Pizensy
lactitol
Species
RatMouse
Longest study
13 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and Tg.rasH2 mouse
“The Applicant has conducted a 28- and 91-day oral (gavage) toxicity studies in Tg.rasH2 mice and rats, respectively, with lactitol at 125, 500 and 2000 mg/kg/day.”
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
“The Applicant has conducted a 28- and 91-day oral (gavage) toxicity studies in Tg.rasH2 mice and rats, respectively, with lactitol at 125, 500 and 2000 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
13 (91-day rat)
“The Applicant has conducted a 28- and 91-day oral (gavage) toxicity studies in Tg.rasH2 mice and rats, respectively, with lactitol at 125, 500 and 2000 mg/kg/day.”
Pivotal GLP studies
28-day Tg.rasH2 mouse and 91-day rat oral gavage studies (carcinogenicity dose-ranging)
“The Applicant has conducted a 28- and 91-day oral (gavage) toxicity studies in Tg.rasH2 mice and rats, respectively, with lactitol at 125, 500 and 2000 mg/kg/day. These studies were conducted to inform the dose selection of the carcinogenicity studies.”
Route in tox
Oral gavage
“The Applicant has conducted a 28- and 91-day oral (gavage) toxicity studies in Tg.rasH2 mice and rats, respectively, with lactitol at 125, 500 and 2000 mg/kg/day.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted by the applicant; published studies negative in Ames, chromosome aberration and in vivo mouse micronucleus tests
“The Applicant did not conduct genotoxicity studies with lactitol and relied on the published literature. Lactitol was examined for potential mutagenicity in the Ames test, chromosome aberration test with cultured mammalian cells, and in vivo mouse micronucleus test. The results showed that lactitol has no mutagenicity potential”
Carcinogenicity
2-year rat and 6-month Tg.rasH2 mouse: no drug-related tumors up to 2 g/kg/day
“In a 2-year carcinogenicity study in rats, lactitol was not tumorigenic at daily oral doses up to 2 g/kg/day (about 0.93 times the recommended daily human dose based on body surface area). In a 6-month carcinogenicity study in Tg.rasH2 mice at daily oral doses of lactitol up to 2 g/kg/day (about 0.47 times the recommended daily human dose based on body surface area), there were no drug-related neoplasms.”
Reproductive & developmental
Rat and rabbit EFD: no embryo-fetal effects at doses well above the human dose
“In animal developmental studies, no effects on embryo-fetal development were observed with oral administration of lactitol to rats and rabbits during organogenesis at doses much higher than the maximum recommended human dosage.”
Safety pharmacology
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 doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Pizensy 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: No target organs identified; NOAEL 2000 mg/kg/day (highest dose) in mice and rats (FDA multi-discipline review, p. 30)
NOAEL / key findings
No target organs identified; NOAEL 2000 mg/kg/day (highest dose) in mice and rats
“Target organs could not be identified in the absence of significant treatment-related histopathological changes in any organ or tissue in either species. The No Observed Adverse Effect Level (NOAEL) was 2000 mg/kg/day for both mice and rats.”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
No dedicated distribution study; in rats lactitol reached mg/g levels throughout the intestine including colon
“Distribution study was not performed. However, GI distribution of lactitol was examined in a pharmacology study in rats after an oral dose of 4 g/kg. Lactitol reached in mg/g levels in all intestinal components including the colon.”
Modality-specific risk
GLP chronic toxicity studies waived given GRAS food-additive status and ex-US experience
“GLP compliant chronic toxicity studies with lactitol were not required because of the Generally Recognized as Safe food additive status of lactitol and extensive ex-US experience with the drug.”