Krazati
adagrasib
Species
RatDog
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”
Why that species
Selected based on in vitro and in vivo metabolism studies
“The rat and dog were selected as preclinical species for toxicology studies based on results from in vitro and in vivo metabolism studies, which is supported.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”
Pivotal GLP studies
GLP 28-day and 13-week oral studies in Sprague-Dawley rats and Beagle dogs
“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”
Route in tox
Oral
“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and in vivo rat micronucleus assays
“Adagrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not genotoxic in an in vitro chromosomal aberration assay or an in vivo micronucleus assay in rats.”
Carcinogenicity
Not conducted (advanced cancer indication)
“Dedicated carcinogenicity studies were not conducted with adagrasib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”
Reproductive & developmental
No fertility, early embryonic or PPND studies (ICH S9); rat and rabbit EFD conducted
“DRF and definitive EFD studies were performed in Wistar rat and NZW rabbits. No fertility, early embryonic development or PPND studies were performed. This is considered acceptable as adagrasib is intended for treatment of advanced cancer, and the ICH S9 guideline applies.”
Safety pharmacology
hERG IC50 3.8 uM, about 48-fold above human free Cmax
“Adagrasib inhibited hERG potassium channel currents with an IC50 of 3.8 μM in a safety pharmacology assessment, which is approximately 48-fold higher than the human free steady-state Cmax of ~0.08 μM based on ~98% protein-binding at the recommended dose.”
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 Krazati 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: Target organs in rats and dogs: heart, lungs, adrenal gland, kidney and liver (FDA multi-discipline review, p. 42)
NOAEL / key findings
Target organs in rats and dogs: heart, lungs, adrenal gland, kidney and liver
“In both rats and dogs, the target organs were heart, lungs, adrenal gland, kidney, and liver.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid tissue changes not considered an immunotoxicity risk; no dedicated immunotoxicity studies
“It is further clarified that adagrasib-induced microscopic changes in lymphoid tissues, do not appear to translate into an immunotoxicity risk is supported. Omission of specific immunotoxicity studies is therefore accepted.”
Biodistribution & persistence
Distributed to nearly all rat tissues by 8 h; affinity for melanin-pigmented tissues
“Following single oral administration to rats, 14C-adagrasib-derived radioactivity distributed to nearly all tissues by 8 hours post-dose. Adagrasib demonstrated affinity for melanin-pigmented tissues.”
Modality-specific risk
Phospholipidosis (macrophage infiltration and vacuolation) in multiple tissues
“Toxicology studies of up to 13 weeks duration in both species revealed microscopic findings of macrophage infiltration and vacuolation in several tissues, suggestive of phospholipidosis”