Fexinidazole
fexinidazole
Sources:FDA multi-discipline review ↗
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.”
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.”
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.”