Livmarli
maralixibat
Species
RatDog
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“repeat-dose oral toxicology studies in rats for up to 6 months and in dogs for up to 12 months”
Why that species
Pharmacokinetic programme considered to justify the toxicity species; very low bioavailability, local mode of action
“Maralixibat has to be characterised as a substance of very low bioavailability, with a local mode of action. Overall, the study programme appears to be appropriate and complete, justifying from pharmacokinetic point of view the species involved in toxicity testing.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 26-week rat toxicity study, maralixibat at 750 mg/kg/day in males and 2000 mg/kg/day in females caused deaths due to bleeding, which was attributed to vitamin K deficiency.”
Study lengthopen answer page →
Longest pivotal study
52 (1-year dog)
“In a 1-year toxicity study in dogs, the no observable adverse effect level in both sexes was 5 mg/kg/day”
Pivotal GLP studies
Oral repeat-dose studies in rats up to 6 months and dogs up to 12 months
“repeat-dose oral toxicology studies in rats for up to 6 months and in dogs for up to 12 months”
Route in tox
Oral
“repeat-dose oral toxicology studies in rats for up to 6 months and in dogs for up to 12 months”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosome aberration and in vivo rat micronucleus assays
“Maralixibat was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using Chinese hamster ovary cells, or the in vivo rat micronucleus assay.”
Carcinogenicity
2-year rat and 26-week TgRasH2 mouse: no drug-related tumors
“Maralixibat chloride was not tumorigenic in a 2-year oral carcinogenicity study in rats with administration of up to 100 mg/kg/day (approximately 233 to 870 times the maximum recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice with doses of up to 25 (males) or 75 (females) mg/kg/day, no drug-related tumors were observed”
Reproductive & developmental
Rat fertility, rat and rabbit EFD, rat PPND: no adverse findings
“Reproductive and developmental toxicology studies included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and post-natal development study in rats. Two juvenile animal toxicity studies were performed in rats. No adverse findings were observed in the reproductive and developmental toxicology studies.”
Safety pharmacology
No effects on rat CNS, dog cardiovascular or guinea pig respiratory function; no hERG inhibition up to 1 µM
“had no significant effect on neurobehavioral functions in rats, cardiovascular function in dogs, or respiratory function in guinea pigs. Maralixibat at concentrations up to 1 µmol/L did not inhibit hERG current.”
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 Livmarli 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: 1-year dog NOAEL 5 mg/kg/day (AUC 57.7 ng•h/mL; 96- to 358-fold human AUC) (FDA integrated review, p. 68)
NOAEL / key findings
1-year dog NOAEL 5 mg/kg/day (AUC 57.7 ng•h/mL; 96- to 358-fold human AUC)
“In a 1-year toxicity study in dogs, the no observable adverse effect level in both sexes was 5 mg/kg/day with an area under the concentration-time curve from time 0 to 24 h (AUC0-24h) of 57.7 ng•h/mL on Day 358 (96 to 358-fold the human AUC of 0.6 and 0.161 ng•h/mL at 50 and 20 mg/day, respectively).”
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
Low bioavailability limits tissue distribution; rat liver and pancreas levels ~10x plasma
“Due to maralixibat’s low bioavailability, distribution to other tissues is low, although maralixibat was also found in the liver and pancreas of the rat at levels approximately 10 times higher than plasma.”
Modality-specific risk
Fat-soluble vitamin reduction with no no-effect dose; FSV monitoring in patients advised
“However, none of the toxicity studies established a no-effect dose for reductions in the serum or liver levels of fat-soluble vitamins. Therefore, the animal data could be relevant to the risk in humans, suggesting a need for monitoring of the levels of FSVs in patients.”