Fexinidazole
fexinidazole
Species
RatDog
Longest study
4 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 dog
“Repeat-dose toxicology studies were conducted in rats and dogs for up to 28 days.”
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
“The liver and thymus were identified as the target organs of toxicity in repeat-dose toxicity studies in rats and dogs at doses of 50, 200, and 800 mg/kg/day for 28 days.”
Species: general tox
Rat and dog (28-day)
“Repeat-dose toxicology studies were conducted in rats and dogs for up to 28 days.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Fertility and pre- and postnatal developmental studies were conducted in rats; embryo-fetal developmental studies in rats and rabbits;”
Species: carcinogenicity
Not conducted
“No carcinogenicity study was performed with fexinidazole.”
Surrogate used in
No surrogate used; rat and dog metabolite exposures exceeded human levels
“Nonclinical studies were considered adequate to assess the effects of these metabolites since levels in rats and dogs were higher than levels observed in humans.”
Study lengthopen answer page →
Longest pivotal study
4 (28-day rat and dog)
“Repeat-dose toxicology studies were conducted in rats and dogs for up to 28 days.”
Pivotal GLP studies
28-day oral studies in rats and dogs
“The liver and thymus were identified as the target organs of toxicity in repeat-dose toxicity studies in rats and dogs at doses of 50, 200, and 800 mg/kg/day for 28 days.”
Route in tox
Oral gavage
“Route of administration: Oral gavage Formulation/vehicle: 5% Tween 80/0.5% Methyl cellulose 400 cP”
Skipped studiesopen answer page →
Genotoxicity
Positive in Ames; negative in in vitro human lymphocyte micronucleus and in vivo mouse bone marrow micronucleus assays
“Fexinidazole was mutagenic (positive in strains TA98, TA100, and TA1535 in the presence and absence of S9 and TA1537, and TA102 in the presence of S9) but was negative in the in vitro micronucleus assays in cultured human peripheral blood lymphocytes up to 180 µg/mL (+/-S9), and the in vivo micronucleus assay in the bone marrow of treated mice (2 oral doses up to 2000 mg/kg).”
Carcinogenicity
Not conducted; related nitroimidazoles are carcinogenic in rodents
“Carcinogenicity studies are not indicated for fexinidazole and were not conducted. However, structurally related compounds such as metronidazole have exhibited carcinogenic potential in lifetime animal studies.”
Reproductive & developmental
Rat EFD: delayed ossification, reduced fetal and placental weights at maternally toxic 800 mg/kg
“Delayed ossification-reduced fetal weights and reduced placental weights were observed at 800 mg/kg in the presence of maternal toxicity (reduced maternal body weights).”
Safety pharmacology
hERG: sulfone metabolite reduced current by 33% at 9.3 µg/mL
“(hERG) assay showed that fexinidazole sulfone, the fexinidazole metabolite, reduced the residual current by 33 % at 9.3 µg/mL.”
Genotox: Ames
Positive (fexinidazole and M2 metabolite mutagenic)
“Fexinidazole and the M2 metabolite were mutagenic in the Ames test.”
Genotox: in vitro mammalian
Negative: in vitro micronucleus in human peripheral blood lymphocytes
“Fexinidazole was negative in the in vitro micronucleus test in cultured human peripheral blood lymphocytes, the rat liver unscheduled DNA synthesis (UDS) assay, and the in vivo mouse micronucleus assay.”
Genotox: in vivo
Negative: mouse micronucleus and rat liver UDS assays
“Fexinidazole was negative in the in vitro micronucleus test in cultured human peripheral blood lymphocytes, the rat liver unscheduled DNA synthesis (UDS) assay, and the in vivo mouse micronucleus assay.”
Carcinogenicity model
Not conducted; related nitroimidazoles carcinogenic in lifetime rodent studies
“No carcinogenicity study was performed with fexinidazole. Carcinogenicity has been observed in mice and rats treated chronically with nitroimidazole-class drugs which are structurally similar to fexinidazole.”
