Orlynvah
sulopenem etzadroxil and probenecid
Species
MonkeyRat
Longest study
4 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 cynomolgus monkey
“Pivotal toxicology studies that were conducted in support of the NDA in adult animals included 1-month toxicology studies in rats and monkeys with sulopenem etzadroxil and a 14-day combination toxicology study with sulopenem etzadroxil and probenecid in rats.”
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
“Adult rats were administered sulopenem etzadroxil in oral doses of 100, 400, and 2000 mg/kg/day in the 1-month toxicology study in rats.”
Species: general tox
Rat and cynomolgus monkey (1-month); rat 14-day combination with probenecid
“Pivotal toxicology studies that were conducted in support of the NDA in adult animals included 1-month toxicology studies in rats and monkeys with sulopenem etzadroxil and a 14-day combination toxicology study with sulopenem etzadroxil and probenecid in rats.”
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile); mouse and rabbit (EFD)
“developmental and reproductive toxicology studies (male and female fertility study in rats, embryo-fetal development studies in mice, rats, and rabbits, a pre-postnatal development study in rats and a juvenile toxicology study in rats).”
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been conducted for sulopenem etzadroxil or sulopenem.”
Surrogate used in
No surrogate used; sulopenem etzadroxil tested directly
“Adult rats were administered sulopenem etzadroxil in oral doses of 100, 400, and 2000 mg/kg/day in the 1-month toxicology study in rats.”
Study lengthopen answer page →
Longest pivotal study
4 (1-month rat and monkey)
“Pivotal toxicology studies that were conducted in support of the NDA in adult animals included 1-month toxicology studies in rats and monkeys with sulopenem etzadroxil and a 14-day combination toxicology study with sulopenem etzadroxil and probenecid in rats.”
Pivotal GLP studies
1-month rat and monkey studies with sulopenem etzadroxil; 14-day rat combination study with probenecid
“Pivotal toxicology studies that were conducted in support of the NDA in adult animals included 1-month toxicology studies in rats and monkeys with sulopenem etzadroxil and a 14-day combination toxicology study with sulopenem etzadroxil and probenecid in rats.”
Route in tox
Oral gavage
“Also, a 14-day combination toxicology study with orally administered sulopenem etzadroxil and probenecid was conducted in rats.”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; chromosome aberrations positive in vitro; negative in vivo rat bone marrow micronucleus
“Sulopenem etzadroxil was negative for mutations in an in vitro Ames assay with and without metabolic activation but positive for chromosome aberrations with and without metabolic activation in vitro in peripheral human lymphocytes and Chinese hamster ovary cells. In vivo, sulopenem etzadroxil was negative for genetic toxicity in a bone marrow micronucleus assay in rats.”
Carcinogenicity
Not conducted
“No carcinogenicity studies have been conducted for sulopenem etzadroxil or sulopenem.”
Reproductive & developmental
No effect on rat fertility; no malformations in rat and rabbit EFD; cleft palate in mice at ~46x clinical exposure
“Sulopenem etzadroxil did not inhibit fertility in male and female rats and was not associated with fetal malformations in embryo-fetal studies in rats and rabbits. However, in mice, a higher litter and fetal incidence of cleft palate in fetuses occurred at a sulopenem etzadroxil dose associated with sulopenem exposures approximately 46-times the mean clinical exposure”
Safety pharmacology
Clinical Cmax ~6- and 40-fold below the hERG IC50s of sulopenem etzadroxil and sulopenem; minimal QT concern
“However, concern for inhibition of hERG potassium channels and possible QT prolongation in the clinic is minimal because the 2.64 µg/ml plasma Cmax for sulopenem associated with administration of a single bilayer tablet containing 500 mg sulopenem etzadroxil in fed patients is approximately 6-fold and 40-fold lower than the hERG IC50 values for sulopenem etzadroxil and sulopenem, respectively.”
Genotox: Ames
Negative (sulopenem etzadroxil and sulopenem)
“Both compounds were shown to be negative for mutagenicity in Ames assays and sulopenem was negative for mutagenicity in an in vitro CHO HGRPT forward mutation assay.”
Genotox: in vitro mammalian
Positive: chromosome aberrations in human lymphocytes and CHO cells
“Sulopenem etzadroxil was negative for mutations in an in vitro Ames assay with and without metabolic activation but positive for chromosome aberrations with and without metabolic activation in vitro in peripheral human lymphocytes and Chinese hamster ovary cells.”
