Population Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects with Rheumatoid Arthritis: Analyses of Phase I and II Clinical Trials

Abstract

Background and objectives: Upadacitinib 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.

Methods: Upadacitinib 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.

Results: A 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.

Conclusions: Upadacitinib 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 registration: ClinicalTrials.gov ( https://ichgcp.net/clinical-trials-registry/NCT01741493" title="See in ClinicalTrials.gov">NCT01741493, NCT02066389, and NCT01960855.

Conflict of interest statement

Funding

The studies were sponsored by AbbVie. AbbVie contributed to the study design, research, and interpretation of data, and the writing, review, and approval of the publication. Medical writing support was provided by Therese Stickler under contract with AbbVie.

Conflict of interest

Drs. Klünder, Mohamed, and Othman are employees and shareholders of AbbVie.

Ethical approval

The studies were conducted in accordance with Good Clinical Practice guidelines and the ethical principles that have their origin in the Declaration of Helsinki. The protocols and informed consent forms were approved by the Institutional Review Board at each site.

Informed consent

All participants provided written informed consent before any study-related procedures were performed.

Figures

Fig. 1

Individual and population-predicted upadacitinib concentration versus observed upadacitinib concentration

Fig. 2

Conditional weighted residuals versus time since last dose and versus population-predicted upadacitinib concentration

Fig. 3

Visual predicted check for observed and model-simulated upadacitinib plasma concentrations versus time since last dose for subjects with rheumatoid arthritis, stratified by dose. The solid red line represents the median observed plasma concentration, and the shaded red area represents a simulation-based 95% confidence interval for the median. The observed 5 and 95% percentiles are presented with dashed red lines, and the 95% confidence intervals for the corresponding model-predicted percentiles are shown as shaded blue areas

Fig. 4

Effect of covariates on upadacitinib exposures in rheumatoid arthritis patients (mean ratio and 90% confidence interval). Reference groups for the ratios presented: males (reference for females), body weight ≥ 60 kg and ≤ 100 kg (for body weight effect), and CrCL ≥ 90 mL/min (for CrCL effect). CrCL creatinine clearance, Cmax maximum concentration, AUC area under the concentration–time curve