Carcinogenicity timing
Not indicated and not conducted (short-course therapy); related nitroimidazoles carcinogenic in lifetime studies
“Carcinogenicity studies are not indicated for fexinidazole and were not conducted. However, structurally related compounds such as metronidazole have exhibited carcinogenic potential in lifetime animal studies.”
hERG / QT
Sulfone metabolite inhibits hERG; patient sulfone Cmax (19.6 µg/mL) about 2 times levels affecting hERG
“Plasma levels of fexinidazole sulfone in patients receiving the recommended dose of fexinidazole (Cmax 19.6 µg/mL) were about two times the levels shown to affect hERG potassium channels.”
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 Fexinidazole 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Target organs liver and thymus in 28-day rat and dog studies (50-800 mg/kg/day) (FDA multi-discipline review, p. 57)
NOAEL / key findings
Target organs liver and thymus in 28-day rat and dog studies (50-800 mg/kg/day)
“The liver and thymus were identified as the target organs of toxicity in repeat-dose toxicity studies in rats and dogs at doses of 50, 200, and 800 mg/kg/day for 28 days.”
Risksopen answer page →
Immune & cytokine safety
Dog: decreased thymus weights at all doses
“In dogs, alkaline phosphatase and cholesterol increased and thymus weights decreased at all doses.”
Biodistribution & persistence
Crosses the blood-brain barrier; brain levels about 0.6x plasma in rats
“Fexinidazole penetrated the blood brain barrier with a brain Tmax of between 2 and 8 hours after dosing in rats. The level of fexinidazole in brain was approximately 0.6 times the levels in plasma.”
Modality-specific risk
QT prolongation from the fexinidazole sulfone metabolite
“Fexinidazole sulfone levels at clinical exposures could therefore contribute to the Qt prolongation described in patients in Section 5.2 of the Fexinidazole Prescribing information.”
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
- Decreased Efficacy in Severe Human African Trypanosomiasis Caused by Trypanosoma brucei gambiense
- QT Interval Prolongation
- Neuropsychiatric Adverse Reactions
- Neutropenia
- Potential for Hepatotoxicity
- Risk of Disulfiram-like Reaction Due to Concomitant Use with Alcohol
- Risk of Psychotic Reactions Due to Concomitant Use with Disulfiram
CardiovascularPsychiatricCytopeniasHepatotoxicity
US prescribing information, 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 Fexinidazole 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Target organs liver and thymus in 28-day rat and dog studies (50-800 mg/kg/day) (FDA multi-discipline review, p. 57)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
28-day oral beagle dog study with 2-week recovery (28-day rat study of equal length)
“Methods of 28-Day Oral Toxicity Study in the Dog, Study # 0505-2007 Parameter Details Dose and frequency of dosing: 0, 50, 200, 800 mg/kg Route of administration: Oral gavage Formulation/vehicle: 5% Tween 80/0.5% Methyl cellulose 400 cP (Methocel) suspension, water for injection Species/strain: Dog/beagle Number/sex/group: 3/sex/group Age: 1 year old Satellite groups/unique design: 2/sex/group (2-week recovery group)”
Pivotal GLP studies
28-day oral studies in rats and dogs
“The liver and thymus were identified as the target organs of toxicity in repeat-dose toxicity studies in rats and dogs at doses of 50, 200, and 800 mg/kg/day for 28 days.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Fertility and pre- and postnatal developmental studies were conducted in rats; embryo-fetal developmental studies in rats and rabbits;”
Reproductive & developmental
Rat EFD: delayed ossification, reduced fetal and placental weights at maternally toxic 800 mg/kg
“Delayed ossification-reduced fetal weights and reduced placental weights were observed at 800 mg/kg in the presence of maternal toxicity (reduced maternal body weights).”
PPND / ePPND: when
GLP PPND in rat completed and reviewed with the marketing application; NOAEL 200 mg/kg
“The NOAEL for maternal toxicity and pre- and postnatal development was 200 mg/kg, similar to the clinical dose based on AUC comparisons.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity study was performed with fexinidazole.”
