Ibsrela
tenapanor
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Repeated dose toxicology studies of up to 6 months and 9 months were conducted in rats and dogs, respectively.”
Why that species
Target (NHE3) expressed at similar intestinal levels in rat, dog and human
“SLC9A3 (NHE3) expression was observed along the entire intestinal tract in the rat, dog, and human. NHE3 expression levels were similar across all three species throughout the intestine with a few segment specific differences noted.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a 6-month toxicology study in rats, tenapanor was administered orally to SD rats at doses of 1, 3, and 10 mg/kg/day.”
Species: general tox
Rat and dog
“Repeated dose toxicology studies of up to 6 months and 9 months were conducted in rats and dogs, respectively.”
Species: DART
Rat and rabbit (embryo-fetal development)
“In reproduction studies with tenapanor in pregnant rats and rabbits, no adverse fetal effects were observed in rats at 0.1 times the maximum recommended human dose and in rabbits at doses up to 8.8 times the maximum recommended human dose (based on body surface area).”
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (6-month)
“Tenapanor was not tumorigenic in 2-year rat and 6- month Tg rasH2 mouse carcinogenicity bioassays.”
Surrogate used in
No surrogate used; tenapanor tested in rats and dogs
“Repeated dose toxicology studies of up to 6 months and 9 months were conducted in rats and dogs, respectively.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“In a 9-month toxicology study in dogs, tenapanor was administered orally to beagle dogs at doses of 50, 300 and 1000 mg/kg/day.”
Pivotal GLP studies
6-month rat and 9-month dog oral studies
“In support of the safety of tenapanor, the Applicant submitted the following nonclinical studies: pharmacology, PK, single dose and repeat dose oral toxicity studies in rats (up to 6 months) and dogs (up to 9 months)”
Route in tox
Oral
“single dose and repeat dose oral toxicity studies in rats (up to 6 months) and dogs (up to 9 months)”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, human lymphocyte chromosome aberration and in vivo micronucleus assays
“Tenapanor was negative in the Ames test, the in vitro mammalian chromosome aberration assay in human peripheral blood lymphocytes, and the in vivo micronucleus assay in mice following oral and IV administration in rats.”
Carcinogenicity
2-year rat and 6-month Tg rasH2 mouse: not tumorigenic
“Tenapanor was not tumorigenic in 2-year rat and 6- month Tg rasH2 mouse carcinogenicity bioassays.”
Reproductive & developmental
No fertility effects (male rat, female mouse); rat EFD doses of 10 and 30 mg/kg/day not tolerated by dams
“There were no tenapanor-related effects on female or male fertility at doses up to 50 mg/kg/day in female mice and up to 10 mg/kg/day in male rats. In an embryofetal developmental study in rats, tenapanor was administered orally at dose levels of 1, 10 and 30 mg/kg/day from Gestation Days 6 through 17. Dose levels of 10 and 30 mg/kg/day were not tolerated”
Safety pharmacology
16.1% hERG inhibition at 10 µM; no cardiovascular/ECG effects in telemetered dogs up to 1000 mg/kg
“Tenapanor showed a slight inhibition (16.1%) of hERG current (IKr) at a concentration 10µM (highest concentration tested) in an in vitro assay in HEK293 cells. However, oral administration of tenapanor to conscious telemetered male beagle dogs at doses up to 1000 mg/kg had no effect on cardiac and circulatory functions”
Genotox: Ames
Negative
“AZD1722 was not mutagenic in the Ames bacterial reverse mutation assay, not clastogenic in an in vitro cultured human lymphocyte assay, and negative in the in vivo oral gavage mouse and intravenous rat micronucleus assays.”
Genotox: in vitro mammalian
Human lymphocyte chromosome aberration assay: negative
“AZD1722 was not mutagenic in the Ames bacterial reverse mutation assay, not clastogenic in an in vitro cultured human lymphocyte assay, and negative in the in vivo oral gavage mouse and intravenous rat micronucleus assays.”
