Blujepa
gepotidacin
Species
RatDog
Longest study
13 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
“toxicology studies (repeat-dose studies in rats (up to 13 weeks) and dogs (up to 13 weeks)), genetic toxicology assays (in vitro and in vivo), and reproductive and developmental toxicity in rats and mice.”
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
“Study #2013N160007 /GSK2140944E: A 13-week Oral (Gavage) Toxicity in Rats Followed by a 28-day Recovery Period”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“toxicology studies (repeat-dose studies in rats (up to 13 weeks) and dogs (up to 13 weeks)), genetic toxicology assays (in vitro and in vivo), and reproductive and developmental toxicity in rats and mice.”
Pivotal GLP studies
13-week rat and 13-week dog repeat-dose studies
“toxicology studies (repeat-dose studies in rats (up to 13 weeks) and dogs (up to 13 weeks)), genetic toxicology assays (in vitro and in vivo), and reproductive and developmental toxicity in rats and mice.”
Route in tox
Oral (gavage)
“Study #2013N160007 /GSK2140944E: A 13-week Oral (Gavage) Toxicity in Rats Followed by a 28-day Recovery Period”
Skipped studiesopen answer page →
Genotoxicity
Positive in vitro (human lymphocyte micronucleus, mouse lymphoma); negative in vivo rat micronucleus and comet assays
“Gepotidacin was positive in an in vitro micronucleus test in human peripheral blood lymphocytes and in an L5178Y mouse lymphoma assay, consistent with the known in vitro clastogenic effects of topoisomerase inhibitors in in vitro mammalian cell assays. Gepotidacin was negative in an in vivo micronucleus test or Comet assay in rat.”
Carcinogenicity
Not conducted
“Long term carcinogenicity studies have not been conducted with gepotidacin.”
Reproductive & developmental
Mouse and rat EFD: decreased fetal weight and late resorptions below clinical exposure; mouse pre/postnatal study: no adverse effects
“In embryo‑fetal development studies in mice and rats, decreased fetal weights and increased fetal mortality (late resorptions) were observed at exposures less than the maximum recommended human dose (MRHD). In a mouse pre- and postnatal development study, there were no adverse developmental effects at exposures approximately equal to the MRHD”
Safety pharmacology
Dog: no arrhythmias or QTc prolongation; increased heart rate, arterial pressure, contractility and cardiac load
“No arrhythmias or heart-rate corrected QT interval (QTc) prolongation were detected in an oral safety pharmacology study in dogs; however, gepotidacin was associated with increases in heart rate, mean arterial pressure, cardiac contractility, and cardiac load.”
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 Blujepa 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: Kidney: tubular basophilia and dilation in 4-week rat at ≥450 mg/kg/day, about the clinical exposure (FDA integrated review, p. 67)
NOAEL / key findings
Kidney: tubular basophilia and dilation in 4-week rat at ≥450 mg/kg/day, about the clinical exposure
“In a 4-week repeat dose study of gepotidacin in rats, tubular basophilia and dilation of proximal and distal tubules in the kidney were observed at doses at and above 450 mg/kg/day (about equal to the clinical exposure based on AUC)”
Risksopen answer page →
Immune & cytokine safety
Thymic lymphoid depletion in high-dose rats, considered stress-related
“Minimal to mild lymphoid depletion of the thymus in high dose rats appears likely to be stress-related (5/10 males, 2/10 females).”
Biodistribution & persistence
Rat QWBA: prolonged retention in ocular uveal tract and meninges up to 35 days
“At 7 days only the ocular uveal tract was above 10 μg equiv/g (at 125.551 μg equiv/g), and at 35 days the meninges (3.318 μg equiv/g) and ocular uveal tract (84.123 μg equiv/g) were the only tissues above the LoQ.”
Modality-specific risk
QTc prolongation via hERG inhibition
“Non-clinical studies indicated gepotidacin causes dose dependent QTc prolongation likely due to hERG current inhibition.”