Ibsrela
tenapanor
Sources:FDA multi-discipline review ↗
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.”
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”
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.”