Tryvio
aprocitentan
Sources:FDA integrated review ↗
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Repeat dose toxicology studies were conducted in rats (up to 26 weeks) and dogs (up to 39 weeks). These animal species were considered relevant for human risk assessment because pharmacodynamic (PD) and PK/ADME profiles are similar to those in humans.”
Why that species
Pharmacodynamic and PK/ADME profiles similar to humans
“Repeat dose toxicology studies were conducted in rats (up to 26 weeks) and dogs (up to 39 weeks). These animal species were considered relevant for human risk assessment because pharmacodynamic (PD) and PK/ADME profiles are similar to those in humans.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the repeat-dose toxicology studies in male rats and dogs given aprocitentan for 26 weeks or 39 weeks, respectively, at doses up to 250 mg/kg/day, an increased incidence of tubular degeneration/atrophy was observed at 250 mg/kg/day in rats and at ≥25 mg/kg/day in dogs, representing approximately 41-fold and 53-fold, respectively, the exposure at the MRHD, based on AUC.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“Repeat dose toxicology studies were conducted in rats (up to 26 weeks) and dogs (up to 39 weeks). These animal species were considered relevant for human risk assessment because pharmacodynamic (PD) and PK/ADME profiles are similar to those in humans.”
Pivotal GLP studies
26-week rat and 39-week dog repeat-dose studies
“General toxicity studies were conducted for durations up to 26 weeks in rats and 39 weeks in dogs.”
Route in tox
Oral
“Repeat dose toxicity studies were conducted in dogs for up to 39 weeks with oral dose levels from 5 to 1000 mg/kg/day.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and in vivo rat micronucleus assays
“There was no evidence of mutagenicity or clastogenicity for aprocitentan in a standard battery of tests that included in vitro bacterial reverse mutation and chromosomal aberration assays, and an in vivo rat micronucleus study.”
Carcinogenicity
Not conducted with aprocitentan; assessment relied on macitentan carcinogenicity studies
“The carcinogenicity assessment of aprocitentan was based on carcinogenicity studies conducted with another ERA, macitentan, for which its major metabolite is aprocitentan. No carcinogenicity studies were conducted with aprocitentan alone.”
Reproductive & developmental
Macitentan rat and rabbit EFD: teratogenic at all doses, no NOAEL; risk extrapolated to aprocitentan
“In embryo-fetal developmental (EFD) toxicity studies, treatment with macitentan (for which aprocitentan is a major metabolite) in pregnant rats and rabbits revealed teratogenicity and developmental toxicity at all doses tested, and therefore a no observed adverse effect level (NOAEL) for embryo fetal toxicity in the rat and rabbits could not be established.”
Safety pharmacology
hERG IC50 28.6 µM (IC20 7.2 µM)
“The IC50 and IC20 values were determined as 28.6μM and 7.2μM, respectively.”
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 Tryvio 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: NOAEL 50 mg/kg/day in rats and 5 mg/kg/day in dogs (~14- and 11-fold MRHD exposure) (FDA integrated review, p. 65)
NOAEL / key findings
NOAEL 50 mg/kg/day in rats and 5 mg/kg/day in dogs (~14- and 11-fold MRHD exposure)
“The NOAEL was thus established at 50 mg/kg/day in rats and 5 mg/kg/day in dogs, which represent approximately 14- and 11-fold, respectively, the exposure at the MRHD based on AUC.”
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
Highest in liver, kidney cortex, lung, pituitary, thyroid, myocardium; no retention in uvea, pigmented skin or brain meninges
“The liver, kidney cortex, lung, pituitary, thyroid, and myocardium showed the highest exposures, with peak exposures observed at 8 hours postdose. No relevant retention of radioactivity in the uveal tract/retina, pigmented skin, or meninges of the brain was observed at any time point.”
Modality-specific risk
Embryo-fetal toxicity/teratogenicity (ERA class effect)
“The mechanism of action for ERAs is well established to be teratogenic in animals.”