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

Clinical Pharmacokinetics
Ben KlünderAhmed A Othman

Abstract

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. 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. 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...Continue Reading

References

Jan 1, 1992·Annual Review of Pharmacology and Toxicology·L B Sheiner, T M Ludden
Jan 5, 2002·Journal of Pharmacokinetics and Pharmacodynamics·S L Beal
May 16, 2003·Nature·Gary S Firestein
Jul 2, 2009·Pharmaceutical Research·Klas J F PeterssonMats O Karlsson
Feb 27, 2010·Arthritis and Rheumatism·Paul EmeryUNKNOWN Combination of Methotrexate and Etanercept in Early Rheumatoid Arthritis Trial Group
Feb 9, 2011·The AAPS Journal·Martin BergstrandMats O Karlsson
May 11, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Leslie J DickmannJ Greg Slatter
Feb 4, 2012·Orthopedics·W S Wilkie, Philip Schwieterman
May 14, 2014·Expert Opinion on Investigational Drugs·Peter Norman
Sep 1, 2016·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Shingo NakayamadaYoshiya Tanaka

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Citations

Feb 25, 2018·Expert Opinion on Emerging Drugs·Judith Rademacher, Denis Poddubnyy
Feb 6, 2018·F1000Research·William VainchenkerStefan N Constantinescu
Nov 6, 2018·Expert Review of Clinical Immunology·Lina Serhal, Christopher J Edwards
Jan 12, 2019·Journal of Clinical Pharmacology·Mohamed-Eslam F MohamedAhmed A Othman
Jan 23, 2019·Inflammatory Bowel Diseases·L C S De VriesM E Wildenberg
Apr 12, 2019·Journal of Clinical Pharmacology·Sheryl TruemanAhmed A Othman
Oct 28, 2019·The AAPS Journal·Mohamed-Eslam F MohamedPatrick Marroum
Jun 14, 2019·Clinical Pharmacology and Therapeutics·Mohamed-Eslam F MohamedAhmed A Othman
Nov 19, 2019·Expert Opinion on Investigational Drugs·Jing WuChanghai Ding
Mar 12, 2020·Journal of Crohn's & Colitis·Pavine L C Lefevre, Niels Vande Casteele
Dec 24, 2019·Clinical Pharmacokinetics·Mohamed-Eslam F MohamedAhmed A Othman
May 6, 2020·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Vijayabhaskar VeeravalliNuggehally R Srinivas
Feb 20, 2020·Journal of Cellular Physiology·Arezoo HosseiniBehzad Baradaran
Oct 24, 2019·Drugs·Sean Duggan, Susan J Keam
Aug 11, 2020·American Journal of Clinical Dermatology·Sandra FerreiraTiago Torres
Sep 10, 2020·Biologics : Targets & Therapy·Maria Sole ChimentiRoberto Perricone
Aug 3, 2020·Journal of Clinical Gastroenterology·Scott D LeeEdward V Loftus
Feb 12, 2020·Gastroenterology·William J SandbornJulian Panes
Jun 11, 2021·Clinical Pharmacology in Drug Development·Mohamed-Eslam F MohamedAhmed A Othman
Dec 4, 2021·Expert Review of Clinical Immunology·Maryam A AdasKatie Bechman
Jan 12, 2022·Expert Opinion on Pharmacotherapy·Akpabio Akpabio, Adewale Adebajo
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