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.
However, in 1995 Aventis (now Sanofi-Aventis) stopped producing the drug, whose main market was African countries, because it did not make a profit.In 2001, Aventis and the WHO formed a five-year partnership, during which more than 320,000 vials of pentamidine, over 420,000 vials of melarsoprol, and over 200,000 bottles of eflornithine were produced by Aventis, to be given to the WHO and distributed by the association Médecins sans Frontières (also known as Doctors Without Borders) in countries where sleeping sickness is endemic. According to Médecins sans Frontières, this only happened after "years of international pressure," and coinciding with the period when media attention was generated because of the launch of another eflornithine-based product (Vaniqa, for the prevention of facial-hair in women), while its life-saving formulation (for sleeping sickness) was not being produced. From 2001 (when production was restarted) through 2006, 14 million diagnoses were made. This greatly contributed to stemming the spread of sleeping sickness, and to saving nearly 110,000 lives. Society and culture
Available forms
Vaniqa is a cream, which is white to off-white in colour. It is supplied in tubes of 30 g and 60 g in Europe. Vaniqa contains 15% w/w eflornithine hydrochloride monohydrate, corresponding to 11.5% w/w anhydrous eflornithine (EU), respectively 13.9% w/w anhydrous eflornithine hydrochloride (U.S.), in a cream for topical administration. Ornidyl, intended for injection, was supplied in the strength of 200 mg eflornithine hydrochloride per ml.