Vanflyta
quizartinib
Species
MonkeyRatDog
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, dog and cynomolgus monkey
“Repeat-dose toxicology studies were conducted in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys given quizartinib dihydrochloride for up to 13 weeks.”
Why that species
Cynomolgus monkey selected as alternate non-rodent based on PK and toxicology data
“Based on pharmacokinetic (PK) and toxicology data, the cynomolgus monkey was selected as a potential alternate nonrodent model for evaluating the toxicity profile of quizartinib to predict human safety risk.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Repeat-dose toxicology studies were conducted in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys given quizartinib dihydrochloride for up to 13 weeks.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat, dog and monkey)
“NOAELs in the 13-week repeated dose toxicity studies were 3 mg/kg/day in rats, 5 mg/kg/day in dogs, and 3 mg/kg/day in monkeys.”
Pivotal GLP studies
13-week rat, dog and cynomolgus monkey repeat-dose studies
“NOAELs in the 13-week repeated dose toxicity studies were 3 mg/kg/day in rats, 5 mg/kg/day in dogs, and 3 mg/kg/day in monkeys.”
Route in tox
Oral (gavage)
“A 13-Week Oral Gavage Toxicity Study of AC220 in the Cynomolgus Monkey With a 4 Week Recovery Period”
Skipped studiesopen answer page →
Genotoxicity
Positive in Ames; negative in mouse lymphoma, human lymphocyte chromosome aberration and rat micronucleus assays
“In genotoxicity studies, quizartinib was mutagenic in a bacterial reverse mutation assay. Quizartinib was not genotoxic in the following assays: mouse lymphoma thymidine kinase mutation assay, chromosome aberration assay in human peripheral blood lymphocytes, and rat bone marrow micronucleus assay (tested to the maximum tolerated dose, MTD).”
Carcinogenicity
Not conducted; not required for the AML indication
“No carcinogenicity studies were conducted or are required to support the marketing of quizartinib for the current indication.”
Reproductive & developmental
Rat EFD: anasarca/edema, lower fetal weight and ossification effects at ~3x MRHD exposure
“In an embryo-fetal development (EFD) study in rats, quizartinib at doses resulting in exposures approximately 3 times the exposure at the maximum recommended human dose (MRHD) was associated with adverse developmental outcomes including structural abnormalities (anasarca and edema) and alterations to growth (lower fetal weights and effects on skeletal ossification).”
Safety pharmacology
No hERG inhibition at clinical concentrations; dose-dependent sustained QTc prolongation in monkeys
“However, quizartinib and the major metabolite AC886 did not inhibit hERG, INa, INa-L, or ICa-L currents at clinically relevant concentrations. In vivo, a single dose of quizartinib administered to monkeys induced a dose-dependent increase in corrected QT interval (QTc) with sustained prolongation over 24 hours.”
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 Vanflyta 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: 13-week NOAELs: rat 3, dog 5, monkey 3 mg/kg/day (FDA multi-discipline review, p. 58)
NOAEL / key findings
13-week NOAELs: rat 3, dog 5, monkey 3 mg/kg/day
“NOAELs in the 13-week repeated dose toxicity studies were 3 mg/kg/day in rats, 5 mg/kg/day in dogs, and 3 mg/kg/day in monkeys.”
Risksopen answer page →
Immune & cytokine safety
Hematologic and lymphoid toxicities from exaggerated pharmacology
“Hematologic and lymphoid toxicities were common and attributable to exaggerated pharmacology.”
Biodistribution & persistence
Melanin binding: pigmented skin accumulated ~9-fold more radioactivity than non-pigmented skin
“Binding to melanin was evident as pigmented skin accumulated about 9-fold more radioactivity than non-pigmented skin.”
Modality-specific risk
QT prolongation via potassium channel inhibition; transient blood pressure increases
“Overall, these studies demonstrated quizartinib exposure was associated with inhibition of potassium channel currents, prolongation of QT intervals, and transient increases in blood pressure.”