Genotox: in vivo
Negative rat (and mouse, sulopenem) bone marrow micronucleus
“These results were balanced by negative results for both compounds in vivo in micronucleus assays in bone marrow cells from rats (both compounds) and mice (sulopenem).”
Carcinogenicity model
Not conducted
“Carcinogenicity studies in animals have not been conducted with ORLYNVAH.”
Carcinogenicity timing
No carcinogenicity studies conducted; no requirement, waiver or reason stated
“No carcinogenicity studies have been conducted for sulopenem etzadroxil or sulopenem.”
hERG / QT
Clinical sulopenem Cmax ~6- and 40-fold below hERG IC50s of prodrug and sulopenem; minimal QT concern
“However, concern for inhibition of hERG potassium channels and possible QT prolongation in the clinic is minimal because the 2.64 µg/ml plasma Cmax for sulopenem associated with administration of a single bilayer tablet containing 500 mg sulopenem etzadroxil in fed patients is approximately 6-fold and 40-fold lower than the hERG IC50 values for sulopenem etzadroxil and sulopenem, respectively.”
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 Orlynvah 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: Monkey ≥400 mg/kg: positive Coombs test, decreased red blood cell parameters and GI effects (FDA integrated review, p. 281)
NOAEL / key findings
Monkey ≥400 mg/kg: positive Coombs test, decreased red blood cell parameters and GI effects
“PF-03709270 administered by oral gavage to Cynomolgus monkeys at ≥400 mg/kg caused positive Coombs’ test, decreased red blood cell parameters, and GI side effects.”
Risksopen answer page →
Immune & cytokine safety
Dose-related positive Coombs test in monkeys, likely antibody-mediated minimal erythrocyte loss
“Monkeys also exhibited positive Coombs test results that tended to increase with sulopenem etzadroxil dose and likely contributed to antibody mediation of minimal erythrocyte loss and compensatory erythropoiesis in monkeys.”
Biodistribution & persistence
Highest radioactivity exposure in kidney, liver, lung, skin, pancreas, spleen and blood
“The tissues with the highest AUC exposures to radioactivity over a period of 168 hours after dosing were in descending order: kidney, liver, lung, skin, pancreas, spleen, and blood.”
Modality-specific risk
Renal toxicity, more severe and poorly reversible in juvenile rats
“The findings in juvenile rats occurred at lower sulopenem etzadroxil doses and exposures than the doses associated with renal findings in adult rats in the 1-month study, and the findings were poorly reversible or, in the case of tubular concretions, irreversible after a 2-week recovery period.”
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
- Clostridioides difficile -Associated Diarrhea
- Risk of Uric Acid Kidney Stone Development
- Exacerbation of Gout
- Uric Acid Nephropathy in Patients at Risk for Tumor Lysis Syndrome
- Development of Drug-Resistant Bacteria
Hypersensitivity & infusion reactionsGastrointestinalNephrotoxicitySecondary malignancy
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 Orlynvah 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: Monkey ≥400 mg/kg: positive Coombs test, decreased red blood cell parameters and GI effects (FDA integrated review, p. 281)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
30-day cynomolgus monkey oral gavage study; no recovery animals included
“Animals were dosed once per day for 30 days in doses of 0 (vehicle), 50, 400, and 1000 mg/kg/day. Route of administration: Oral gavage Formulation/Vehicle: 0.5% methylcellulose Species/Strain: Cynomolgus monkeys Number/Sex/Group: 3/sex/group Age: 3 to 3.5 years of age Satellite groups/ unique design: No separate toxicokinetic animals or recovery animals were included in the study.”
Pivotal GLP studies
1-month rat and monkey studies with sulopenem etzadroxil; 14-day rat combination study with probenecid
“Pivotal toxicology studies that were conducted in support of the NDA in adult animals included 1-month toxicology studies in rats and monkeys with sulopenem etzadroxil and a 14-day combination toxicology study with sulopenem etzadroxil and probenecid in rats.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile); mouse and rabbit (EFD)
“developmental and reproductive toxicology studies (male and female fertility study in rats, embryo-fetal development studies in mice, rats, and rabbits, a pre-postnatal development study in rats and a juvenile toxicology study in rats).”
