Neither the subject nor the healthcare providers knew which medication was being given until after this 24-week treatment period.Trial 2 enrolled participants in whom MTX did not work well. Participants were randomly assigned to receive one of two doses of upadacitinib daily by mouth or continue their usual dose of MTX for 14 weeks. At week 14, participants who were assigned to MTX received upadacitinib by mouth daily. Neither the subject nor the healthcare providers knew which medication was being given.Trial 3 enrolled participants in whom DMARDS did not work well. Participants were randomly assigned to receive one of two doses of upadacitinib or placebo daily by mouth in addition to DMARDS for 12 weeks. At week 12, participants who received placebo were reassigned to upadacitinib daily. Neither the subject nor the healthcare providers knew which medication was being given.Trial 4 enrolled participants in whom MTX did not work well. Participants were randomly assigned to receive upadacitinib or placebo daily by mouth in addition to MTX for 14 weeks. Participants receiving placebo who did not have adequate improvement of signs and/or symptoms could be switched to upadacitinib after week 14. At week 26, all participants receiving placebo were switched to upadacitinib once daily by mouth. Neither the subject nor the healthcare providers knew which medication was being given.Trial 5 enrolled participants in whom DMARDS did not work well or could not be tolerated. Participants were randomly assigned to receive one of two doses of upadacitinib or placebo treatment daily added to DMARDs for 12 weeks.
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.