Rinvoq
upadacitinib
Species
RatDog
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 dog
“General toxicology studies were conducted via the oral route of administration in rats and dogs.”
Why that species
Higher systemic exposure than other species; elimination pathways and metabolic profiles similar to human
“The selection was based on the systemic exposure in rats and dogs which was much higher than in other investigated species. As discussed in the pharmacokinetics section, these species were shown to have similar elimination pathways and metabolic profiles of upadacitinib as in humans”
Surrogate molecule
No surrogate; the clinical compound was tested
“Upadacitinib was administered to beagle dogs at oral doses of 0, 0.1, 0.5, and 1.5 mg/kg/day for up to 39 weeks.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“The GLP-compliant studies included 4-week studies in rats and dogs (each with a 4-week recovery period) followed by chronic toxicity studies in rats (26-weeks duration) and dogs (39-weeks duration).”
Pivotal GLP studies
GLP oral studies: 4-week rat and dog, 26-week rat and 39-week dog
“The GLP-compliant studies included 4-week studies in rats and dogs (each with a 4-week recovery period) followed by chronic toxicity studies in rats (26-weeks duration) and dogs (39-weeks duration).”
Route in tox
Oral
“General toxicology studies were conducted via the oral route of administration in rats and dogs.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and in vivo rat micronucleus; in vitro chromosome aberration negative for structural, positive for numerical (polyploidy)
“The outcome of the bacterial Ames test and the micronucleus test was negative. In the in vitro mammalian chromosome aberration test in human peripheral blood lymphocytes, upadacitinib was found negative for induction of structural chromosome aberrations but positive for induction of numerical chromosome aberration.”
Carcinogenicity
Not carcinogenic in 2-year rat (~4-10x clinical AUC) or 26-week Tg(HRAS) transgenic mouse studies
“Upadacitinib, at exposures (based on AUC) approximately 4 and 10 times the clinical dose of 15 mg in male and female Sprague-Dawley rats, respectively, was not carcinogenic in a 2 year carcinogenicity study in Sprague-Dawley rats. Upadacitinib was not carcinogenic in a 26 week carcinogenicity study in CByB6F1-Tg(HRAS)2Jic transgenic mice.”
Reproductive & developmental
Rat fertility (post-implantation loss), rat and rabbit EFD (skeletal malformations); no adverse PPND findings
“Adverse effects attributed to UPA were observed in the rat fertility (increased postimplantation loss and reduced live fetuses per litter), rat EFD (skeletal malformations), and rabbit EFD (skeletal malformations, postimplantation loss, decreased fetal body weights) studies. No adverse findings were noted in the PPND study.”
Safety pharmacology
hERG IC50 39.5 µg/mL, several hundred-fold above clinical plasma concentrations
“The IC50 for hERG blockade was 39.5 μg/mL, which is several hundred-fold above clinical plasma concentrations.”
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 Rinvoq 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 26-week NOAEL 20 mg/kg/day, based on kidney histopathology at 50 mg/kg/day (FDA pharmacology/toxicology review, p. 36)
NOAEL / key findings
Rat 26-week NOAEL 20 mg/kg/day, based on kidney histopathology at 50 mg/kg/day
“A No Observed Adverse Effect Level (NOAEL) of 20 mg/kg/day was established for this study based upon observed histopathological findings in the kidneys at 50 mg/kg/day.”
Risksopen answer page →
Immune & cytokine safety
Decreased circulating lymphocytes and lymphoid depletion in spleen, thymus and lymph nodes (JAK inhibition)
“The findings included decreases in circulating lymphocytes and lymphoid depletion in spleen, thymus, and lymph nodes.”
Biodistribution & persistence
Rat QWBA: not measurable in CNS or lens; prolonged uveal tract and pigmented skin retention (melanin affinity)
“Radioactivity concentrations were below measurable levels in the CNS tissues and the lens of the eye at all collection times throughout the study. Radioactivity was present in the uveal tract through 192 hours postdose and a slower clearance in pigmented skin indicating an apparent affinity for melanin.”
Modality-specific risk
Embryofetal toxicity (teratogenicity) without exposure margin to the clinical dose
“Upadacitinib is a potent teratogen in rats and rabbits, with NOAELs in these studies associated with exposes similar to or less than the proposed clinical dose.”