Reproductive & developmental
No effect on rat fertility; no malformations in rat and rabbit EFD; cleft palate in mice at ~46x clinical exposure
“Sulopenem etzadroxil did not inhibit fertility in male and female rats and was not associated with fetal malformations in embryo-fetal studies in rats and rabbits. However, in mice, a higher litter and fetal incidence of cleft palate in fetuses occurred at a sulopenem etzadroxil dose associated with sulopenem exposures approximately 46-times the mean clinical exposure”
PPND / ePPND: when
PPND in rat completed and submitted with the NDA
“developmental and reproductive toxicology studies (male and female fertility study in rats, embryo-fetal development studies in mice, rats, and rabbits, a pre-postnatal development study in rats and a juvenile toxicology study in rats).”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been conducted for sulopenem etzadroxil or sulopenem.”
Carcinogenicity model
Not conducted
“Carcinogenicity studies in animals have not been conducted with ORLYNVAH.”
Carcinogenicity timing
No carcinogenicity studies conducted; no requirement, waiver or reason stated
“No carcinogenicity studies have been conducted for sulopenem etzadroxil or sulopenem.”
Safety marginopen answer page →
Safety margin at NOAEL
No repeat-dose NOAEL multiple stated; rabbit EFD maternal toxicity and reduced fetal weights at ~0.1 and 0.2x clinical exposure
“In rabbits, maternal toxicity and reduced fetal body weights occurred at sulopenem etzadroxil doses associated with sulopenem plasma exposures approximately 0.1 and 0.2 times, respectively, the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil.”
NOAEL / key findings
Monkey ≥400 mg/kg: positive Coombs test, decreased red blood cell parameters and GI effects
“PF-03709270 administered by oral gavage to Cynomolgus monkeys at ≥400 mg/kg caused positive Coombs’ test, decreased red blood cell parameters, and GI side effects.”
Efficacy evidenceopen answer page →
Efficacy evidence
Neutropenic and immune-competent murine thigh infection models plus in vitro hollow-fiber infection model
“PK/PD index and target determination for sulopenem were previously conducted using neutropenic and immune-competent murine thigh infection models.”
Why that model
No established nonclinical model reliably reflects the uUTI infection site
“For uUTI, there is no established nonclinical model to reliably determine PK/PD targets relevant to the site of infection.”
Reviewer's view of the efficacy data
FDA: murine thigh targets unreliable; nonclinical data support activity but translational utility is limited
“Therefore, while the nonclinical data support sulopenem’s activity against uropathogens, the translational utility of these nonclinical PK/PD findings is limited.”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityAcceptedBeyond the letter
Positive in vitro clastogenicity for sulopenem etzadroxil and sulopenem; judged non-genotoxic on negative in vivo micronucleus and Ames results
Why: Negative in vitro mutagenicity and in vivo micronucleus assays · Weight of evidence
“Based on the negative results in the in vitro mutagenicity assays and the in vivo micronucleus assays, the weight of evidence supports a negative potential for genotoxicity for sulopenem etzadroxil.”
Impurity or metaboliteAcceptedBeyond the letter
Formaldehyde released on prodrug hydrolysis not measurable in toxicology studies because of a high quantitation limit
Why: Formaldehyde formed is much smaller than the normal body burden · Pharmacology or kinetics
“However, measurable quantities of formaldehyde were not observed in any of the rat or monkey toxicology studies, although the lower limit of quantitation for formaldehyde in these studies was high, µg/ml.”
“Because the amount of formaldehyde formed through hydrolysis of sulopenem etzadroxil is expected to be much smaller than the normal body burden, the formation of formaldehyde is not a safety concern.”
Efficacy modelCriticised but acceptedBeyond the letter
Murine thigh infection model PK/PD targets deemed unreliable because of study design deficiencies
Why: In vitro target attainment and hollow-fiber model results supportive · Other reason
“Due to deficiencies in the murine thigh infection model study design and limited interpretability of the findings, the resulting targets (i.e., 16.6 and 20.3% fT>MIC for stasis and 1-log kill, respectively) were deemed unreliable.”
“Despite the limitations of nonclinical PK/PD data (see Section 5.1), the results of PTA analyses and a 5-day in vitro hollow-fiber infection model study are supportive of the effectiveness of 500 mg sulopenem etzadroxil/500 mg probenecid BID in the treatment of uUTI.”
Safety marginVerdict not stated
Rabbit maternal toxicity and reduced fetal weights at about 0.1 and 0.2 times clinical sulopenem exposure
“In rabbits, maternal toxicity and reduced fetal body weights occurred at sulopenem etzadroxil doses associated with sulopenem plasma exposures approximately 0.1 and 0.2 times, respectively, the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil.”
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