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).”
Species: general tox
Rat and monkey (28-day GLP; 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).”
Species: DART
Rat (fertility, EFD, pre/postnatal); mouse, rabbit and monkey (EFD)
“reproductive and developmental toxicity studies including fertility studies in male and female rats, embryo-fetal developmental studies in mice, rats, rabbits, and monkeys, and a peri- and post-natal developmental study in rats”
Species: 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.
Surrogate used in
No surrogate used; clinical prodrug formulation 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).”
Genotox: Ames
Inconclusive for prodrug and tebipenem due to excessive cytotoxicity
“Bacterial reverse mutation assays (Ames tests) conducted with both tebipenem pivoxil and tebipenem were inconclusive due to excessive cytotoxicity.”
Genotox: in vitro mammalian
Prodrug positive in mammalian cell gene mutation assay and CHO chromosomal aberration assay
“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.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“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 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.
Carcinogenicity timing
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.
hERG / QT
No hERG inhibition, but validity limited by failed positive control; no QT/QTc effect in monkeys up to 300 mg/kg
“No drug-related inhibition of hERG current was observed, though the validity of this finding is limited by the failure of the positive control to demonstrate inhibition. An oral in vivo cardiovascular safety pharmacology study in monkeys up to 300 mg/kg revealed no effects on the heart rate and blood pressure.”
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.”
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
- Hypersensitivity Reactions
- Seizures and Other Central Nervous System (CNS) Adverse Reactions
- Interaction with Valproic Acid
- Carnitine Depletion
- Clostridioides difficile Infection
- Interference with Newborn Screening Test
- Development of Drug-Resistant Bacteria
Hypersensitivity & infusion reactionsNeurotoxicityInfections
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week cynomolgus monkey (non-GLP) with 4-week recovery; longest GLP studies were 4-week rat and monkey
“Study # LJT 2561. A 13-Week Repeated Oral Dose Toxicity Study on LJC 11,084 Using Cynomolgus Monkeys With a 4-Week Recovery Segment”
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).”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal); mouse, rabbit and monkey (EFD)
“reproductive and developmental toxicity studies including fertility studies in male and female rats, embryo-fetal developmental studies in mice, rats, rabbits, and monkeys, and a peri- and post-natal developmental study in rats”
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.”
PPND / ePPND: when
Rat PPND completed and reviewed in the NDA; offspring effects secondary to maternal toxicity
“In the pre- and postnatal development (PPND) study in rats, oral administration of tebipenem pivoxil resulted in adverse findings in offspring (stillborn litters, reduced postnatal survival, and decreased body weights through postnatal day 4) that were considered secondary to maternal toxicity.”
Carcinogenicity
Species: 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.
Carcinogenicity 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.
Carcinogenicity timing
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.
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 28-day GLP NOAEL 300 mg/kg/day ~1.5x MRHD exposure (13-week monkey NOAEL 0.9x)
“In monkeys, GI findings included emesis, watery/soft feces, diarrhea, large intestine inflammation, and altered microflora (28-day good laboratory practice [GLP] study; no observed adverse effect level [NOAEL] 300 mg/kg/day; 1.5 times maximum recommended human dose [MRHD] based on exposure), and minimal cecal erosion in the 13-week monkey study (NOAEL 300 mg/kg/day; 0.9 times the MRHD based on exposure)”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Neutropenic mouse and immunocompetent rat pyelonephritis infection models
“In vivo nonclinical infection model studies summarized below evaluated the bactericidal effects of tebipenem using clinically relevant dosing regimens in neutropenic mouse and immunocompetent rat pyelonephritis 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: bacterial killing supports activity at clinical exposures, but not benchmarked against a validated positive control, limiting translation
“In conclusion, observed bacterial killing in the AP model suggests TBPM antibacterial activity at the clinically relevant exposures anticipated with the proposed dosing regimen. However, the observed bacterial reductions were not benchmarked against a clinically validated positive control”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityAcceptedBeyond the letter
Prodrug tebipenem pivoxil positive in vitro (mammalian gene mutation, CHO chromosomal aberration); in vivo micronucleus negative
Why: Totality of evidence; rapid gut conversion of the prodrug to the non-mutagenic active moiety · Weight of evidence · Pharmacology or kinetics
“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.”
“Considering the totality of evidence and the evidence of rapid conversion of the prodrug tebipenem pivoxil in the gut to the non-mutagenic active moiety, tebipenem pivoxil is not considered to pose a meaningful mutagenic risk following oral administration.”
Impurity or metaboliteAccepted
Impurity with mutagenicity structural alerts specified above ICH M7 TTC-based limits
Why: TTC-based limits not practically achievable; oral route of administration · Within the guideline · Pharmacology or kinetics
“Chemistry, manufacturing, and controls (CMC) noted that ICH M7(R2) threshold of toxicological concern (TTC)-based limits are not practically achievable given observed batch levels up to %. Given the oral route of administration, the not more than (NMT) % limit was therefore acceptable from both CMC and pharmacology/toxicology perspectives but should be re-evaluated if the route of administration changes.”
GLPVerdict not stated
Clinical salt form tested only in 28-day GLP studies; longer (90-day) and juvenile studies with the prodrug were non-GLP
“Specifically, 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).”
Safety marginVerdict not stated
13-week monkey NOAEL at 0.9 times the MRHD exposure
“and minimal cecal erosion in the 13-week monkey study (NOAEL 300 mg/kg/day; 0.9 times the MRHD based on exposure), consistent with the antibacterial class of drugs.”
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