Rozlytrek
entrectinib
Species
RatDog
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“considering that the majority of toxicology studies, including the pivotal 13-week rat and dog studies, tested the Form II (A) also used in clinical trials, results from toxicology studies are considered reliable for extrapolation to humans.”
Why that species
100% or near-100% sequence homology of the entrectinib binding site in the toxicology species
“Sequence comparisons showed 100% or near 100% sequence homologies in the entrectinib binding site, building confidence on the theoretical validity of the selected species used for the safety validation.”
Surrogate molecule
No surrogate; the clinical compound was tested
“considering that the majority of toxicology studies, including the pivotal 13-week rat and dog studies, tested the Form II (A) also used in clinical trials, results from toxicology studies are considered reliable for extrapolation to humans.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“considering that the majority of toxicology studies, including the pivotal 13-week rat and dog studies, tested the Form II (A) also used in clinical trials, results from toxicology studies are considered reliable for extrapolation to humans.”
Pivotal GLP studies
13-week rat and dog repeat-dose studies
“considering that the majority of toxicology studies, including the pivotal 13-week rat and dog studies, tested the Form II (A) also used in clinical trials, results from toxicology studies are considered reliable for extrapolation to humans.”
Route in tox
Oral
“The studies were carried out primarily with oral administration, which is the proposed clinical route of administration. Pharmacokinetic analysis following repeated doses was performed in pharmacology studies in mice and in all repeated-dose toxicology studies.”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; aneugenic in vitro (human lymphocytes); negative in rat micronucleus and comet assays
“Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay, but demonstrated a potential for abnormal chromosome segregation (aneugenicity) in cultured human peripheral blood lymphocytes. Entrectinib was not clastogenic or aneugenic in the in vivo micronucleus assay in rats and did not induce DNA damage in a comet assay in rats.”
Carcinogenicity
Not conducted
“Carcinogenicity studies were not conducted with entrectinib.”
Reproductive & developmental
Rat EFD: maternal toxicity and fetal malformations (body closure, vertebrae, ribs) at 200 mg/kg/day
“In an embryo-foetal developmental study in rats, maternal toxicity (decreased body weight gain and food consumption) and foetal malformations (including body closure defects and malformations of the vertebrae and ribs), were observed at 200 mg/kg/day of entrectinib”
Safety pharmacology
hERG IC50 0.6 µM (free drug), indicating potential cardiovascular risk
“In vitro, entrectinib inhibited hERG with an IC50 of 0.6 µM as a free drug, indicating a potential for cardiovascular risk.”
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 Rozlytrek 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 oncology small molecules (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Targets: CNS (convulsions, abnormal gait, tremors), skin (scabs/sores), decreased RBC parameters, at sub-clinical exposures (EMA assessment report, p. 66)
NOAEL / key findings
Targets: CNS (convulsions, abnormal gait, tremors), skin (scabs/sores), decreased RBC parameters, at sub-clinical exposures
“Entrectinib-related toxicities in repeat-dose studies in adult rats and dogs, and juvenile rats were observed in the CNS (convulsions, abnormal gait, tremors) at ≥0.2 times the human exposures by Cmax at the recommended dose, skin (scabs/sores) and decreased RBC parameters at ≥0.1 times the human exposure by AUC at the recommended dose.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion in rat spleen (≥25 mg/kg/day), lymph nodes and thymus (≥200 mg/kg/day)
“Lymphoid depletion was observed at ≥25 mg/kg/day in the 4-week study in spleen, and also in lymph nodes and thymus at ≥200 mg/kg/day in the 4-week 2x2 intermittent dosing and 14-day studies.”
Biodistribution & persistence
Brain-penetrant: steady-state brain-to-plasma ratios ~0.4 (mouse), 0.6–1.5 (rat), 1.4–2.2 (dog)
“In addition, after repeated oral doses brain-to-plasma concentration ratios of entrectinib were higher at 24 hours post last dose in mice (~0.4), rats (0.6–1.5), and dogs (1.4-2.2), indicating brain penetration occurred under steady-state conditions.”
Modality-specific risk
QT/QTcF prolongation in dogs at 120 mg/kg/day
“In the 4-week (2x2 intermittent dosing) study, moderate prolongation of the QT/QTcF intervals was noted at 120 mg/kg/day (recorded on Day 11), where a Cmax of >7 µM was observed.”