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.”
Species: general tox
Rat (6-month) and dog (9-month)
“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.”
Species: DART
Rat and rabbit (embryo-fetal development)
“The Applicant conducted embryo-fetal development studies in rats and rabbits.”
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (26-week)
“The Applicant conducted a two-year (104-week) carcinogenicity study with pexidartinib in rats and a 26-week carcinogenicity study in rasH2 transgenic mice (See Appendix 19.3 for full review).”
Surrogate used in
No surrogate used; pexidartinib tested directly in 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.”
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”
Genotox: Ames
Negative
“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.”
Genotox: in vitro mammalian
Chromosomal aberration in human peripheral lymphocytes: negative
“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.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“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 model
2-year rat; 26-week rasH2 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.”
Carcinogenicity timing
2-year rat and 26-week rasH2 mouse studies completed before the marketing application
“The Applicant conducted a two-year (104-week) carcinogenicity study with pexidartinib in rats and a 26-week carcinogenicity study in rasH2 transgenic mice (See Appendix 19.3 for full review).”
hERG / QT
hERG IC50 0.7 µM; no QTc or ECG effects in vivo in animals, attributed to high protein binding
“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 and no evidence of QT prolongation occurring in humans at the 800 mg dose, likely due to the high protein binding of pexidartinib in human plasma”
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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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).”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
Boxed warning: Hepatotoxicity
- Hepatotoxicity
- TURALIO REMS Program
- Embryo-Fetal Toxicity
- Potential Risks Associated with a High-Fat Meal
HepatotoxicityEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month dog (oral gavage) with 16-week recovery
“A 9-month oral (gavage) toxicity study of PLX3397 with a 16-week recovery period 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.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“The Applicant conducted embryo-fetal development studies in rats and rabbits.”
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 ) .”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In a pre-and postnatal development study, female rats received pexidartinib once daily from GD 6 to lactation day (LD) 20 at doses up to 10 mg/kg/day (approximately 0.3 times the exposure at the 800 mg clinical dose).”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (26-week)
“The Applicant conducted a two-year (104-week) carcinogenicity study with pexidartinib in rats and a 26-week carcinogenicity study in rasH2 transgenic mice (See Appendix 19.3 for full review).”
Carcinogenicity model
2-year rat; 26-week rasH2 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.”
Carcinogenicity timing
2-year rat and 26-week rasH2 mouse studies completed before the marketing application
“The Applicant conducted a two-year (104-week) carcinogenicity study with pexidartinib in rats and a 26-week carcinogenicity study in rasH2 transgenic mice (See Appendix 19.3 for full review).”
Safety marginopen answer page →
Safety margin at NOAEL
Rat liver toxicity at ≥20 mg/kg (~0.6x clinical exposure at 800 mg)
“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).”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse model of splenomegaly from injected CSF1R signaling-dependent cells: inhibited 79%
“In an in vivo model in which injection of CSFR1 signaling-dependent cells results in splenomegaly, pexidartinib inhibited splenomegaly by 79%, compared to the vehicle control.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
FDA: no outstanding pharmacology/toxicology issues preventing approval for TGCT
“There are no outstanding issues from a pharmacology/toxicology perspective that would prevent the approval of TURALIO for the treatment of adult patients with symptomatic tenosynovial giant cell tumors (TGCT) associated with severe morbidity or functional limitations which is not amenable to improvement with surgery.”
Flexibilityopen answer page →
Flexibility accepted
Impurity or metaboliteAccepted with a conditionBeyond the letter
Major human metabolite ZAAD-1006a not measured in rat and dog toxicity studies; off-target screening deferred to a postmarketing commitment
Why: Deficiency addressed by a PMC for additional in vitro screening assays
“In the repeat-dose toxicology studies in rats and dogs, systemic exposure of ZAAD-1006a was not assessed, and therefore its toxicological potential was not evaluated.”
“This deficiency resulted in a PMC for additional in vitro screening assays for ZAAD-1006a.”
DARTCriticised but acceptedBeyond the letter
Fertility study dosed both sexes before mating, so effects on fertility cannot be attributed by sex
Why: Histopathology in both sexes plus reduced pregnancy suffice to warn; further fertility studies would not mitigate findings · Weight of evidence
“The suboptimal study design in which both sexes received pexidartinib prior to mating makes clear attribution of the reduced fertility by sex impossible.”
“Despite this deficiency, the histopathological findings in both male and female animals coupled with reduced pregnancy are adequate to warn patients about the potential risk of reduced fertility with pexidartinib and additional individual fertility studies would not mitigate the compelling histopathological findings from the existing data.”
Safety marginVerdict not stated
Rat liver toxicity at exposures about 0.6 times the clinical exposure at 800 mg
“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).”
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