Genotox: in vivo
Oral mouse and intravenous rat micronucleus assays: negative
“AZD1722 was not mutagenic in the Ames bacterial reverse mutation assay, not clastogenic in an in vitro cultured human lymphocyte assay, and negative in the in vivo oral gavage mouse and intravenous rat micronucleus assays.”
Carcinogenicity model
2-year rat; 6-month Tg rasH2 mouse (not tumorigenic)
“Tenapanor was not tumorigenic in 2-year rat and 6- month Tg rasH2 mouse carcinogenicity bioassays.”
Carcinogenicity timing
2-year rat and 26-week Tg rasH2 mouse studies completed before the marketing application
“Tenapanor was not tumorigenic in 2-year rat and 6- month Tg rasH2 mouse carcinogenicity bioassays.”
hERG / QT
Slight hERG inhibition (16.1% at 10 µM, highest tested); 10 µM >24300-fold clinical exposure
“RDX5791 at 1μM had no effect (0%) on the hERG currents but at 3μM and 10μM caused slight inhibitions of hERG currents by 5% and 16.1%, respectively. The clinical exposures in humans at 50 mg BID were <0.5 ng/mL. The, 10μM concentration is >24300-fold higher than the clinical exposures at the proposed dose.”
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 Ibsrela 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 3 mg/kg/day (males) and 10 mg/kg/day (females); adverse GI effects are expected pharmacology (FDA multi-discipline review, p. 35)
NOAEL / key findings
Rat NOAEL 3 mg/kg/day (males) and 10 mg/kg/day (females); adverse GI effects are expected pharmacology
“These adverse gastrointestinal effects in rats are expected pharmacological effects of tenapanor. The NOAEL was determined to be 3 mg/kg/day for males and 10 mg/kg/day for females.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion in spleen and thymus in high-dose rat decedents
“Histological examinations of these animals showed hemorrhage and acute inflammation of the cecum; luminal dilatation of the duodenum, jejunum, ileum, and colon; and lymphoid depletion in the spleen and thymus.”
Biodistribution & persistence
Mostly confined to GI tract; at 24 h radioactivity measurable only in liver and GI tract, plus uveal tract in pigmented rats
“Excluding the uveal tract in the Long Evans rat, radioactivity concentrations in tissues of both rat strains were measurable only in the liver and GI tract at 24 hours postdose.”
Modality-specific risk
Juvenile toxicity: juvenile rat NOAEL 0.1 mg/kg/day gives no safety margin for pediatric patients <12 years
“The NOAEL was determined to be 0.1 mg/kg/day, which does not provide a margin of safety to support study of pediatric patients <12 years of age.”
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
Boxed warning: Risk of serious dehydration in pediatric patients
- Risk of Serious Dehydration in Pediatric Patients
- Diarrhea
Gastrointestinal
US prescribing information, Boxed Warning and 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 Ibsrela 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 3 mg/kg/day (males) and 10 mg/kg/day (females); adverse GI effects are expected pharmacology (FDA multi-discipline review, p. 35)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month beagle dog oral study; recovery not stated
“In a 9-month toxicology study in dogs, tenapanor was administered orally to beagle dogs at doses of 50, 300 and 1000 mg/kg/day.”
Pivotal GLP studies
6-month rat and 9-month dog oral studies
“In support of the safety of tenapanor, the Applicant submitted the following nonclinical studies: pharmacology, PK, single dose and repeat dose oral toxicity studies in rats (up to 6 months) and dogs (up to 9 months)”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“In reproduction studies with tenapanor in pregnant rats and rabbits, no adverse fetal effects were observed in rats at 0.1 times the maximum recommended human dose and in rabbits at doses up to 8.8 times the maximum recommended human dose (based on body surface area).”
