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.”
Species: general tox
Rat (28-day, 13-week) and dog (28-day, 52-week)
“repeated-dose toxicology studies in rats (28-day and 13-week studies) and dogs (28-day and 52-week studies)”
Species: DART
Rat (fertility, pre/postnatal); mouse, rat and rabbit (EFD)
“fertility and pre-postnatal studies in rats; and embryo-fetal studies in mice, rats, and rabbits.”
Species: carcinogenicity
Mouse (60-day intraperitoneal literature study)
“In one study in mice, nifurtimox administered intraperitoneally for 60 days was associated with an increased prevalence of lymphoblastic lymphomas in lymph nodes, spleen, and liver.”
Surrogate used in
No surrogate used; nifurtimox itself 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.”
Genotox: Ames
Positive: dose-dependent mutant increases with and without S9
“In Ames assays, nifurtimox produced dose-dependent increases in the number of mutants with and without S9 activation, and, in an in vitro micronucleus assay, nifurtimox was clastogenic in human lymphocytes.”
Genotox: in vitro mammalian
Positive: in vitro micronucleus, clastogenic in human lymphocytes
“In Ames assays, nifurtimox produced dose-dependent increases in the number of mutants with and without S9 activation, and, in an in vitro micronucleus assay, nifurtimox was clastogenic in human lymphocytes.”
Genotox: in vivo
Positive: mouse micronucleus and mouse sister chromatid exchange; chromosome aberrations in Chagas patients
“In vivo, nifurtimox was shown to be positive for clastogenesis in a mouse micronucleus assay, a mouse sister chromatid exchange assay, and a chromosome aberration assay in Chagas patients.”
Carcinogenicity model
Not required (treatment under 6 months); deficient literature studies in mice and rats submitted
“Because the proposed treatment duration of nifurtimox is less than 6 months, a carcinogenicity assessment is not required. However, three carcinogenicity studies for nifurtimox were submitted in NDA 213464, two in limited brief study reports and one in a published manuscript.”
Carcinogenicity timing
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.”
hERG / QT
hERG IC50 28.2 mcg/mL, ~38-fold the clinical Cmax
“The 28.2 mcg/ml IC50 value for nifurtimox inhibition of hERG channels is approximately 38-fold higher than the clinical Cmax value of 751 ng/ml measured in healthy human subjects administered a single dose of 15 mg/kg nifurtimox (Paulos et al. 1989).”
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.”
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 applicable (small molecule)
“Immunogenicity Not applicable for this NDA.”
Label warnings
- Potential for Genotoxicity and Carcinogenicity
- Embryo-Fetal Toxicity
- Worsening of Neurological and Psychiatric Conditions
- Hypersensitivity
- Decreased Appetite and Weight Loss
- Porphyria
Embryo-fetal toxicityNeurotoxicityPsychiatricHypersensitivity & infusion reactions
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week (1-year) dog, non-GLP (1970), no recovery period; no repeat-dose study was GLP-compliant
“Oral Toxicity Study in Purebred Dogs Repeated Dosage for One Year/Study No. 3048/69/474; Study Report No.: 3048-69-474 Also described in: Toxicological Investigations on the Tolerability of Nifurtimox (Hoffmann 1972) Reviewer Comment: This non-GLP study was conducted in 1970, and did not include a recovery period.”
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.”
DART package
Species: DART
Rat (fertility, pre/postnatal); mouse, rat and rabbit (EFD)
“fertility and pre-postnatal studies in rats; and embryo-fetal studies in mice, rats, and rabbits.”
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.”
PPND / ePPND: when
Pre-postnatal study in rat completed and reviewed in the marketing application
“In a pre-postnatal study in rats, maternal findings included reduced maternal body weights in mid- and high-dose dams during dosing, but no changes in uterine content parameters.”
