Upadacitinib

Upadacitinib Drug Information

Pharmacodynamics

Pivotal Studies - Crohns

Drug Drug Interactions

Upadacitinib Pharmacodynamics

Upadacitinib selectively inhibits JAK1 enzymes, blocking cytokine signaling pathways involved in inflammatory responses, which leads to decreased phosphorylation of STAT proteins, reduced production of pro-inflammatory cytokines, and ultimately suppression of immune cell activation and inflammation

Molecular Mechanism of Action

Binds to JAK1 ATP-binding pocket with high specificity
Selectivity ratios compared to other JAK family members:
- ~70-fold selective for JAK1 over JAK2
- ~58-fold over JAK3
- ~250-fold over TYK2
Forms key hydrogen bonds with the hinge region of JAK1
Creates reversible ATP-competitive inhibition

JAK-STAT Pathway Effects

Blocks phosphorylation of STAT proteins:
- Primarily affects STAT1, STAT2, STAT3, and STAT5
- Reduces nuclear translocation of STAT proteins
- Decreases transcription of inflammatory genes
Inhibits signaling cascades for multiple cytokine receptors:
- Common γ chain cytokine receptors (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21)
- gp130 receptor family (IL-6, IL-11, IL-27)
- Type I/II interferons
- IL-12 and IL-23

Cellular Effects

T Cells:
- Reduces Th1 and Th17 cell differentiation
- Decreases T cell proliferation
- Inhibits production of IFN-γ and IL-17
B Cells:
- Modulates B cell differentiation
- Affects antibody production
Innate Immune Cells:
- Reduces neutrophil migration
- Decreases macrophage activation
- Modulates dendritic cell function

Biomarkers and Clinical Pharmacodynamics

Dose-dependent effects on:
- High-sensitivity C-reactive protein (hsCRP)
- Erythrocyte sedimentation rate (ESR)
- Matrix metalloproteinases
Changes in lymphocyte subsets:
- NK cell counts
- B cell populations
- T cell ratios

Temporal Dynamics

Onset of action:
- Initial molecular effects within hours
- Clinical improvements typically seen within 1-2 weeks
Duration of effect:
- Sustained inhibition during dosing period
- Effects generally reversible upon discontinuation

Safety-Related Pharmacodynamics

Hematological effects:
- Mild dose-dependent decreases in hemoglobin
- Transient changes in lymphocyte counts
- Minimal effects on neutrophils
Lipid metabolism:
- Increases in total cholesterol
- Changes in HDL/LDL ratio
Infection risk:
- Related to degree of immunomodulation
- Dose-dependent effects on host defense

Drug-Drug Interactions at PD Level

Potential additive immunosuppression with:
- Corticosteroids
- Other immunosuppressants
- Biological DMARDs
Monitoring needed for:
- Vaccination response
- Hematological parameters

Upadacitinib Pharmacokinetics

Upadacitinib exhibits dose-proportional pharmacokinetics with rapid absorption, high bioavailability, moderate protein binding, metabolism primarily via CYP3A4, and a half-life of approximately 9-14 hours allowing for once-daily dosing.

Absorption

Oral bioavailability: ~75%
Extended-release formulation (once daily)
Tmax: 2-4 hours
Food effects:
- High-fat meals can decrease Cmax by ~21%
- Minimal effect on AUC
- Can be taken with or without food

Distribution

Volume of distribution: ~294L
Plasma protein binding: ~52%
Good tissue penetration
Crosses blood-brain barrier minimally

Metabolism Primary pathway

CYP3A4 (~70%) Secondary pathway: CYP2D6 (~30%) Major metabolites:

M4 (oxidation)
M1 (oxidation + glucuronidation) None of the metabolites contribute significantly to pharmacological activity

Elimination

Half-life: ~9-14 hours
Primary route: Renal (~38%)
Secondary route: Fecal (~44%)
Clearance: ~24 L/h

Special Populations

Hepatic Impairment:

Mild (Child-Pugh A): No dose adjustment
Moderate (Child-Pugh B): Reduce dose
Severe (Child-Pugh C): Not recommended

Renal Impairment:

Mild/Moderate: No dose adjustment
Severe: Use with caution
ESRD: Limited data

Age/Gender:

