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.”
Species: general tox
Rat and dog
“Pivotal nonclinical toxicology studies of upadacitinib were conducted in rats and dogs.”
Species: DART
Sprague Dawley rat and New Zealand White rabbit
“The reproductive and developmental toxicity studies were conducted in Sprague Dawley rat and New Zealand White rabbit.”
Species: carcinogenicity
Sprague Dawley rat and Tg(HRAS) mouse
“The Sprague Dawley rat and Tg(HRAS) mouse were selected for the carcinogenicity studies.”
Surrogate used in
No surrogate used; upadacitinib tested directly
“Pivotal nonclinical toxicology studies of upadacitinib were conducted in rats and dogs.”
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.”
Genotox: Ames
Negative (Ames)
“The genotoxic potential of upadacitinib was characterized by Ames test, a chromosome aberration test in human peripheral blood lymphocytes, and an in vivo rat bone marrow erythrocyte micronucleus test. The outcome of the bacterial Ames test and the micronucleus test was negative.”
Genotox: in vitro mammalian
Chromosome aberration in human lymphocytes: negative for structural, positive for numerical aberrations
“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.”
Genotox: in vivo
In vivo rat bone marrow micronucleus: negative
“The genotoxic potential of upadacitinib was characterized by Ames test, a chromosome aberration test in human peripheral blood lymphocytes, and an in vivo rat bone marrow erythrocyte micronucleus test. The outcome of the bacterial Ames test and the micronucleus test was negative.”
Carcinogenicity model
2-year Sprague Dawley rat; 6-month rasH2 mouse
“The carcinogenic potential of upadacitinib was evaluated in a 6 month study in rasH2 mice and a two year study in Sprague Dawley rats.”
Carcinogenicity timing
26-week Tg.rasH2 mouse and 104-week rat completed and reviewed under the IND before the marketing application
“The 26-week mouse and 104-week rat carcinogenicity studies were submitted and reviewed under IND 114,717”
hERG / QT
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.”
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: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, and THROMBOSIS
- Serious Infections
- Mortality
- 3 Malignancy and Lymphoproliferative Disorders
- Major Adverse Cardiovascular Events
- 5 Thrombosis
- 6 Hypersensitivity Reactions
- 7 Gastrointestinal Perforations
- Hypoglycemia in Patients with Diabetes
- 9 Laboratory Abnormalities
- 10 Embryo-Fetal Toxicity
- 1 1 Vaccination s
- 2 Medication Residue in Stool
Thrombosis & embolismInfectionsCardiovascularSecondary malignancyHypersensitivity & infusion reactionsGastrointestinalMetabolic & endocrineEmbryo-fetal toxicity
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (oral) with no recovery phase
“Upadacitinib was evaluated in repeat-dose toxicity studies in mice (4 weeks with no recovery), rats (4 weeks with 4 weeks recovery, and 26 weeks with no recovery), and dogs (4 weeks with 4 weeks recovery, and 39 weeks with no recovery).”
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).”
DART package
Species: DART
Sprague Dawley rat and New Zealand White rabbit
“The reproductive and developmental toxicity studies were conducted in Sprague Dawley rat and New Zealand White rabbit.”
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.”
PPND / ePPND: when
Rat PPND completed before the marketing application; no maternal, embryofetal or postnatal toxicity
“In the oral PPND study with pregnant rats, UPA at doses up to 10 mg/kg/day produced no evidence of maternal toxicity, embryofetal toxicity, or postnatal toxicity.”
Carcinogenicity
Species: carcinogenicity
Sprague Dawley rat and Tg(HRAS) mouse
“The Sprague Dawley rat and Tg(HRAS) mouse were selected for the carcinogenicity studies.”
Carcinogenicity model
2-year Sprague Dawley rat; 6-month rasH2 mouse
“The carcinogenic potential of upadacitinib was evaluated in a 6 month study in rasH2 mice and a two year study in Sprague Dawley rats.”
Carcinogenicity timing
26-week Tg.rasH2 mouse and 104-week rat completed and reviewed under the IND before the marketing application
“The 26-week mouse and 104-week rat carcinogenicity studies were submitted and reviewed under IND 114,717”
Safety marginopen answer page →
Safety margin at NOAEL
Chronic dog NOAEL exposure ~2x the clinical dose (rat ~13x)
“No adverse findings were noted in a chronic rat study at a dose level resulting in exposures 13 times higher than the proposed clinical dose. In a chronic dog study, no adverse findings were noted at a dose level resulting in exposures 2 times higher than the proposed clinical dose.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rat adjuvant-induced arthritis model (paw swelling, bone erosion, ankle histology)
“An Adjuvant-induced arthritis (AIA) model in rats was also used to determine the efficacy of UPA on the development of paw swelling inhibition, bone erosion, and ankle histology.”
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
EMA: cellular EC50s covered by clinical Cmax, so JAK1 and JAK1/3 activity expected at therapeutic concentrations
“Both these EC50 values are well covered by the clinical Cmax of upadacitinib in human plasma following the recommended dosing of 15 mg ER QD. Therefore, pharmacological activity at JAK1 and JAK1/3 could be expected at therapeutic plasma concentrations of upadacitinib.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAccepted with a conditionBeyond the letter
No exposure margin for teratogenicity: rat and rabbit embryo-fetal NOAELs at exposures similar to or below the clinical dose
Why: Label carries a Warning for embryo-fetal toxicity based on nonclinical data
“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. While other approved JAK inhibitors are also teratogenic, the review team expressed concern regarding the lack of exposure margins between the embryo-fetal toxicity and the proposed clinical dose level.”
“Based on discussion among the nonclinical review team, clinical review team (Dr. Keith Hull and Dr. Rachel Glaser), DPARP management, ODE2 Pharmacology-Toxicology Associate Director Dr. Timothy McGovern, and the Division of Pediatric and Maternal Health, a consensus was reached that the UPA label should include a Warning for embryo-fetal toxicity based on nonclinical data.”
Impurity or metaboliteAccepted
Major human metabolite M4 (glucuronide) not covered in rat or dog; no additional safety testing
Why: Glucuronide formed after monooxidation not a safety concern, consistent with ICH M3(R) Questions and Answers · Within the guideline
“The major metabolite of UPA in human plasma (i.e., M4, 13%) following a single oral dose is not covered by equivalent amounts detected in either dog (i.e., M4, 0.9%) or rat (i.e., M4, not detected) ADME studies.”
“However, as the M4 human metabolite is a product of monooxidation followed by glucuronidation it was not considered a safety concern, consistent with ICH M3(R) Questions & Answers (June 2011).”
GenotoxicityAcceptedBeyond the letter
Positive for numerical chromosome aberrations in vitro in human lymphocytes; negative for structural aberrations and in vivo micronucleus
Why: No structural chromosome breakage and negative in vivo micronucleus assay reassure against aneuploidy · Weight of evidence
“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.”
“Since no effect was observed on the structural chromosome breakage and the in vivo micronucleus assay was found negative, this is considered sufficient reassurance of lack of potential for aneuploidy induction.”
Similar precedents
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