Utebzi
tebipenem pivoxil
Sources:FDA integrated review ↗
Species
MonkeyRat
Longest study
4 wk
Genotox
Conducted Conducted
Carcinogenicity
Not stated Not stated
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“oral administration of the proposed clinical formulation, tebipenem pivoxil hydrobromide has been studied in rats and monkeys in repeat dose 28-day GLP toxicology studies, while tebipenem pivoxil has been studied in rats and monkeys in non-GLP studies (i.e. 14-day, 28-day, and 90-day 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 formulation, tebipenem pivoxil hydrobromide, was tested
“oral administration of the proposed clinical formulation, tebipenem pivoxil hydrobromide has been studied in rats and monkeys in repeat dose 28-day GLP toxicology studies, while tebipenem pivoxil has been studied in rats and monkeys in non-GLP studies (i.e. 14-day, 28-day, and 90-day studies).”
Study lengthopen answer page →
Longest pivotal study
4 (28-day GLP rat and monkey; non-GLP studies up to 90 days)
“oral administration of the proposed clinical formulation, tebipenem pivoxil hydrobromide has been studied in rats and monkeys in repeat dose 28-day GLP toxicology studies, while tebipenem pivoxil has been studied in rats and monkeys in non-GLP studies (i.e. 14-day, 28-day, and 90-day studies).”
Pivotal GLP studies
28-day GLP oral rat and monkey studies; supporting non-GLP 14-, 28- and 90-day rat and monkey studies
“oral administration of the proposed clinical formulation, tebipenem pivoxil hydrobromide has been studied in rats and monkeys in repeat dose 28-day GLP toxicology studies, while tebipenem pivoxil has been studied in rats and monkeys in non-GLP studies (i.e. 14-day, 28-day, and 90-day studies).”
Route in tox
Oral
“oral administration of the proposed clinical formulation, tebipenem pivoxil hydrobromide has been studied in rats and monkeys in repeat dose 28-day GLP toxicology studies, while tebipenem pivoxil has been studied in rats and monkeys in non-GLP studies (i.e. 14-day, 28-day, and 90-day studies).”
Skipped studiesopen answer page →
Genotoxicity
Prodrug positive in vitro (mammalian gene mutation, CHO chromosomal aberration); negative in mouse bone marrow micronucleus
“The prodrug, tebipenem pivoxil was found to be mutagenic in a mammalian cell gene mutation assay and induced chromosomal aberrations in Chinese hamster ovary (CHO) cells in vitro; however, it was not clastogenic in an in vivo bone marrow micronucleus study in mice.”
Carcinogenicity
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.
Reproductive & developmental
Mouse, rat and monkey EFD: no adverse developmental effects
“As noted in that review, no adverse developmental effects were noted in embryofetal development (EFD) studies following oral administration of tebipenem pivoxil to pregnant mice, rats and monkeys during periods of organogenesis.”
Safety pharmacology
No clinically relevant findings in hERG, CNS, cardiovascular or respiratory studies
“There were no clinically relevant safety concerns observed with tebipenem pivoxil or tebipenem in any nonclinical in vitro and in vivo safety pharmacology studies (e.g., human ether a-go-go-related gene [hERG], CNS, cardiovascular, and respiratory).”
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 Utebzi 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: Rat NOAEL 1000 mg/kg/day (28-day GLP) and 300 mg/kg/day (90-day); low-grade stomach and heart findings (FDA integrated review, p. 211)
NOAEL / key findings
Rat NOAEL 1000 mg/kg/day (28-day GLP) and 300 mg/kg/day (90-day); low-grade stomach and heart findings
“Because of the low incidence, low severity and the absence of dose-dependency of findings in the stomach and heart, the NOAELs of the GLP 28-day study and non-GLP 14- and 28-day studies in rats are considered to be the high dose of 1000 mg/kg/day and the NOAEL of the non-GLP 90-day study in rats is considered to be 300 mg/kg/day”
Risksopen answer page →
Immune & cytokine safety
Negative in guinea pig delayed hypersensitivity and mouse/guinea pig antigenicity studies
“Orally administered tebipenem pivoxil was negative in a delayed hypersensitivity study using guinea pigs and in antigenicity studies in mice and guinea pigs.”
Biodistribution & persistence
Rat QWBA: extensive distribution except brain medulla, spinal cord, abdominal fat and eye lens
“Tissue distribution of radiolabeled tebipenem pivoxil was evaluated using quantitative whole-body autoradiography in male rats and showed extensive quantifiable levels of radioactivity measured in most analyzed tissues, with the exception of the brain medulla, spinal cord, abdominal fat, and eye lens.”
Modality-specific risk
Dose-dependent hypocarnitinemia in rats and monkeys
“Treatment-related and dose-dependent hypocarnitinemia was noted in rats and monkeys.”