Population Pharmacokinetics of Upadacitinib Using the Immediate-Release and Extended-Release Formulations in Healthy Subjects and Subjects with Rheumatoid Arthritis: Analyses of Phase I–III Clinical Trials

Abstract

Background and Objectives Upadacitinib is a selective Janus kinase (JAK) 1 inhibitor being developed as an orally administered treatment for patients with moderate to severe rheumatoid arthritis (RA) and other autoimmune disorders. These analyses characterized the population pharmacokinetics of upadacitinib across phase I–III clinical trials using data for immediate-release (IR) and extended-release (ER) formulations. Methods Pharmacokinetic data from 4170 subjects taking IR doses of 1–48 mg and ER doses of 7.5–30 mg across 12 studies spanning phase I–III clinical trials, with a total of 29,372 upadacitinib plasma concentrations, were analyzed using non-linear mixed-effects modeling. The model was evaluated using bootstrap analyses and visual predictive checks. Results A two-compartment model with first-order absorption with lag time for the IR formulation, mixed zero- and first-order absorption with lag time for the ER formulation, and linear elimination, adequately described upadacitinib plasma concentration–time profiles. Population estimates of upadacitinib apparent oral clearance and steady-state volume of distribution in healthy volunteers for the ER formulation were 53.7 L/h and 294 L, respectively. The relative bioavailability of the ER formulation compared with the IR formulation was estimated to be 76.2%. Statistically significant covariates were patient population (RA subjects vs. healthy subjects), creatinine clearance, and baseline bodyweight on apparent clearance (CL/F) and bodyweight on volume of distribution of the central compartment (Vc/F). The intersubject variability for upadacitinib CL/F and Vc/F were estimated to be 21% and 24%, respectively, in the phase I studies, and 37% and 53%, respectively, in the phase II/III studies. Upadacitinib area under the concentration–time curve (AUC) was estimated to be only 5% higher or lower for RA patients who were < 60 or > 100 kg, respectively, relative to subjects with a bodyweight of 60–100 kg. RA subjects with mild or moderate renal impairment had 13% and 26% higher AUC, respectively, compared with RA subjects with normal renal function. Sex, race, concomitant use of pH-modifying drugs, moderate cytochrome P450 3A inhibitors, or methotrexate use had no effect on upadacitinib exposure. Conclusions A robust population pharmacokinetic model was developed for upadacitinib using a large dataset from phase I–III clinical trials in healthy volunteers and subjects with RA. None of the identified covariates had a clinically meaningful effect on upadacitinib exposures. The model is appropriate to use for simulations and to evaluate the exposure–response relationship of upadacitinib. Electronic supplementary material The online version of this article (10.1007/s40262-019-00739-3) contains supplementary material, which is available to authorized users.

Characterization of the Effect of Hepatic Impairment on Upadacitinib Pharmacokinetics

“…The effect of hepatic impairment on the upadacitinib pharmacokinetics characterized in this study is considered applicable to subjects with immunologic disorders (eg, rheumatoid arthritis). In the population pharmacokinetic analyses across phase 1 to 3 studies encompassing healthy subjects and subjects with RA, baseline AST, ALT, and bilirubin had no impact on upadacitinib exposure, consistent with lack of a clinically meaningful impact of mild and moderate hepatic impairment on the upadacitinib exposure observed in this dedicated phase 1 study. In addition, the effect of renal impairment on upadacitinib exposure was similar in RA patients and non‐RA patients …”

“…The ER formulation of upadacitinib was developed to enable once‐daily dosing in phase 3 studies. Upadacitinib plasma exposure was approximately dose proportional and time independent over the range of IR and ER doses evaluated in clinical studies . The bioavailability of the ER formulation used in this study as well as in phase 3 studies is 76% relative to the IR formulation .…”

“…This study was conducted in accordance with the Food and Drug Administration guidance on conducting pharmacokinetic studies in subjects with impaired hepatic function . Because upadacitinib exhibits linear and time‐independent pharmacokinetics at the doses evaluated in phase 1, phase 2, and phase 3 clinical studies, a single‐dose assessment was considered sufficient to provide adequate information about the impact of the compound on hepatic impairment. Considering that upadacitinib is not extensively bound to plasma proteins (data on file at AbbVie), changes in the free fraction associated with decreased protein binding in hepatic impairment were not anticipated to have a relevant impact on upadacitinib clearance or total exposure.…”

Exposure–Response Analyses for Upadacitinib Efficacy and Safety in the Crohn's Disease CELEST Study and Bridging to the Extended‐Release Formulation

“…The absorption of upadacitinib ER formulation was adequately described by mixed first‐order and zero‐order processes with lag time with upadacitinib bioavailability of 74% from the ER relative to the IR formulation ( Figure ). These results were in agreement with a later analysis conducted using a larger dataset for the ER formulation from upadacitinib RA phase III trials . Summary of upadacitinib model‐predicted plasma exposures for both formulations in patients with CD based on simulations are provided in Table .…”

“…The present analysis estimated the bioavailability of upadacitinib ER formulation to be 74% relative to the IR formulation. This estimate is in close agreement with the relative bioavailability estimate (76%) based on a more extensive dataset for the ER formulation in subjects with RA, which became available after this analysis was conducted . The lower bioavailability of upadacitinib from the ER compared to the IR formulations is potentially due to incomplete release from the ER formulation in vivo .…”