Carcinogenicity model
Not conducted; related nitroimidazoles carcinogenic in lifetime rodent studies
“No carcinogenicity study was performed with fexinidazole. Carcinogenicity has been observed in mice and rats treated chronically with nitroimidazole-class drugs which are structurally similar to fexinidazole.”
Carcinogenicity timing
Not indicated and not conducted (short-course therapy); related nitroimidazoles carcinogenic in lifetime studies
“Carcinogenicity studies are not indicated for fexinidazole and were not conducted. However, structurally related compounds such as metronidazole have exhibited carcinogenic potential in lifetime animal studies.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat NOAEL 200 mg/kg (males): 0.7 times clinical exposure; 800 mg/kg (females) similar to clinical
“The no-observed-adverse-effect level (NOAEL) was estimated to be 200 mg/kg for males (0.7 times the clinical exposure, which is approximately 7 µg*hr/mL) and 800 mg/kg for females (similar to the clinical exposure).”
NOAEL / key findings
Target organs liver and thymus in 28-day rat and dog studies (50-800 mg/kg/day)
“The liver and thymus were identified as the target organs of toxicity in repeat-dose toxicity studies in rats and dogs at doses of 50, 200, and 800 mg/kg/day for 28 days.”
Efficacy evidenceopen answer page →
Efficacy evidence
Acute and chronic murine T. brucei infection models of HAT
“The activity of fexinidazole was measured in acute and chronic murine infection models of HAT.”
Why that model
T. brucei-infected mice mimic human disease despite intraperitoneal infection route
“Although the route of infection in mice is intraperitoneal, several aspects of the disease in T. brucei-infected animal models mimic human disease.”
Reviewer's view of the efficacy data
FDA: no relapse in acute models; relapse in some chronic (CNS-stage) studies, probably from residual brain parasites
“In the acute infection model, no relapse was reported in any study under the experimental conditions tested. However, in the chronic infection model, relapse was reported in some of the studies, which is probably due to the presence of the residual parasites in the brain.”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityAccepted with a conditionBeyond the letter
Positive Ames assay, including nitroreductase-deficient strains; applicant argued no human relevance
Why: Applicant: bacterial nitroreductases drive mutagenicity; reviewer: nitroreductase-deficient strains also positive, so results described in prescribing information
“The Applicant argues that the positive finding in the Ames assay does not indicate a risk to humans because bacterial nitroreductase enzymes contribute to the mutagenicity of fexinidazole and equivalent enzymes in mammalian cells cannot nitroreduce compounds with low redox potential and generate mutagenic by-products.”
“This reviewer notes that even the nitroreductase-deficient strains the Applicant tested in the Ames assay were positive; therefore, the positive mutagenicity results will be described in the prescribing information.”
CarcinogenicityVerdict not stated
No carcinogenicity studies despite a positive Ames assay and carcinogenic nitroimidazole analogues
“Carcinogenicity studies are not indicated for fexinidazole and were not conducted. However, structurally related compounds such as metronidazole have exhibited carcinogenic potential in lifetime animal studies.”
Safety marginVerdict not stated
Rat NOAEL in males at 0.7 times the clinical exposure
“The no-observed-adverse-effect level (NOAEL) was estimated to be 200 mg/kg for males (0.7 times the clinical exposure, which is approximately 7 µg*hr/mL) and 800 mg/kg for females (similar to the clinical exposure).”
DARTAcceptedBeyond the letter
Rabbit embryo-fetal study limited by maternal toxicity and abortions; NOAEL below 0.01 times clinical Cmax
Why: Excessive maternal toxicity is common in rabbits given antibiotics; rabbit not a good model for antibiotics · Class precedent
“Based on these findings, the NOAEL for maternal toxicity and embryofetal development in the rabbit was 10 mg/kg/day, equivalent to a dose of less than 0.01 times the maintenance dose based on Cmax comparisons).”
“Excessive maternal toxicity is not uncommon when rabbits are used in embryo-fetal toxicity testing of antibiotics. The rabbit does not therefore serve as a good model for embryo-fetal toxicity testing of antibiotics.”
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