Lampit
nifurtimox
Sources:FDA multi-discipline review ↗
Species
RatDog
Longest study
52 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
“repeated-dose toxicology studies in rats (28-day and 13-week studies) and dogs (28-day and 52-week studies)”
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
“Beagle dogs (n=4/sex/group) were dosed with vehicle, or 30, 60, 120, or 240 mg/kg/day BAY 2502 (nifurtimox) administered orally in gelatin capsules for 52 weeks.”
Study lengthopen answer page →
Longest pivotal study
52 (52-week dog)
“Pivotal studies included a 13-week study in rats and dog studies of 8, 16, 30, and 52 weeks.”
Pivotal GLP studies
Non-GLP 13-week rat and 52-week dog studies
“None of the repeated-dose toxicology studies were GLP-compliant. Pivotal studies included a 13-week study in rats and dog studies of 8, 16, 30, and 52 weeks.”
Route in tox
Oral
“Beagle dogs (n=4/sex/group) were dosed with vehicle, or 30, 60, 120, or 240 mg/kg/day BAY 2502 (nifurtimox) administered orally in gelatin capsules for 52 weeks.”
Skipped studiesopen answer page →
Genotoxicity
Considered genotoxic by weight of evidence; labeled with a genotoxicity Warning
“Based on the weight of evidence from these studies, nifurtimox is considered to be genotoxic and the product label for Lampit will include a Warning for genotoxicity.”
Carcinogenicity
Not required (treatment duration under 6 months)
“Because the proposed treatment duration of nifurtimox is less than 6 months, a carcinogenicity assessment is not required.”
Reproductive & developmental
Mouse, rat and rabbit EFD: maternal and/or fetal toxicity in all species; fetal malformation in rabbits
“In preliminary embryo-fetal studies in rats and mice and a comprehensive study in rabbits, nifurtimox produced dose-related maternal and/or fetal toxicity in all test species as well as a fetal malformation in rabbits.”
Safety pharmacology
hERG IC50 98 µM (28.2 µg/mL); slight QTc increase at 80 mg/kg in telemetered dogs
“Nifurtimox at high concentrations was shown to inhibit hERG channels with an estimated IC50 value of 98 mcM (28.2 mcg/ml). In a cardiovascular study in conscious telemetered dogs, QTc intervals were slightly increased at a nifurtimox dose of 80 mg/kg.”
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 Lampit 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: NOAEL 25 mg/kg/day (13-week rat) and 30 mg/kg/day (1-year dog) (FDA multi-discipline review, p. 44)
NOAEL / key findings
NOAEL 25 mg/kg/day (13-week rat) and 30 mg/kg/day (1-year dog)
“The NOAEL values for nifurtimox in rats and dogs in the 13-week and 1-year toxicology studies were considered to be 25 and 30 mg/kg/day, respectively.”
Risksopen answer page →
Immune & cytokine safety
Decreased thymus weights in high-dose rats without correlating histopathology
“Thymus: Mean absolute and relative thymus weights in HD male and female rats were decreased. The thymus weight changes were not accompanied by correlating histopathology.”
Biodistribution & persistence
Extensive tissue distribution; highest in kidney and liver, also lung, adrenal, thyroid, testes, brain, spinal cord
“In a mass-balance study, [35S]nifurtimox was shown to extensively distribute to tissues, with the highest concentrations of radioactivity in the kidneys and liver followed by lung, adrenal and thyroid glands, testes, brain, and spinal cord.”
Modality-specific risk
CNS toxicity (seizures) and testicular atrophy/impaired male fertility at near-therapeutic exposures
“In summary, in nonclinical studies nifurtimox was associated with serious toxicities including seizures in rats and dogs and testicular atrophy and impaired fertility in male rats at near therapeutic exposures.”