Carcinogenicity
Species: carcinogenicity
Mouse (60-day intraperitoneal literature study)
“In one study in mice, nifurtimox administered intraperitoneally for 60 days was associated with an increased prevalence of lymphoblastic lymphomas in lymph nodes, spleen, and liver.”
Carcinogenicity model
Not required (treatment under 6 months); deficient literature studies in mice and rats submitted
“Because the proposed treatment duration of nifurtimox is less than 6 months, a carcinogenicity assessment is not required. However, three carcinogenicity studies for nifurtimox were submitted in NDA 213464, two in limited brief study reports and one in a published manuscript.”
Carcinogenicity timing
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.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat and dog NOAEL HEDs 0.2-1.7x the 10-20 mg/kg/day clinical dose (body surface area)
“The human equivalent dose (HED) values for the rat and dog NOAEL values based on body surface area comparison provide only low safety margins of 0.4 for rats and 1.7 for dogs with respect to a 10 mg/kg/day clinical dose and 0.2 for rats and 0.8 for dogs with respect to a 20 mg/kg/day clinical dose.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Acute and chronic T. cruzi infection models in mice, rats, hamsters, guinea pigs, rabbits and dogs
“Several studies reported the activity of nifurtimox in acute and/or chronic infection models of T. cruzi. Approximately 62 strains/isolates were tested in several animal species that include mice, rats, hamsters, guinea pigs, rabbits and dogs.”
Why that model
T. cruzi infection in animals reproduces chronic human pathology including myocarditis and heart failure signs
“The lesions and characteristic chronic pathology, in general, are similar to those observed in human disease, and include diffuse myocarditis and signs of heart failure.”
Reviewer's view of the efficacy data
FDA microbiology reviewer: animal T. cruzi infection models mimic aspects of human disease
“Several aspects of T. cruzi infection in these animal models mimic human disease.”
Flexibilityopen answer page →
Flexibility accepted
GLPVerdict not stated
Most nonclinical studies, including all repeat-dose toxicity studies, decades old, non-GLP and reported in literature publications
“Many of the submitted studies were conducted decades ago, without GLP compliance, and are reported in literature publications.”
Safety marginVerdict not stated
NOAEL-based human equivalent dose margins only 0.2-1.7 versus the 10-20 mg/kg/day clinical dose
“The human equivalent dose (HED) values for the rat and dog NOAEL values based on body surface area comparison provide only low safety margins of 0.4 for rats and 1.7 for dogs with respect to a 10 mg/kg/day clinical dose and 0.2 for rats and 0.8 for dogs with respect to a 20 mg/kg/day clinical dose.”
DARTAccepted with a conditionBeyond the letter
Rat and mouse embryo-fetal studies deficient; new rat embryo-fetal study required after approval
Why: Embryo-fetal toxicity Warning in label; new rat study as postmarketing requirement
“Because of the deficiencies in the embryo-fetal studies in rats and mice, a new embryo-fetal study of acceptable design in rats will be conducted as a postmarketing requirement.”
“Based on these findings, nifurtimox-related embryo-fetal toxicity will be addressed in a Warning in the Lampit label, and a new embryo-fetal study in rats will be conducted as a postmarketing requirement to more fully elucidate the effects of nifurtimox in pregnant animals.”
CarcinogenicityAccepted
No adequate carcinogenicity study; only limited legacy reports submitted, as treatment lasts under 6 months
Why: Treatment duration under 6 months; genotoxicity and nitrofuran class findings suggest carcinogenic potential · Within the guideline · Class precedent
“Because the proposed treatment duration of nifurtimox is less than 6 months, a carcinogenicity assessment is not required. However, three carcinogenicity studies for nifurtimox were submitted in NDA 213464, two in limited brief study reports and one in a published manuscript.”
“However, other findings including the genotoxicity findings for nifurtimox and carcinogenicity findings for other nitrofuran antimicrobials more definitively suggest a carcinogenicity potential for nifurtimox in humans.”
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