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”
Species: general tox
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)”
Species: DART
Mouse and rat (EFD); mouse (pre- and postnatal development)
“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”
Species: carcinogenicity
Not conducted
“Long term carcinogenicity studies have not been conducted with gepotidacin.”
Surrogate used in
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.
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.”
Genotox: Ames
Not informative: gepotidacin cytotoxic to test bacteria, Ames deemed not useful
“Gepotidacin was cytotoxic to Salmonella typhimurium and Escherichia coli and therefore an Ames assay was determined to not be a useful assay.”
Genotox: in vitro mammalian
Positive: in vitro micronucleus (human lymphocytes) and L5178Y mouse lymphoma assay
“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.”
Genotox: in vivo
Negative: rat in vivo micronucleus and comet assay
“An in vivo rat micronucleus assay and comet assay was negative for both endpoints.”
Carcinogenicity model
Not conducted
“Long term carcinogenicity studies have not been conducted with gepotidacin.”
Carcinogenicity timing
No carcinogenicity studies conducted; no reason given in the review
“13.1.4.3. Carcinogenicity No studies were available.”
hERG / QT
Concentration-dependent hERG inhibition, IC50 0.588 mg/mL, >100-fold above clinical Cmax
“In an in vitro human ether-a-go-go related gene (hERG) study, gepotidacin inhibited hERG currents in a concentration-dependent manner with an IC50 of 0.588 mg/mL, which is more than 100-fold higher than the maximum plasma concentration (Cmax) calculated from clinical studies.”
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.”
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
- QTc Prolongation
- Acetylcholinesterase Inhibition
- Hypersensitivity Reactions
- Clostridioides difficile Infection
- Development of Drug-Resistant Bacteria
CardiovascularHypersensitivity & infusion reactionsInfections
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat (oral gavage) with 28-day recovery; 13-week dog of equal length also had recovery groups
“Study #2013N160007 /GSK2140944E: A 13-week Oral (Gavage) Toxicity in Rats Followed by a 28-day Recovery Period”
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.”
DART package
Species: DART
Mouse and rat (EFD); mouse (pre- and postnatal development)
“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”
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”
PPND / ePPND: when
PPND in mouse (oral) completed before the marketing application
“In a pre- and postnatal development mouse study, 0 (vehicle), 200, 500, or 1000 mg/kg/day gepotidacin was administered by oral gavage to female mice from GD6 to lactation day 20 (LD20).”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Long term carcinogenicity studies have not been conducted with gepotidacin.”
Carcinogenicity model
Not conducted
“Long term carcinogenicity studies have not been conducted with gepotidacin.”
Carcinogenicity timing
No carcinogenicity studies conducted; no reason given in the review
“13.1.4.3. Carcinogenicity No studies were available.”
Safety marginopen answer page →
Safety margin at NOAEL
13-week dog NOAEL 60 mg/kg/day ~2x and 13-week rat NOAEL ~4x human AUC (4-week rat NOAEL 0.3x)
“Safety Margin Multiples Based on Exposure1 4-week rat 150 12.7 0.3 28-day dog 125 143.5 3 13-week rat 750 197 4 13-week dog 60 82.3 2”
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)”
Efficacy evidenceopen answer page →
Efficacy evidence
Neutropenic murine thigh infection models (Enterobacterales, S. aureus); in vitro E. coli chemostat model
“The Applicant conducted several nonclinical PK-PD studies examining the effect of gepotidacin on Enterobacterales and Staphylococcus aureus in vivo (neutropenic murine thigh infection models) and Escherichia coli in vitro (1-compartment “chemostat” models).”
Why that model
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.
Reviewer's view of the efficacy data
FDA: murine thigh and chemostat PK-PD findings deemed unreliable for uUTI; chemostat ignores bladder architecture, urodynamics, urine pH
“the findings from both murine thigh infection model and in vitro 1-compartment (chemostat) model were deemed unreliable for assessing uUTI for the following reasons: 1) the in vitro 1- compartment model does not account for bladder tissue architecture, the complexities of urodynamics, or the pH of urine”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityAcceptedBeyond the letter
Positive in vitro micronucleus and mouse lymphoma assays; negative in vivo rat micronucleus and comet assays
Why: Weight of evidence from in vitro and in vivo data; class known to be clastogenic in vitro only · Weight of evidence · Class precedent
“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.”
“Based on a weight of evidence, taking in vitro and in vivo data into consideration, gepotidacin is unlikely to pose a risk for genotoxicity to patients.”
Safety marginVerdict not stated
Decreased fetal weight and late resorptions in mouse and rat EFD at exposures below the MRHD
“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).”
Efficacy modelQuestioned
PK-PD targets for uUTI derived from murine thigh infection and in vitro chemostat models, which do not reflect bladder infection
“the findings from both murine thigh infection model and in vitro 1-compartment (chemostat) model were deemed unreliable for assessing uUTI for the following reasons: 1) the in vitro 1- compartment model does not account for bladder tissue architecture, the complexities of urodynamics, or the pH of urine”
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