Steady-state conditions are reached after four days; accumulation is minimal. There is no significant first pass effect. When in the bloodstream, 52% of the substance are bound to plasma proteins. It is mainly metabolized by CYP3A4, and possibly to a minor extent by CYP2D6. The most important pathway consists of oxidation to a carboxylic acid and subsequent glucuronidation, yielding a metabolite called M4. However, 79% of the drug are circulating in form of upadacitinib itself, and only 13% as M4. Other metabolites are only present in small fractions. None are pharmacologically active.The drug is excreted mainly as the original substance, of which 38% are found in the feces and 24% in the urine. The mean terminal half-life is 9 to 14 hours. Clinical trials
Phase I studies
A phase I study revealed that upadacitinib followed a bi-exponential disposition with a terminal half-life of 6–16 hours. There was no significant accumulation over the dose range of 3–36 mg per day. No interaction was found in rheumatoid arthritis patients taking methotrexate. The most common adverse event was headache but its incidence was similar to that when taking placebo (15.6% for upadacitinib vs. 16.7% for placebo). An investigation into absorption and metabolism found that dosing after a high-fat meal had no effect on upadacitinib total drug exposure over time (area under the curve or AUC). Phase II studies
Two phase IIb studies were initiated to study the efficacy and safety of upadacitinib in patients with rheumatoid arthritis and one phase II study was initiated in patients with Crohns disease.
BALANCE I
In the first study, 276 rheumatoid arthritis patients were recruited who had previously experienced inadequate response to anti–tumor necrosis factor (TNF) therapy and were currently on a stable dose of methotrexate. Patients were randomized to receive 3, 6, 12, or 18 mg twice daily or placebo. The primary endpoint was a 20% improvement in symptoms according to the American College of Rheumatology improvement criteria (ACR20). At the completion of the study it was found that response rates were significantly higher in those receiving upadacitinib versus in those receiving placebo alone (36–42% and 22– 26%, respectively). Adverse events included headache, nausea, and infection but no infections were serious. BALANCE II
In the second phase IIb study, 300 rheumatoid arthritis patients were recruited who have had an inadequate response to methotrexate. Patients were randomized to receive 3, 6, 12, or 18 mg twice daily or placebo. The primary endpoint was a 20% improvement in symptoms according to the American College of Rheumatology improvement criteria (ACR20). At the completion of the study it was found that response rates were significantly higher in those receiving upadacitinib versus in those receiving placebo alone. (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%). Improvement in symptoms was rapid, with significant changes in disease scores by week 2. Adverse events were mild with infection being the most serious. One case of community-acquired pneumonia occurred at 12 mg.

CELEST
In this 16-week study, 220 patients were recruited with moderately to severely active Crohns disease.