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.”
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.”
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.”