Fotivda
tivozanib
Species
MonkeyRat
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 cynomolgus monkey
“The selection of animal models to be used in toxicology and safety pharmacology studies (rats and monkeys) was based on PK and/or metabolic profiles of tivozanib.”
Why that species
Metabolic profile: monkey liver microsomal metabolism most similar to human, followed by rat
“Comparison of the metabolic profile of tivozanib in liver microsomes showed that monkey most closely resembled the human, followed by the rat. These data provided support for species selection.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Oral administration of tivozanib in rats for 26 weeks produced non-adverse decreases in body weights, abnormal whitening of the teeth and changes in hematology/clinical chemistry at 0.08 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“In a 39-week oral toxicity study in monkeys, the highest dose tested 0.1 mg/kg/day (HED=1.95 g/day; 1. 5-fold of the recommended human dose) was well tolerated.”
Pivotal GLP studies
Up to 26-week rat and 39-week cynomolgus monkey oral studies
“Single-oral and intravenous (IV) dose toxicity studies in CD-1 mice and Sprague-Dawley (SD) rats were conducted followed by oral repeat-dose studies in SD rats (up to 26 weeks) and cynomolgus monkeys (up to 39 weeks).”
Route in tox
Oral
“The oral route was utilized in nonclinical studies as this is the intended clinical route of exposure.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO cytogenetic and in vivo mouse bone marrow micronucleus assays
“Tivozanib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro cytogenetic assay in Chinese hamster ovary cells or in an in vivo mouse bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“As it is intended for advanced Renal Cell Carcinoma, in accordance with ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, carcinogenicity studies are not required.”
Reproductive & developmental
Rat fertility: increased epididymis/testis weights at ≥0.03 mg/kg/day; reduced mating and infertility at ≥0.3 mg/kg/day
“In animal studies assessing mating and fertility parameters, oral doses ≥ 0.03 mg/kg/day (0.2 times the maximum recommended clinical dose on a mg/m 2 basis) in rats were associated with increased epididymis and testis weights, and doses ≥ 0.3 mg/kg/day (2 times the maximum recommended clinical dose on a mg/m 2 basis) reduced mating and produced infertility.”
Safety pharmacology
Telemetered monkeys: increased blood pressure at 3 mg/kg; no effects on heart rate, QT/QTc or QRS
“A dose of 3 mg/kg resulted in increases in systolic, diastolic and mean arterial blood pressure 90 minutes post-dose. There were no test article-related effects on heart rates, RR, PR, QT, QTcF, QTcQ intervals and the QRS duration at any dose level.”
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 Fotivda 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: Rat and monkey targets: adrenal, GI (stomach, duodenum, pancreas), kidney, bone, liver, brain, pituitary, heart, incisors, ovaries/uterus (FDA multi-discipline review, p. 29)
NOAEL / key findings
Rat and monkey targets: adrenal, GI (stomach, duodenum, pancreas), kidney, bone, liver, brain, pituitary, heart, incisors, ovaries/uterus
“The predominant toxicities in both species were associated with the following systems/organs: adrenal gland, gastrointestinal system (stomach, duodenum, and pancreas), kidney, bone (femur and tibia), liver, brain, pituitary gland, heart, incisors and reproductive system (ovaries and uterus).”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion of thymus, lymph nodes and spleen
“gastric system (stomach, duodenum and pancreas), reproductive system (ovary and corpora lutea) and lymphoid organs (lymphoid depletion of thymus, lymph nodes and spleen).”
Biodistribution & persistence
Melanin binding to choroid of eye in pigmented rats, declining over 120 hours
“In pigmented rats, melanin binding to the choroid layer of the eye was apparent and levels decreased steadily over 120 hours post-dose.”
Modality-specific risk
Embryo-fetal toxicity: malformations and embryo-fetal death below clinical dose
“In embryo-fetal developmental studies, oral administration of tivozanib to pregnant animals during the period of organogenesis caused maternal toxicity, fetal malformations and embryo- fetal death at doses below the maximum recommended clinical dose on a mg/m 2 basis [see DATA ] .”