Upadacitinib pharmacokinetics and exposure-response analyses of efficacy and safety in psoriatic arthritis patients - Analyses of phase III clinical trials

Abstract

Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA) and recently approved by the European Medicines Agency for the treatment of psoriatic arthritis (PsA). The efficacy and safety profile of upadacitinib in PsA have been established in the SELECT-PsA program in two global phase III studies, which evaluated upadacitinib 15 and 30 mg q.d. The analyses described here characterized upadacitinib pharmacokinetics and exposure-response relationships for efficacy and safety endpoints using data from the SELECT-PsA studies. Upadacitinib pharmacokinetics in patients with PsA were characterized through a Bayesian population analysis approach and were comparable to pharmacokinetics in patients with RA. Exposure-response relationships for key efficacy and safety endpoints were characterized using data from 1916 patients with PsA. The percentage of patients achieving efficacy endpoints at week 12 (American College of Rheumatology [ACR]50 and ACR70), 16 and 24 (sIGA0/1) increased with increasing upadacitinib average plasma concentration over a dosing interval, whereas no clear exposure-response trend was observed for ACR20 at week 12 or ACR20/50/70 at week 24 within the range of plasma exposures evaluated in the phase III PsA studies. No clear trends for exposure-response relationships were identified for experiencing pneumonia, herpes zoster infection, hemoglobin less than 8 g/dl, lymphopenia (grade ≥ 3), or neutropenia (grade ≥ 3) after 24 weeks of treatment. Shallow relationships with plasma exposures were observed for serious infections and hemoglobin decrease greater than 2 g/dl from baseline at week 24. Based on exposure-response analyses, the upadacitinib 15 mg q.d. regimen is predicted to achieve robust efficacy in patients with PsA and to be associated with limited incidences of reductions in hemoglobin or occurrence of serious infections.

Trial registration: ClinicalTrials.gov NCT03104374 NCT03104400.

Conflict of interest statement

B.E., J.K.A., and M.F.M. are employees of AbbVie and may hold AbbVie stock or stock options. E.M. and S.G. are former employees of AbbVie and may hold stock or stock options.

© 2021 AbbVie Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1

Goodness‐of‐fit plots of upadacitinib pharmacokinetic model and visual predictive checks (VPCs) of upadacitinib concentration versus time since last dose for patients with PsA stratified by dose (data from phase III PsA studies). (a) Observed versus population predicted concentrations. (b) Observed versus individual predicted concentrations. (c) Conditional weighted residuals versus time since last dose. (d) Conditional weighted residuals versus population predicted concentrations. (e) VPCs 15 mg upadacitinib. (f) VPCs 15 mg upadacitinib. VPCs: The shaded blue areas represent the 95% prediction interval of the 2.5th and 97.5th percentiles of simulated concentrations, the red shaded areas represent the 95% prediction interval of the 50th percentile of simulated concentrations, the solid red line represents median of the observed concentrations and dashed red lines represent the 2.5th and 97.5th percentile of the observed concentrations. PsA, psoriatic arthritis

FIGURE 2

Observed and model‐predicted ACR50 and ACR70 responses (NRI) at week 12 and sIGA 0/1 responses at week 16 and week 24 versus upadacitinib Cavg (final models). The blue solid line represents median predicted response and the blue shaded area represent 95% confidence intervals of the predicted response. The dots and error bars represent median and 95% binomial confidence intervals of binned observed rates. ACR, American College of Rheumatology; Cavg, average plasma concentration

FIGURE 3

Model‐predicted ACR50 and ACR70 response for 15 mg q.d., 30 mg q.d. regimens and placebo at week 12 stratified by covariate subgroups. ACR, American College of Rheumatology; bDMARD, disease‐modifying antirheumatic drugs; BMI, body mass index; DMARD, modifying antirheumatic drugs

FIGURE 4

Observed and model‐predicted percentage of patients with PsA with serious infections, greater than 2 g/dl decrease in hemoglobin, or greater than 2 g/dl with hemoglobin less than the lower limit for normal up to week 24 (final model). The blue solid line represents median predicted response and the blue shaded area represent 95% confidence intervals of the predicted response. The dots and error bars represent median and 95% binomial confidence intervals of binned observed rates. LOCF, last observation carried forward; PsA, psoriatic arthritis