Background and ObjectivesUpadacitinib is a janus kinase (JAK) 1 inhibitor being developed for the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. This work characterized upadacitinib population pharmacokinetics in healthy subjects and RA patients and the effects of covariates on upadacitinib exposure.MethodsUpadacitinib plasma concentrations (n = 6399) from 107 healthy subjects and 466 RA patients from three phase I and two 12-week RA phase IIb trials (1–48 mg immediate-release doses across studies) were analyzed using non-linear mixed-effects modeling. The models were qualified using bootstrap and stochastic simulations.ResultsA two-compartment model with first-order absorption and elimination described upadacitinib pharmacokinetics. Estimates (95% bootstrap confidence interval) for upadacitinib oral clearance, steady-state volume of distribution, absorption lag time, and mean absorption time were 39.7 (37.8–41.5) L/h, 210 (196–231) L, 0.48 (0.47–0.49) h, and 0.08 (0.04–0.12) h, respectively, for a typical healthy male. Matching on other covariates, a 16 and 32% higher upadacitinib area under the concentration–time curve (AUC) was estimated for females relative to males, and for subjects with RA relative to healthy volunteers, respectively. Subjects with RA with mild or moderate renal impairment were estimated to have 16 and 32% higher upadacitinib AUC, respectively, compared with subjects with RA with normal renal function. Upadacitinib clearance was not correlated with body weight.ConclusionsUpadacitinib pharmacokinetics follow dose-proportional, bi-exponential disposition. A slightly lower upadacitinib clearance is estimated in subjects with RA than in healthy volunteers, consistent with observations for other JAK inhibitors. Other covariates (weight, sex, mild or moderate renal impairment) are not associated with clinically relevant effects on upadacitinib exposure.Trial RegistrationClinicalTrials.gov (https://clinicaltrials.gov/) identifiers: NCT01741493, NCT02066389, and NCT01960855.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0605-6) contains supplementary material, which is available to authorized users.

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.

Upadacitinib is a Janus kinase 1 inhibitor developed for treatment of moderate to severe rheumatoid arthritis (RA) and was recently approved by the US Food and Drug Administration for this indication in adults who have had an inadequate response or intolerance to methotrexate. Upadacitinib is currently under regulatory review by other agencies around the world. Ongoing trials are investigating the use of upadacitinib in other inflammatory autoimmune diseases. In this article, we review the clinical pharmacokinetic data available to date for upadacitinib that supported the clinical development program in RA and ultimately regulatory applications for upadacitinib in treatment of patients with moderate to severe RA.

The relationships between upadacitinib, an oral selective Janus kinase 1 inhibitor, plasma exposures, and its efficacy (assessed by the American College of Rheumatology 20%/50%/70% responses over time) in moderate-to-severe active rheumatoid arthritis (RA) were characterized using data from 574 patients, on background methotrexate and inadequate response to methotrexate or anti-TNF therapy, from two phase II trials conducted with twice-daily dosing of an immediate-release formulation. The developed time-continuous Markov models were used to simulate efficacy of once-daily (q.d.). regimens of upadacitinib extended-release incorporating sources of uncertainty. Upadacitinib plasma concentrations associated with 15 and 30 mg extended-release q.d. doses were predicted to achieve that plateau of response across RA subpopulations. Results from these analyses provided the rationale that supported selection and de-risked evaluation of upadacitinib extended-release doses for the first time in >4,000 patients in five large phase III trials.Upadacitinib (ABT-494) is a selective inhibitor of Janus kinase 1 (JAK1), an intracellular tyrosine kinase that mediates receptor signaling for several inflammatory cytokines. 1 The JAKs are a family of four tyrosine kinases (JAK1, 2, and 3, and tyrosine kinase 2) that function as heterodimers or homodimers (for JAK2) to mediate receptor signaling for almost 40 cytokines involved in inflammatory diseases as well as in hematopoiesis and normal immune function. 2 Selective inhibition of JAK1 has the potential to offer advantages over nonspecific inhibition of multiple JAKs by reducing inflammation while limiting the unwanted effects on hematopoiesis and normal immune responses. 3,4 Accordingly, upadacitinib has been or is being evaluated in several phase III studies in rheumatoid arthritis (RA), 5-10 psoriatic arthritis, 11,12 giant cell arteritis, 13 and Crohn's disease, 14,15 and phase II studies in atopic dermatitis, ulcerative colitis, and ankylosing spondylitis. [16][17][18] Upadacitinib was evaluated in two phase IIb studies in patients with RA who were inadequate responders to anti-TNF

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