Gavreto
pralsetinib
Species
MonkeyRat
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 cynomolgus monkey
“The Applicant evaluated the safety of pralsetinib using Sprague-Dawley rats and Cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 13 weeks duration.”
Why that species
Dog also tested but unsuitable beyond 7 days due to species-specific p38 MAPK-related toxicities; rat and monkey used
“The dog was also investigated as a non-rodent species, but due to species specific toxicities, related to p38 MAPK inhibition, and exacerbated toxicities following this inhibition, the dog was not suitable for further toxicity studies beyond single dose or 7 days repeat-dose studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the GLP-compliant 13-week repeated-dose toxicology study in rats (10 animals/sex/group), pralsetinib was administered at oral doses of 5, 10, and 20 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and monkey)
“The Applicant evaluated the safety of pralsetinib using Sprague-Dawley rats and Cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 13 weeks duration.”
Pivotal GLP studies
28-day and 13-week GLP oral gavage studies in rats and cynomolgus monkeys
“The rat and cynomolgus monkey were used in GLP-compliant 28-days and 13-week repeat dose”
Route in tox
Oral gavage
“A GLP-compliant 13-Week Once Daily Oral Gavage Toxicity and Toxicokinetic Study of Pralsetinib in Sprague-Dawley Rats (Report 00124770)”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro TK6 micronucleus and rat bone marrow micronucleus assays
“Pralsetinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro micronucleus assay in TK6 cells or the in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Not conducted (advanced cancer indication)
“The Applicant did not conduct carcinogenicity or fertility studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
Reproductive & developmental
Rat EFD: visceral and skeletal malformations from 5 mg/kg/day; 100% post-implantation loss at ≥20 mg/kg/day
“In the EFD study, multiple visceral and skeletal malformations were observed, as well as developmental variation, even from the lowest dose level of 5 mg/kg/day. 100% post implantation loss was seen at 20 mg/kg/day and above.”
Safety pharmacology
No relevant hERG inhibition or QTc prolongation in monkeys; increased blood pressure with decreased heart rate in rats at ≥25 mg/kg
“Pralsetinib did not inhibit in vitro hERG potassium currents at relevant concentrations or induce QTc prolongation in the 13-week repeat-dose study in cynomolgus monkeys. Single oral administration of ≥25 mg/kg pralsetinib resulted in increased blood pressure with concomitant decreases in heart rate in male Sprague-Dawley 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 Gavreto 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 in rat and monkey: bone marrow (decreased RBCs, WBCs), kidney (tubular basophilia/mineralization) and lung (macrophage aggregation) (FDA multi-discipline review, p. 42)
NOAEL / key findings
Targets in rat and monkey: bone marrow (decreased RBCs, WBCs), kidney (tubular basophilia/mineralization) and lung (macrophage aggregation)
“Target organs in both species included the bone marrow, with findings of decreased cellularity histopathologically consistent with decreases in red blood cells (RBCs) and mild decreases in white blood cells (WBCs), kidney (decreased weight and tubular basophilia/mineralization), and lung (macrophage aggregation).”
Risksopen answer page →
Immune & cytokine safety
No dedicated immunotoxicity studies; decreased cellularity of haematopoietic and lymphoid organs in rats and monkeys
“Although no dedicated immunotoxicity studies were conducted with pralsetinib, some of the toxicological findings reported in repeat-dose toxicity studies were related to its actions on immune system (i.e., decreased cellularity of multiple haematopoietic and lymphoid organs in rats, and bone marrow cellularity and decreased cellularity of lymphoid organs in monkeys).”
Biodistribution & persistence
Wide distribution (intestine, liver, adrenal, uveal tract, pigmented skin); melanin affinity; crosses blood-brain barrier in rats
“Following single oral administration, 14C-pralsetinib-derived radioactivity distributed widely to rat tissues especially the small intestine wall, liver, adrenal gland, uveal tract, and pigmented skin. Pralsetinib crossed the blood-brain barrier in rats”
Modality-specific risk
Embryofetal toxicity: renal malformations consistent with the role of RET in renal organogenesis
“The observed renal malformations/variations were consistent with the role of RET in renal organogenesis. The pharmacology/toxicology team recommends a warning for embryo-fetal toxicity in the label for GAVRETO.”