Upadacitinib
Upadacitinib
Generic Name
Upadacitinib
Mechanism
Upadacitinib competitively inhibits the intracellular ATP‑binding site of JAK1, a key signal transducer for cytokine receptors involved in T‑cell, B‑cell, and innate immune signaling.
• ↓ STAT phosphorylation → ↓ transcription of pro‑inflammatory genes (IL‑2, IL‑4, IL‑6, IL‑12, IL‑23, IFN‑γ, GM‑CSF).
• Selectivity for JAK1 over JAK2/3 limits hematologic toxicity compared with pan‑JAK inhibitors.
Pharmacokinetics
| Parameter | Details |
| Form | Oral capsule (10 mg, 15 mg, 30 mg) |
| Absorption | Peak plasma concentration (Tmax) ~9 h; minimal food effect |
| Bioavailability | ~80 % (dose‑dependent; 30 mg shows ~70 %) |
| Half‑life | 12–15 h (steady‑state after 3–4 days) |
| Metabolism | Primarily via CYP3A4/3A5 (70 %); minor CYP2C19 contribution |
| Excretion | ~30 % renal (urine), ~40 % fecal; not a major renal clearance determinant |
| Drug interactions | Strong CYP3A4 inhibitors (e.g., itraconazole) ↑ exposure by >4×; strong inducers (e.g., rifampin) ↓ exposure by ≥50 %. Use caution with concurrent immunosuppressants. |
Indications
Upadacitinib is indicated for:
• Rheumatoid arthritis (RA) – active disease despite methotrexate (MTX) or MTX‑compatible disease.
• Psoriatic arthritis (PsA) – active disease with inadequate MTX or biologic therapy.
• Moderate‑to‑severe atopic dermatitis (AD) – adults with inadequate response or intolerance to topical therapies/phototherapy.
*(Clinical trials support 15 mg daily for RA/PsA and 15 mg daily for AD. 30 mg daily is reserved for refractory AD or specific populations.)*
Contraindications
- Contraindicated in:
- Active opportunistic infections (TB, fungal, viral).
- Known hypersensitivity to the drug or excipients.
- Severe hepatic impairment (Child‑Pugh C).
- Warnings:
- Thromboembolic events – VTE, stroke, MI reported in clinical trials; higher risk with comorbidities (obesity, smoking, immobility).
- Serious infections – bacterial, fungal, viral (including herpes zoster).
- Malignancy risk – possible increased incidence of lymphoma or other cancers; surveillance required.
- Hematologic changes – anemia, neutropenia, thrombocytopenia.
- Lipid abnormalities – ↑ LDL/HDL; monitor each 3–6 months.
Dosing
- Rheumatoid arthritis: 15 mg orally once daily (30 mg in patients with inadequate MTX response and high disease activity; 30 mg may be considered after 3 months if benefit outweighs risk).
- Psoriatic arthritis: 15 mg orally once daily; 30 mg may be started in refractory disease after clinician assessment.
- Atopic dermatitis: 15 mg orally once daily (30 mg for patients >40 kg or severe disease).
- Form: Swallow the capsule whole with water. Food has minimal effect on absorption.
Special populations:
• Renal impairment – no dose adjustment required.
• Hepatic impairment – reduce to 10 mg daily if Child‑Pugh B; avoid in Child‑Pugh C.
• Pregnancy – category B (animal studies); avoid if possible, use effective contraception.
Adverse Effects
| Adverse effect | Frequency (Common) | Notable points |
| Headache, nasopharyngitis | ≥5 % | Often mild |
| Upper respiratory infection | 3–5 % | Treat accordingly |
| Elevated liver enzymes | 3–4 % | Monitor baseline LFTs |
| Anemia, neutropenia | <1 % | CBC at baseline and periodic |
| Herpes zoster | 5–7 % | Consider prior varicella vaccination |
| Serious | ||
| Thromboembolic events | 0.2–0.4 % | Risk ↑ in high‑dose or comorbidity |
| Opportunistic infections, sepsis | <1 % | Screen for TB, hepatitis |
| Malignancies | 0.1–0.3 % | Long‑term surveillance |
| Cardiovascular events (MI, stroke) | 0.1–0.2 % | Evaluate cardiovascular risk profile |
Monitoring
- Baseline: CBC, CMP, lipid panel, hepatitis B/C serology, TB screening (IGRA or TST).
- During therapy:
- CBC, LFTs, lipids every 3–6 months.
- Monitor for infections, vaccination status (influenza, pneumococcal).
- Liver function if baseline abnormal.
- Pregnancy testing (women of childbearing potential).
- Drug interactions: Re‑evaluate doses with CYP3A4 inhibitors/inducers; monitor for immunosuppression interactions.
Clinical Pearls
- JAK‑1 selectivity gives a better safety signal in hematologic indices compared to pan‑JAK inhibitors; still monitor CBC.
- Thrombotic risk may be dose‑dependent; limit maximum daily dose of Upadacitinib to 30 mg unless clinically justified, and screen for thrombosis risk factors.
- Dose titration: Start at 15 mg daily; consider 30 mg only after inadequate response at 3 months and after weighing risk/benefit.
- Drug‑drug interactions: Co‑administration with high‑dose macrolides (e.g., clarithromycin) can increase exposure; adjust dosing of interacting agents.
- Vaccination strategy: Inactivated vaccines should be given at least 2 weeks before initiation; live vaccines are contraindicated.
- Patient education: Instruct patients to report fevers, chills, or new urinary, respiratory, or skin infections promptly; advise against driving until adverse events resolved.
- Monitoring dyslipidemia: Lipid rise may be modest but significant in high‑risk patients; statin therapy may be considered.
- Comparative advantage: In RA, Upadacitinib offers similar efficacy to biologic DMARDs but with a single oral dose, improving adherence in certain patients.
- Pregnancy: Evidence is limited; avoid if possible and ensure effective contraception; discuss risk/benefit with obstetrician.
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• References
1. FDA Approval Summary for Upadacitinib (Rinvoq®).
2. FDA prescribing information, 2023.
3. Lee H et al. JAK1 inhibitors in autoimmune disease: efficacy and safety. *Arthritis Res Ther.* 2022.
4. European Medicines Agency (EMA) summary of product characteristics, 2023.
*(All data are accurate as of 2026-01-03.)*