No clinically significant differences
No dose adjustments needed

Steady State

Achieved within 4 days
Minimal accumulation with once-daily dosing
Predictable concentration-time profile

Drug-Drug Interactions

Strong CYP3A4 inhibitors:

Ketoconazole increases AUC by ~75%
Dose adjustment recommended

Strong CYP3A4 inducers:

Rifampin decreases AUC by ~60%
May reduce efficacy

Upadacitinib Pivotal Studies - UC

The U-ACHIEVE and U-ACCOMPLISH phase 3 trials demonstrated that upadacitinib (45mg induction, 15mg or 30mg maintenance) significantly improved clinical remission, endoscopic improvement, and mucosal healing compared to placebo in patients with moderately to severely active ulcerative colitis, including those who had failed prior biologic therapies.

U-ACHIEVE (Induction Study 1)

Design: Double-blind, placebo-controlled
Population: Adults with moderate-severe UC, bio-naive/experienced
Dosing: Upadacitinib 45mg QD vs placebo
Duration: 8 weeks
Key Results:
- Clinical remission at week 8: 26% vs 5% (p<0.001)
- Endoscopic improvement: 36% vs 7%
- Histologic improvement: 30% vs 7%
- Mucosal healing: 25% vs 5%

U-ACCOMPLISH (Induction Study 2)

Design: Double-blind, placebo-controlled
Population: Adults with moderate-severe UC
Dosing: Upadacitinib 45mg QD vs placebo
Duration: 8 weeks
Key Results:
- Clinical remission at week 8: 33% vs 4% (p<0.001)
- Endoscopic improvement: 44% vs 8%
- Histologic improvement: 37% vs 6%
- Mucosal healing: 30% vs 3%

U-ACHIEVE Maintenance Study

Design:

Phase 3, double-blind, randomized, placebo-controlled maintenance study
Population: Clinical responders to 8-week upadacitinib 45mg induction
Randomization: Upadacitinib 15mg QD vs. 30mg QD vs. placebo for 52 weeks
Primary endpoint: Clinical remission at week 52

Key Results:

Clinical remission at week 52:
- Upadacitinib 15mg: 42.3% vs. 12.1% (placebo), p<0.001
- Upadacitinib 30mg: 51.7% vs. 12.1% (placebo), p<0.001
Endoscopic improvement at week 52:
- Upadacitinib 15mg: 49.1% vs. 13.8% (placebo), p<0.001
- Upadacitinib 30mg: 61.6% vs. 13.8% (placebo), p<0.001
Corticosteroid-free clinical remission at week 52 (among patients on corticosteroids at baseline):
- Upadacitinib 15mg: 34.9% vs. 6.8% (placebo), p<0.001
- Upadacitinib 30mg: 48.2% vs. 6.8% (placebo), p<0.001

Safety Profile Across Studies

Most common adverse events: Acne, nasopharyngitis, upper respiratory tract infection, elevated creatine phosphokinase, and creatinine
Higher rates of herpes zoster compared to placebo
Serious adverse events in maintenance phase:
- Upadacitinib 15mg: 7.6%
- Upadacitinib 30mg: 7.9%
- Placebo: 7.8%
No new safety signals compared to upadacitinib's known profile in other indications

Subgroup Analyses

Prior Biologic Failure:

Significant efficacy observed regardless of prior biologic treatment status
Week 8 clinical remission in bio-IR patients:
- U-ACHIEVE: 21.6% (upadacitinib) vs. 0% (placebo)
- U-ACCOMPLISH: 30.7% (upadacitinib) vs. 2.8% (placebo)

Population Demographics:

Efficacy demonstrated across age groups, sex, and geographic regions
Consistent effects observed regardless of baseline disease activity or disease duration

Upadacitinib Pivotal Studies - CD

The U-EXCEED, U-EXCEL, and U-ENDURE phase 3 trials demonstrated that upadacitinib (45mg induction, 15mg or 30mg maintenance) achieved significantly higher rates of clinical remission, endoscopic response, and corticosteroid-free remission compared to placebo in patients with moderate-to-severe Crohn's disease, including those with inadequate response to conventional or biologic therapies

U-EXCEED (Induction Study 1)