Reproductive & developmental
No fertility effects (male rat, female mouse); rat EFD doses of 10 and 30 mg/kg/day not tolerated by dams
“There were no tenapanor-related effects on female or male fertility at doses up to 50 mg/kg/day in female mice and up to 10 mg/kg/day in male rats. In an embryofetal developmental study in rats, tenapanor was administered orally at dose levels of 1, 10 and 30 mg/kg/day from Gestation Days 6 through 17. Dose levels of 10 and 30 mg/kg/day were not tolerated”
PPND / ePPND: when
PPND in mouse completed before the marketing application
“In a pre- and postnatal development study in mice, tenapanor had no treatment-related effects on the maternal animals, including gestation lengths, parturition or the mean number of implantation sites.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (6-month)
“Tenapanor was not tumorigenic in 2-year rat and 6- month Tg rasH2 mouse carcinogenicity bioassays.”
Carcinogenicity model
2-year rat; 6-month Tg rasH2 mouse (not tumorigenic)
“Tenapanor was not tumorigenic in 2-year rat and 6- month Tg rasH2 mouse carcinogenicity bioassays.”
Carcinogenicity timing
2-year rat and 26-week Tg rasH2 mouse studies completed before the marketing application
“Tenapanor was not tumorigenic in 2-year rat and 6- month Tg rasH2 mouse carcinogenicity bioassays.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat NOAEL 1.8x (males) and 5.9x (females) the 100 mg/day clinical dose (mg/kg basis)
“The NOAEL doses in male and female rats are 1.8 times and 5.9 times the recommended daily clinical dose of 100 mg (1,7 mg/kg/day).”
NOAEL / key findings
Rat NOAEL 3 mg/kg/day (males) and 10 mg/kg/day (females); adverse GI effects are expected pharmacology
“These adverse gastrointestinal effects in rats are expected pharmacological effects of tenapanor. The NOAEL was determined to be 3 mg/kg/day for males and 10 mg/kg/day for females.”
Efficacy evidenceopen answer page →
Efficacy evidence
Stress-induced IBS-C rat model, mouse opioid-induced constipation model, neonatal acetic-acid IBS-like rat model
“In a stress-induced IBS-C model of rat, and a mouse model of opioid-induced constipation, tenapanor showed a significant improvement of GI function following oral doses of up to 50 mg/kg. Oral administration of tenapanor (0.5 mg/kg) to a rat model of IBS-like syndrome (intracolonic infusion of 0.5% acetic acid) resulted in reductions in colonic hypersensitivity”
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
Significant improvement in GI function in normal animals and IBS-C and opioid-induced constipation models
“Oral administration of tenapanor to mice, cynomolgus monkeys, a stress-induced IBS-C model of rat, and a mouse model of opioid-induced constipation showed a significant improvement in GI function.”
Flexibilityopen answer page →
Flexibility accepted
Juvenile toxAccepted with a conditionBeyond the letter
Juvenile rat NOAEL gives no safety margin for patients under 12; additional juvenile study (from postnatal day 21) deferred to postmarketing
“The NOAEL was determined to be 0.1 mg/kg/day, which does not provide a margin of safety to support study of pediatric patients <12 years of age. An additional juvenile toxicity study in juvenile rats starting at postnatal day 21 will be required (refer to Postmarketing Requirements and Commitment, Section 14) below.”
Impurity or metaboliteVerdict not stated
Major metabolite M1: sponsor proposed exposure-ratio calculations in lieu of a dedicated repeat-dose study; only a rodent study up to 4 weeks conducted
“The Applicant responded that, in lieu of a repeated dose toxicity study, they planned to quantify M1 in plasma samples from phase 2 patients and calculate the ratio of exposure multiples to M1 in the dog to human M1 exposure at the anticipated dose of 50 mg BID.”
“In support of the safety of AZ13792925, the Applicant conducted the following studies with the metabolite: single dose toxicity and repeat-dose oral toxicity studies in a rodent up to 4 weeks, genotoxicity (Ames test and in vitro micronucleus assay), 6-month carcinogenicity study in Tg rasH2 mouse, and an embryo-fetal development study in rats.”
First doseQuestioned
Proposed first-in-human doses based on the NOAEL of a 7-day rat study
“The Division stated that basing doses for phase 1 clinical studies on the no adverse effect level (NOAEL) from the 7-day rat toxicology study was unacceptable.”
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