodynamic data show cabotegravir is a highly specific and selective HIV-1 integrase inhibitor
“Based on the pharmacodynamics data, CAB is a highly specific and selective HIV-1 integrase inhibitor and the potential for pharmacodynamic drug interactions is unlikely.”
Flexibilityopen answer page →
Flexibility accepted
OtherVerdict not stated
Pivotal cabotegravir toxicity studies used the oral route; IM/SC route covered only by a 3-month rat bridging study
“All studies were conducted using the oral formulation of CAB, with the exception of a 3-month bridging study in rats using the subcutaneous and IM routes.”
OtherAcceptedBeyond the letter
No repeat-dose combination toxicity studies of cabotegravir plus rilpivirine
Why: Clinical experience with both drugs; no shared target organ; given as separate injections in separate locations · Human data · Pharmacology or kinetics
“Concerning the association CAB/RPV, it should be acknowledged the lack of combination toxicity studies due to the clinical experience with CAB and RPV, the lack of similar target organ indicating a potential additive/synergic interaction.”
“Because CAB and RPV will be administered clinically as two separate IM injections in separate locations, the coadministration of these two drugs in humans was considered acceptable from a pharmacology/toxicology perspective.”
DARTAcceptedBeyond the letter
No reproductive toxicity study with the cabotegravir-rilpivirine combination
Why: Rilpivirine already marketed; its animal studies showed no effect on reproductive function · Human data · Class precedent
“No study was conducted with the CAB-RPV combination which is acceptable. RPV is already marketed in Europe, and studies conducted in animals have shown no effect on reproductive function.”
Safety marginVerdict not stated
Rabbit embryo-fetal NOAEL exposure only 0.7-fold human exposure
“No drug-related effects on rabbit embryo-fetal development were observed up to 2,000 mg/kg/dose (0.7× the human exposure at the proposed human dose).”
Similar precedents
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