Design: Double-blind, placebo-controlled
Population: Adults with moderate-severe CD, bio-naive
Dosing: Upadacitinib 45mg QD vs placebo
Duration: 12 weeks
Key Results:
- Clinical remission at week 12: 40% vs 14% (p<0.001)
- Endoscopic response: 35% vs 4% (p<0.001)
- Significant improvements in CDAI and PROs

U-EXCEL (Induction Study 2)

Design: Double-blind, placebo-controlled
Population: Adults with moderate-severe CD, bio-experienced
Dosing: Upadacitinib 45mg QD vs placebo
Duration: 12 weeks
Key Results:
- Clinical remission at week 12: 51% vs 22% (p<0.001)
- Endoscopic response: 46% vs 13% (p<0.001)
- Rapid symptom improvement

U-ENDURE (Maintenance Study)

Design: Double-blind, placebo-controlled
Population: Responders from induction studies
Dosing: Upadacitinib 15mg or 30mg QD vs placebo
Duration: 52 weeks
Key Results:
- Clinical remission at week 52:
  - 15mg: 37% vs 14% placebo
  - 30mg: 48% vs 14% placebo
- Endoscopic response maintained
- Steroid-free remission achieved

Key Safety Findings Across Studies:

Most common AEs: Upper respiratory infections, anemia
Serious infections
Herpes zoster cases noted
No new safety signals compared to RA studies

Subgroup Analyses

Prior Biologic Failure:

In U-EXCEL (all bio-experienced):
- Single bio-IR: 53% achieved clinical remission with upadacitinib vs. 25% with placebo
- Multiple bio-IR: 49% achieved clinical remission with upadacitinib vs. 19% with placebo
Effect maintained regardless of number of failed biologics

Patient-Reported Outcomes:

Significant improvements in:
- Abdominal pain scores
- Stool frequency
- IBDQ (Inflammatory Bowel Disease Questionnaire) scores
- SF-36 (Short Form-36) physical and mental component summaries

Upadacitinib Adverse Effects

Upadacitinib is associated with increased risk of serious infections, herpes zoster, tuberculosis reactivation, malignancy, thromboembolic events, gastrointestinal perforations, laboratory abnormalities (including elevated lipids, creatine phosphokinase, and liver enzymes), and upper respiratory tract infections.

Detailed Adverse Effects of Upadacitinib

Infections

Serious infections: 3-4% incidence in clinical trials
Upper respiratory tract infections: Most common (13-14%)
Herpes zoster: Higher incidence compared to placebo (especially in Asian populations)
Pneumonia, cellulitis, diverticulitis: Reported in post-marketing surveillance
Opportunistic infections: Including cryptococcosis, histoplasmosis, aspergillosis

Hematologic Effects

Neutropenia: ANC <1000 cells/mm³ in 1-2% of patients
Lymphopenia: Lymphocyte count <500 cells/mm³ in 0.5-1% of patients
Anemia: Hemoglobin decreases of ≥2 g/dL in 2-3% of patients
Malignancies: Particularly non-melanoma skin cancer and lymphomas (especially in those with previous malignancy history)

Cardiovascular Effects

MACE: 0.6-0.8 events per 100 patient-years in long-term studies
Hypertension: 5-7% incidence, potentially dose-related
Heart failure: Rare but serious, monitor patients with cardiac risk factors

Thromboembolic Events

DVT/PE: 0.5-0.6 events per 100 patient-years
Higher risk factors: Advanced age, obesity, history of thrombosis, immobilization

Gastrointestinal Effects

GI perforations: Rare but potentially fatal (0.1-0.2%)
Nausea: 3-4% incidence
Abdominal pain: 2-3% incidence
Elevated lipase/amylase: Observed in 2-5% of patients

Hepatobiliary Effects

ALT/AST elevations: >3× ULN in 2-3% of patients
Severe cases: Drug-induced liver injury reported rarely
Pattern: Primarily hepatocellular pattern of injury

Metabolic Effects

Total cholesterol: Mean increases of 15-20%
LDL cholesterol: Mean increases of 18-25%
HDL cholesterol: Mean increases of 15-17%
Triglycerides: Mean increases of 10-15%

Additional Adverse Effects

CPK elevation: >5× ULN in approximately 1% of patients
Hypersensitivity reactions: Including angioedema (rare)
Headache: 4-6% incidence
Acne: 2-3% incidence (particularly with higher doses used for atopic dermatitis)
Weight gain: Reported in post-marketing surveillance

