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.”
Species: general tox
Tg.rasH2 mouse (28-day) and rat (91-day)
“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.”
Species: DART
Rat and rabbit (EFD)
“Embryofetal development studies have been performed in pregnant rats at oral doses of lactitol up to 2000 mg/kg/day (about 0.93 times the recommended daily human dose based on body surface area) and in pregnant rabbits at oral doses up to 1000 mg/kg/day”
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and rat (104-week, report post approval)
“In a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice at 225, 675 and 2000 mg/kg/day, there were no drug-related neoplasms in either males or females. The 104-week oral carcinogenicity study in rats was initiated in February 2017, and the study report will be submitted post approval, as per agreement with the Agency.”
Surrogate used in
No surrogate used; lactitol itself tested in mice and rats
“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.
Genotox: Ames
Negative (published Ames test)
“Published studies (referenced in Section 5.5.1/General toxicology; additional studies) indicated that lactitol was negative in the Ames test, chromosome aberration test with cultured mammalian cells, and in vivo mouse micronucleus test.”
Genotox: in vitro mammalian
Chromosome aberration test in cultured mammalian cells (published): negative
“Published studies (referenced in Section 5.5.1/General toxicology; additional studies) indicated that lactitol was negative in the Ames test, chromosome aberration test with cultured mammalian cells, and in vivo mouse micronucleus test.”
Genotox: in vivo
Mouse micronucleus (published): negative
“Published studies (referenced in Section 5.5.1/General toxicology; additional studies) indicated that lactitol was negative in the Ames test, chromosome aberration test with cultured mammalian cells, and in vivo mouse micronucleus test.”
Carcinogenicity model
26-week Tg.rasH2 mouse (no drug-related neoplasms); 104-week rat
“In a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice at 225, 675 and 2000 mg/kg/day, there were no drug-related neoplasms in either males or females. The 104-week oral carcinogenicity study in rats was initiated in February 2017, and the study report will be submitted post approval, as per agreement with the Agency.”
Carcinogenicity timing
26-week Tg.rasH2 mouse completed; 104-week rat started February 2017, report to be submitted after approval
“In a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice at 225, 675 and 2000 mg/kg/day, there were no drug-related neoplasms in either males or females. The 104-week oral carcinogenicity study in rats was initiated in February 2017, and the study report will be submitted post approval, as per agreement with the Agency.”
hERG / QT
No hERG or dedicated QT study; phase 3 ECG data showed no clinically relevant QT effect
“The Applicant has not conducted a dedicated QT prolongation study. The ECG data from phase 3 studies BLI400-301 and BLI400-302 did not indicate clinically relevant effects of lactitol on the QT interval in CIC patients.”
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.”
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.
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week beagle dog oral study (published literature, Onishi 1994) with 9-week recovery
“In a 52-week oral toxicity study with 9-week recovery period in beagle dogs, animals were administered lactitol at 250, 1250 and 6250 mg/kg/day (Onishi M, et al., 1994).”
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.”
DART package
Species: DART
Rat and rabbit (EFD)
“Embryofetal development studies have been performed in pregnant rats at oral doses of lactitol up to 2000 mg/kg/day (about 0.93 times the recommended daily human dose based on body surface area) and in pregnant rabbits at oral doses up to 1000 mg/kg/day”
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.”
PPND / ePPND: when
Rat PPND conducted at FDA request and submitted with the NDA
“To support the NDA, FDA stated that the Applicant should conduct the required carcinogenicity and reproductive toxicity nonclinical studies. These studies were submitted and reviewed by Tamal Chakraborti, PhD.”
Carcinogenicity
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and rat (104-week, report post approval)
“In a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice at 225, 675 and 2000 mg/kg/day, there were no drug-related neoplasms in either males or females. The 104-week oral carcinogenicity study in rats was initiated in February 2017, and the study report will be submitted post approval, as per agreement with the Agency.”
Carcinogenicity model
26-week Tg.rasH2 mouse (no drug-related neoplasms); 104-week rat
“In a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice at 225, 675 and 2000 mg/kg/day, there were no drug-related neoplasms in either males or females. The 104-week oral carcinogenicity study in rats was initiated in February 2017, and the study report will be submitted post approval, as per agreement with the Agency.”
Carcinogenicity timing
26-week Tg.rasH2 mouse completed; 104-week rat started February 2017, report to be submitted after approval
“In a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice at 225, 675 and 2000 mg/kg/day, there were no drug-related neoplasms in either males or females. The 104-week oral carcinogenicity study in rats was initiated in February 2017, and the study report will be submitted post approval, as per agreement with the Agency.”
Safety marginopen answer page →
Safety margin at NOAEL
Mouse and rat NOAEL 0.7- to 1.5-fold human AUC (fasted), 1.8- to 3.7-fold (fed)
“Based on the AUC at the NOAEL, the exposure multiples in animals compared to humans ranged from 0.7 to 1.5-fold (compared to fasted healthy humans, AUC0-24h = 14827 ng.h/mL from clinical study BLI400-101) to approximately 3.7 to 1.8-fold (compared to fed healthy humans, AUC0-24h = 5842 ng.h/mL from clinical study BLI400-101).”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Normal rats: increased small intestine contents (osmotic effect), independent of fermentation
“In pharmacology studies in rats, following oral administration, lactitol increased the weight of the contents of the small intestine and fermentation was not necessary for lactitol-induced osmotic effects in the small intestine.”
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: no approvability issues from the nonclinical perspective
“From the nonclinical perspective, there are no approvability issues.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAcceptedBeyond the letter
No GLP chronic toxicity studies by the applicant; chronic toxicity supported by published literature
Why: GRAS food additive status and extensive ex-US clinical experience; published studies adequate · Human data · Low-risk modality · Weight of evidence
“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.”
“The published studies are considered adequate to support the safety of lactitol for the proposed indication.”
GenotoxicityAcceptedBeyond the letter
No genotoxicity studies by the applicant; published Ames, chromosome aberration and mouse micronucleus data relied on
Why: Agreed with FDA; published studies considered adequate · Weight of evidence
“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 Applicant did not conduct any chronic toxicity, fertility and early embryonic development and genotoxicity studies per the agreement with the Agency (FDA meeting minutes dated 1/21/2014) and relied on the published literature for chronic toxicity, fertility and early embryonic development and genotoxicity studies.”
DARTAcceptedBeyond the letter
No fertility and early embryonic development study by the applicant; published rat data relied on
Why: Published literature showed no fertility effects in rats; published studies considered adequate · Weight of evidence
“The Applicant did not conduct any fertility and early embryonic development study. The Applicant relied on published literature, which indicated that lactitol did not cause any adverse effect on fertility and early embryonic development in rats at doses up to 10000 mg/kg/day (about 4.6 times the recommended daily human dose based on body surface area).”
“The published studies are considered adequate to support the safety of lactitol for the proposed indication.”
CarcinogenicityAcceptedBeyond the letter
2-year rat carcinogenicity study report deferred until after approval; only 26-week Tg.rasH2 mouse study submitted
Why: Prior agreement with FDA
“The 104-week oral carcinogenicity study in rats was initiated in February 2017, and the study report will be submitted post approval, as per agreement with the Agency.”
Juvenile toxAccepted with a conditionBeyond the letter
Juvenile rat toxicity study deferred to a postmarketing requirement to support paediatric trials
“An oral (gavage) toxicity study with lactitol in juvenile rats from postnatal day (PND) 14 through PND 91 to support clinical trials in patients 6 months to less than 6 years of age.”
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