Brukinsa
zanubrutinib
Species
RatDog
Longest study
39 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
“Zanubrutinib was administered once daily to rats and dogs in studies up to 6 months in rats and 9 months in dogs.”
Why that species
Pharmacologically relevant species based on BTK sequence homology and functional assay
“Rats and dogs were chosen for the in vivo toxicity evaluation, as they are pharmacologically relevant species based on BTK sequence homology and functional assay.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 26-week study in rats, zanubrutinib was administered by oral gavage at 30, 100, 300, or 1000 mg/kg/day with a 4-week recovery period.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“In the 39-week study in dogs, zanubrutinib was administered orally at doses of 10, 30, or 100 mg/kg/day with a 4-week recovery period.”
Pivotal GLP studies
6-month rat and 9-month dog oral once-daily studies
“Zanubrutinib was administered once daily to rats and dogs in studies up to 6 months in rats and 9 months in dogs. The studies were conducted using the oral route of administration, which is consistent with the intended clinical route of administration.”
Route in tox
Oral
“The studies were conducted using the oral route of administration, which is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and rat bone marrow micronucleus assays
“Zanubrutinib was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in either the in vitro chromosomal aberrations assay or in the in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Not conducted; not required for the indication
“No carcinogenicity studies have been conducted or are required to support marketing of zanubrutinib for the current indication.”
Reproductive & developmental
Rat EFD: fetal heart malformations (2- or 3-chambered hearts) at 30-150 mg/kg/day
“In an embryo-fetal development study in female rats, once daily administration of zanubrutinib at 30, 75, or 150 mg/kg/day on GD 6-17 resulted in fetal heart malformations in the form of 2- or 3-chambered hearts.”
Safety pharmacology
No significant effects in dog telemetry, rat CNS (neurobehavior, temperature) or respiratory studies
“Zanubrutinib had no toxicologically-significant effects on cardiovascular function in a cardiovascular study in telemetered dogs, and had no effects on neurobehavioral function, temperature, or respiratory function in CNS and respiratory studies conducted in male rats.”
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 Brukinsa 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: Increased WBCs, multi-organ inflammation, GI necrosis, hemorrhage, lymphoid depletion; pancreatic lesions in rats (FDA multi-discipline review, p. 26)
NOAEL / key findings
Increased WBCs, multi-organ inflammation, GI necrosis, hemorrhage, lymphoid depletion; pancreatic lesions in rats
“Drug-related findings included increased white blood cells (WBCs) and differentials, multi-organ inflammation, GI tract necrosis, multi-organ hemorrhage, and lymphoid depletion. The findings were more prominent in the rat, particularly those in the pancreas (e.g. fibrin deposit and hemorrhage).”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion in dogs (also rats); inflammatory responses with elevated WBCs
“Other findings in the dog included lymphoid depletion and reduced red blood cells (RBCs) and lineages, which may be at least partially related to bleeding noted on histopathology.”
Biodistribution & persistence
Preferential distribution to stomach, small intestine and liver; very low brain and testis levels
“BGB-3111 showed preference for stomach, small intestine and liver. Very low concentration was found in brain and testes, however elimination from testes appeared to be slower than for other tissues.”
Modality-specific risk
Developmental toxicity: cataracts and corneal opacity in offspring at all PPND doses
“All dosing levels were associated with adverse ocular findings, including cataracts and corneal opacity in the offspring.”