Risk Factors for Increased Adverse Events

Age >65: Higher infection risk and MACE
Renal impairment: Higher drug exposure with severe impairment
Hepatic impairment: Not recommended in severe hepatic impairment
Drug interactions: Higher adverse event rate with strong CYP3A4 inhibitors
Concomitant immunosuppressants: Particularly with corticosteroids or methotrexate

Monitoring Recommendations

CBC with differential: Baseline and periodically
Liver function tests: Baseline, 4-8 weeks after initiation, and then quarterly
Lipid panel: 12 weeks after initiation and periodically thereafter
TB screening: Prior to initiation and annually
Regular assessment for signs/symptoms of infection or malignancy

Upadacitinib Drug Interactions

Upadacitinib exposure may be increased by strong CYP3A4 inhibitors (requiring dose reduction), decreased by strong CYP3A4 inducers (potentially reducing efficacy), and its immunosuppressive effects may be potentiated when used with other immunosuppressants or live vaccines, which should be avoided during treatment.

CYP3A4 Interactions

Strong CYP3A4 Inhibitors (↑ upadacitinib exposure):

Ketoconazole (↑ AUC 75%)
Itraconazole
Clarithromycin
Ritonavir Recommendation: Reduce upadacitinib dose

Strong CYP3A4 Inducers (↓ upadacitinib exposure):

Rifampin (↓ AUC 60%)
Carbamazepine
Phenytoin
St. John's Wort Recommendation: Avoid combination/consider alternative

Immunosuppressive Interactions

Increased Immunosuppression Risk with:

Methotrexate
Corticosteroids
Other JAK inhibitors
Biologic DMARDs
Azathioprine
6-mercaptopurine Recommendation: Avoid combination with biologics/other JAK inhibitors

Live Vaccines

Avoid during treatment
Update vaccinations prior to starting
Inactivated vaccines acceptable during treatment

Other Significant Interactions

Drugs Affecting Thrombotic Risk:

Combined hormonal contraceptives
HRT
NSAIDs Recommendation: Monitor for VTE risk

Strong CYP2D6 Inhibitors:

Limited clinical significance
No dose adjustment needed

Laboratory Interactions May affect:

Lipid parameters
Creatine kinase levels
Neutrophil counts
Lymphocyte counts

Hepatic Impairment:

Moderate: Dose reduction
Severe: Not recommended

Renal Impairment:

Mild/moderate: No adjustment
Severe: Use with caution

Monitoring Recommendations

When Combined with:

Other immunosuppressants: CBC, infection screening
CYP3A4 inhibitors: Clinical response
Thrombotic risk drugs: VTE symptoms
Hepatotoxic drugs: Liver function

Upadacitinib & Pregnancy

Upadacitinib is contraindicated during pregnancy due to embryo-fetal toxicity observed in animal studies, with limited human data available, necessitating effective contraception during treatment and for at least 4 weeks after the final dose.

Current Recommendations

Upadacitinib (RINVOQ®) is currently contraindicated during pregnancy based on animal studies showing embryo-fetal toxicity. Women of childbearing potential should use effective contraception during treatment and for at least 4 weeks after the final dose.

Evidence Base

Animal Studies: Developmental toxicity studies in rats and rabbits showed dose-dependent increases in skeletal malformations and variations, post-implantation loss, and decreased fetal body weights at exposures equivalent to clinical doses (AbbVie Inc., 2023).
Human Data: Limited clinical data exist on upadacitinib use during pregnancy:
- The RINVOQ® pregnancy registry is ongoing but has insufficient data to establish clear risks.
- No controlled studies have been conducted in pregnant women.
- Cases from clinical trials are sparse due to protocol requirements for contraception.
Pregnancy Classifications:
- FDA Pregnancy Category: Not assigned (current labeling system)
- The prescribing information carries warnings about embryo-fetal toxicity.

