Pharmacokinetics of Upadacitinib with Clinical Regimens of the Extended-Release Formulation Utilized in Rheumatoid Arthritis Phase 3 Trials

Clin Pharmacol Drug Dev. 2019 Feb;8(2):208-216. doi: 10.1002/cpdd.462

Upadacitinib (UPA) extended release (ER) formulation dosing achieved the target profile that enables single dosing in patients with RA. In early clinical studies, UPA was given as an immediate release (IR) formulation, however patients were noted to experience fluctuations in blood plasma concentrations. To enhance patient compliance in UPA Phase 3 trials, ER tablets have been developed. Here, authors aimed at characterising the pharmacokinetics of UPA single and multiple doses of ER compared with IR dosing strategies. This was a 5-part study comparing the different dosing strategies, as well as the effect of fasting and non-fasting on ER formulation. All patients were aged between 18 and 55 years old, and were considered in general good health based on medical history. UPA plasma concentrations and pharmacokinetic parameters, including Cmax, Cmin and AUC were monitored. Data indicated that multiple dosing with UPA 15 and 30 mg QD ER tablet had the same AUC as UPA 6 and 12 mg BID IR capsules, under fasting conditions. Single ER dosing regimens took longer to reach peak plasma concentrations compared with single IR doses. Multiple dosing with 15- and 30 mg once daily ER tablets had comparable Cmax and Cmin compared with 6 and 12 mg twice daily IR doses. No patterns in the frequency or type of AEs were observed, and no serious AEs were noted throughout the study duration. The authors concluded that the ER formulation achieved the target profile of the IR formulation and can be used in once-daily dosing regimens. The data also supported the use of 15- and 30 mg ER doses in ongoing, Phase 3 RA studies.