Turalio
pexidartinib
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“To assess its safety, the Applicant conducted GLP-compliant toxicology studies of daily oral pexidartinib of up to six months in Sprague Dawley rats and up to nine months in Beagle dogs.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“To assess its safety, the Applicant conducted GLP-compliant toxicology studies of daily oral pexidartinib of up to six months in Sprague Dawley rats and up to nine months in Beagle dogs.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“To assess its safety, the Applicant conducted GLP-compliant toxicology studies of daily oral pexidartinib of up to six months in Sprague Dawley rats and up to nine months in Beagle dogs.”
Pivotal GLP studies
6-month rat and 9-month dog oral GLP studies
“To assess its safety, the Applicant conducted GLP-compliant toxicology studies of daily oral pexidartinib of up to six months in Sprague Dawley rats and up to nine months in Beagle dogs.”
Route in tox
Oral gavage
“A 6-month oral (gavage) toxicity study of PLX3397 with a 16-week recovery period in Sprague Dawley rats/Study -578139”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (human lymphocytes) and rat bone marrow micronucleus assays
“Pexidartinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in either the in vitro chromosomal aberrations assay in peripheral human lymphocytes or the in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
2-year rat and 26-week transgenic mouse: negative
“The Applicant also conducted a two-year (104-week) carcinogenicity study in rats and a 26-week carcinogenicity study in transgenic mice. Pexidartinib was negative for carcinogenicity in these studies.”
Reproductive & developmental
EFD: malformations, post-implantation loss and abortion at maternal exposures about equal to human exposure
“Oral administration of pexidartinib to pregnant animals during the period of organogenesis resulted in malformations, post-implantation loss, and abortion at maternal exposures that were approximately equal to the human exposure at the recommended dose (see Data ) .”
Safety pharmacology
No CNS or respiratory effects up to 200 mg/kg; hERG IC50 0.7 µM but no QTc or other ECG effects in vivo
“There were no pexidartinib-related adverse effects on the central nervous system or respiratory function following a single dose up to 200 mg/kg. Pexidartinib inhibited the hERG potassium channel with an IC50=0.7 μM, suggesting some potential for QTc prolongation; however, there were no effects on QTc or other electrocardiogram parameters in in vivo animal studies”
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 Turalio 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: Liver: hemosiderin, necrotizing inflammation and raised AST/ALT at ≥20 mg/kg (~0.6x clinical exposure) (FDA multi-discipline review, p. 40)
NOAEL / key findings
Liver: hemosiderin, necrotizing inflammation and raised AST/ALT at ≥20 mg/kg (~0.6x clinical exposure)
“In the liver, hemosiderin deposition and necrotizing inflammation with increased levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) occurred at doses ≥20 mg/kg (approximately 0.6 times the clinical exposure at 800 mg).”
Risksopen answer page →
Immune & cytokine safety
Thymic lymphoid depletion with decreased thymus weight and lymphocytes; lymphoid hyperplasia with lymph node enlargement
“Pexidartinib-related observations on the lymph/hematopoietic compartments include lymphoid depletion of the thymus with decreased thymus weight and lymphocyte counts and lymphoid hyperplasia with lymph node enlargement and increases in neutrophils and large unstained cells (LUC).”
Biodistribution & persistence
Highest exposure in uveal tract, liver, pancreas, Harderian gland and eye; still present in uveal tract at 336 h
“Tissues with the highest exposure (Cmax) to pexidartinib were the uveal tract, liver, pancreas, Harderian gland, and the entire eye. At the last sampling time of 336 hours post-dose, pexidartinib was still present in the eye including the uveal tract.”
Modality-specific risk
Hepatotoxicity
“The liver is a major target organ clinically, with frequent elevations in transaminases, including serious ones (refer to Section 8.3 of the review for details).”