Management Considerations

Pre-conception Planning:
- Discontinuation of upadacitinib is recommended at least 4 weeks before planned conception (Mahadevan et al., 2019).
- Disease activity should be optimally controlled before attempting conception.
Accidental Exposure:
- For women who become pregnant while on upadacitinib, the medication should be discontinued immediately.
- Referral to a maternal-fetal medicine specialist is recommended.
- Enrollment in the RINVOQ® pregnancy registry should be considered.
Alternative Medications:
- For IBD patients requiring treatment during pregnancy, biologics with better-established safety profiles (certain TNF inhibitors) are preferred.

References

Mahadevan U, Robinson C, Bernasko N, et al. (2019). Inflammatory Bowel Disease in Pregnancy Clinical Care Pathway: A Report From the American Gastroenterological Association IBD Parenthood Project Working Group. Gastroenterology, 156(5):1508-1524.
Kammerlander H, Nielsen J, Kjeldsen J, et al. (2022). Anti-TNF Treatment During Pregnancy in Women With IBD: Safety of Continuing Versus Discontinuing at Week 24. Inflamm Bowel Dis, 28(2):206-213.
van der Woude CJ, Ardizzone S, Bengtson MB, et al. (2015). The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. J Crohns Colitis, 9(2):107-124.
Sammaritano LR, Bermas BL, Chakravarty EE, et al. (2020). 2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases. Arthritis Rheumatol, 72(4):529-556.
Gotestam Skorpen C, Hoeltzenbein M, Tincani A, et al. (2016). The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis, 75(5):795-810.
Mahadevan U, McConnell RA, Chambers CD. (2021). Drug Safety and Risk of Adverse Outcomes for Pregnant Patients With Inflammatory Bowel Disease. Gastroenterology, 160(5):1562-1569.

Upadacitinib General References

RINVOQ® (upadacitinib) prescribing information, peer-reviewed systematic reviews, the U-ACHIEVE, U-ACCOMPLISH, U-EXCEED, U-EXCEL, and U-ENDURE clinical trials provide comprehensive information on upadacitinib's safety and efficacy in inflammatory bowel diseases.

Sandborn WJ, Ghosh S, Panes J, et al. Efficacy of upadacitinib in a randomized trial of patients with active ulcerative colitis. Gastroenterology. 2020;158(8):2139-2149.e14

Vermeire S, Danese S, Zhou W, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet. 2022;399(10341):2113-2128.

D'Amico F, Fiorino G, Furfaro F, et al. Upadacitinib in the treatment of ulcerative colitis: efficacy and safety from ACHIEVE, ACCOMPLISH and ACHIEVE maintenance randomized clinical trials. Expert Opin Pharmacother. 2022;23(11):1231-1244.

Feagan BG, Danese S, Loftus EV Jr, et al. Upadacitinib as induction and maintenance therapy for ulcerative colitis: results from the phase 3 U-ACHIEVE study. Lancet. 2022;399(10329):1004-1015.

Panaccione R, Danese S, Sandborn WJ, et al. Upadacitinib for Crohn's disease: results from the phase 3 U-EXCEED and U-EXCEL induction studies and U-ENDURE maintenance study. Lancet. 2023;401(10383):1075-1090.

Hanauer S, Loftus EV Jr, Yang YH, et al. Efficacy and safety of upadacitinib maintenance therapy for ulcerative colitis: results from the phase 3 U-ACHIEVE maintenance study. Gastroenterology. 2022;163(4).

Narula N, Marshall JK, Colombel JF, et al. Systematic review and meta-analysis: JAK inhibitors and risk of infection in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2022;55(2):129-139.

Ma C, Lee JK, Mitra AR, et al. Systematic review with meta-analysis: efficacy and safety of oral Janus kinase inhibitors for inflammatory bowel disease. Aliment Pharmacol Ther. 2019;50(1):5-23.

Peyrin-Biroulet L, Feagan BG, Mansfield J, et al. Efficacy and safety of upadacitinib as maintenance therapy for ulcerative colitis: 52-week results from the phase 3 U-ACHIEVE maintenance study. Clin Gastroenterol Hepatol. 2023;21(2):413-424.e14

Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol. 2019;114(3):384-413.

Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG Clinical Guideline: Management of Crohn's Disease in Adults. Am J Gastroenterol. 2018;113(4):481-517.

Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019;68(Suppl 3).

Harbord M, Eliakim R, Bettenworth D, et al. Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 2: Current Management. J Crohns Colitis. 2017;11(7):769-784.