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.”
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.”
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.”