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.”
Species: general tox
Rat (26-week) and dog (39-week)
“General toxicity studies were conducted for durations up to 26 weeks in rats and 39 weeks in dogs.”
Species: DART
Rat and rabbit (EFD with aprocitentan alone)
“No embryo-fetal toxicity was observed in the EFD studies with aprocitentan alone at 5-fold and 29-fold the human exposure at the MRHD in rats and rabbits, respectively.”
Species: carcinogenicity
Mouse and rat 2-year studies with macitentan (aprocitentan's parent drug)
“Two-year carcinogenicity studies with macitentan did not identify any carcinogenic potential at doses up to 100 mg/kg/day and 250 mg/kg/day in mice and rats, where aprocitentan exposures represented approximately 30-fold and 11-fold, respectively, the clinical aprocitentan exposure at the MRHD based on AUC.”
Surrogate used in
Yes: macitentan (aprocitentan is its major metabolite) used for carcinogenicity and EFD risk assessment
“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”
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.”
Genotox: Ames
Negative (bacterial reverse mutation)
“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.”
Genotox: in vitro mammalian
In vitro chromosomal aberration: negative
“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.”
Genotox: in vivo
Rat micronucleus: negative
“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 model
2-year mouse and rat with macitentan: negative (~30x and 11x aprocitentan AUC at MRHD)
“Two-year carcinogenicity studies with macitentan did not identify any carcinogenic potential at doses up to 100 mg/kg/day and 250 mg/kg/day in mice and rats, where aprocitentan exposures represented approximately 30-fold and 11-fold, respectively, the clinical aprocitentan exposure at the MRHD based on AUC.”
Carcinogenicity timing
2-year mouse and rat studies with macitentan (parent drug) completed before the marketing application
“Two-year carcinogenicity studies with macitentan did not identify any carcinogenic potential at doses up to 100 mg/kg/day and 250 mg/kg/day in mice and rats”
hERG / QT
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.”
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: Embryo-fetal toxicity
- Embryo-Fetal Toxicity
- Hepatotoxicity
- Fluid Retention
- Hemoglobin Decrease
- Decreased Sperm Counts
Embryo-fetal toxicityHepatotoxicityMetabolic & endocrine
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (oral) with 13-week recovery
“Repeat dose toxicity studies were conducted in dogs for up to 39 weeks with oral dose levels from 5 to 1000 mg/kg/day. Key findings are summarized below. 39-Week (13-Week Recovery) Toxicology Study”
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.”
DART package
Species: DART
Rat and rabbit (EFD with aprocitentan alone)
“No embryo-fetal toxicity was observed in the EFD studies with aprocitentan alone at 5-fold and 29-fold the human exposure at the MRHD in rats and rabbits, respectively.”
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.”
PPND / ePPND: when
PPND in rat with macitentan (parent drug) completed before the marketing application
“In a pre- and postnatal developmental study in female rats, oral administration of 10, 50 or 250 mg/kg/day macitentan during the pregnancy and the lactational periods reduced pup survival and impaired male fertility of offspring at all doses.”
Carcinogenicity
Species: carcinogenicity
Mouse and rat 2-year studies with macitentan (aprocitentan's parent drug)
“Two-year carcinogenicity studies with macitentan did not identify any carcinogenic potential at doses up to 100 mg/kg/day and 250 mg/kg/day in mice and rats, where aprocitentan exposures represented approximately 30-fold and 11-fold, respectively, the clinical aprocitentan exposure at the MRHD based on AUC.”
Carcinogenicity model
2-year mouse and rat with macitentan: negative (~30x and 11x aprocitentan AUC at MRHD)
“Two-year carcinogenicity studies with macitentan did not identify any carcinogenic potential at doses up to 100 mg/kg/day and 250 mg/kg/day in mice and rats, where aprocitentan exposures represented approximately 30-fold and 11-fold, respectively, the clinical aprocitentan exposure at the MRHD based on AUC.”
Carcinogenicity timing
2-year mouse and rat studies with macitentan (parent drug) completed before the marketing application
“Two-year carcinogenicity studies with macitentan did not identify any carcinogenic potential at doses up to 100 mg/kg/day and 250 mg/kg/day in mice and rats”
Safety marginopen answer page →
Safety margin at NOAEL
Rat and dog NOAELs ~14x and 11x human AUC at the MRHD
“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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Hypertensive rat models: DOCA-salt, Dahl-S and SHR rats
“Aprocitentan showed acute antihypertensive effects, including decreased mean arterial pressure (MAP), in salt-sensitive and volume-dependent hypertensive (i.e., deoxycorticosterone acetate [DOCA]-salt rat and Dahl-S rat) or spontaneously hypertensive (SHR) rat models.”
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
Reviewer: aprocitentan may partially improve cardiac and renal function in a hypertensive rat model
“The results of this study suggest that aprocitentan treatment may partially improve cardiac and renal function in a hypertensive rat model.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No dedicated carcinogenicity studies with aprocitentan; mouse and rat studies of parent drug macitentan used instead
Why: Aprocitentan is a major metabolite of macitentan, at least 38% of total exposure in those studies · Pharmacology or kinetics · Weight of evidence
“No dedicated carcinogenicity studies were conducted with aprocitentan. Aprocitentan is a major metabolite of macitentan, and its exposure represented ≥38% of the total exposure to macitentan and aprocitentan in the macitentan carcinogenicity studies. Therefore, the macitentan carcinogenicity studies, conducted in B6C3F1 mice and Wistar rats, were considered acceptable to assess the carcinogenic potential of aprocitentan.”
Similar precedents
VanrafiaSmall molecules · atrasentan · Endothelin A receptorRodent + dog or minipig · 39 wkFilspariSmall molecules · sparsentan · Endothelin A / angiotensin II receptorsMonkey + rodent · 39 wkRapiblykSmall molecules · landiolol · β1-adrenergic receptorRodent + dog or minipig · 4 wkFoundayoSmall molecules · orforglipron · GLP-1 receptor (non-peptide)Monkey + rodent · 39 wkAttrubySmall molecules · acoramidis · Transthyretin (stabiliser)Rodent + dog or minipig · 39 wkAyvakitSmall molecules · avapritinib · KIT/PDGFRARodent + dog or minipig · 39 wk