Jesduvroq
daprodustat
Species
MonkeyRatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (dog in studies up to 13 weeks)
“General toxicology studies of 4- and 13-weeks duration were conducted in Sprague Dawley rats and Beagle Dogs with rats receiving daily oral doses by gavage and dogs by capsule. A 13-week toxicity study was also conducted in the cynomolgus monkey with daily dosing by oral gavage.”
Why that species
Monkey forms the three major human metabolites (M2, M3, M13) at ≥1x human exposure; rodents and dog do not
“The 3 major circulating human metabolites (M2, M3, and M13) were present in rabbit and monkey plasma with an animal:human AUC ratio of at least 1X in monkeys (comparing the 50 mg/kg MTD dose in the 39-week toxicity study and human exposure at the 48 mg three times a week (TIW) human dose).”
Surrogate molecule
No surrogate; the clinical compound was tested
“Title/ Study No.: GSK1278863A: A 26-week Oral (Gavage) Toxicity Study in the Rat/ 2011N126130”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“Title/ Study No.: GSK1278863A: A 39-week Oral (Gavage) Toxicity Study in the Cynomolgus Monkey with a 6-week Recovery Period /2011N126131”
Pivotal GLP studies
39-week cynomolgus monkey oral gavage study with 6-week recovery; 26-week rat study
“Title/ Study No.: GSK1278863A: A 39-week Oral (Gavage) Toxicity Study in the Cynomolgus Monkey with a 6-week Recovery Period /2011N126131”
Route in tox
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosomal aberration and in vivo rat bone marrow micronucleus assays
“Daprodustat was negative for mutagenic or clastogenic potential in the in vitro bacterial reverse mutation assay, the in vitro human lymphocyte chromosomal aberration assay, and the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
2-year rat and 2-year mouse (with major human metabolites): not carcinogenic
“Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males) / 7 mg/kg/day (females) in rats (up to 3 times the MRHD based on body surface area) and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”
Reproductive & developmental
Rat and rabbit EFD: embryofetal loss and reduced fetal weight at maternally toxic, polycythemic doses
“Daprodustat administered orally to pregnant rats and rabbits during the period of organogenesis was associated with adverse fetal outcomes, including embryonic and fetal loss and reduced fetal weight, at doses that caused maternal toxicity and polycythemia ( see Data ).”
Safety pharmacology
No effect on hERG (up to 47.66 µM), neurobehavioral or respiratory function (up to 20 mg/kg)
“Daprodustat had no effect on hERG channel activity (up to 47.66µM), neurobehavioral, and respiratory activity (up to 20 mg/kg).”
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 Jesduvroq 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: 39-week monkey NOAEL 3 mg/kg/day; choroid plexus, kidney and stomach findings at ≥10 mg/kg/day (FDA integrated review, p. 257)
NOAEL / key findings
39-week monkey NOAEL 3 mg/kg/day; choroid plexus, kidney and stomach findings at ≥10 mg/kg/day
“The NOAEL is determined at 3 mg/kg/day based on the microscopic findings in choroid plexus, kidney, and stomach at ≥10 mg/kg/day.”
Risksopen answer page →
Immune & cytokine safety
Thymic lymphoid atrophy in the 13-week monkey study
“In monkeys, there were fewer organs of toxicity (only bone marrow [erythroid hypercellulartity], lung [alveolar hemorrhage], thymus [lymphoid atrophy], and stomach”
Biodistribution & persistence
Rat QWBA: uveal tract and pigmented skin radioactivity undetectable by Day 7; no irreversible melanin binding
“Radioactivity concentrations in the uveal tract, pigmented skin, and meninges peak at 1h or 4h declining steadily afterwards until undetectable by Day 7. This finding suggests no irreversible binding to melanin-containing tissues.”
Modality-specific risk
Exaggerated pharmacology: polycythemia with thrombosis, hemorrhage and mortality in rats
“Cause of death appeared related to hemorrhage, systemic thrombosis and/or necrosis and thrombosis of various organs including the heart, lung, kidney, and cecum. These findings are consistent with the drug’s primary pharmacology and secondary impact on hemodynamics.”