Evaluating the pharmacokinetics of upadacitinib for the treatment of moderate-to-severe Crohn’s disease

ABSTRACT

Introduction

Janus kinases (JAK) are enzymes involved in signaling pathways that activate the immune system. Upadacitinib, an oral small molecule, is the first JAK inhibitor approved by FDA and EMA for the treatment of moderately to severely active Crohn’s disease (CD), following successful phase II and III trials. Compared to other JAK inhibitors, upadacitinib has a high selectivity toward JAK1. This characteristic could improve its efficacy and safety.

Areas covered

This review provides an overview of the available knowledge on the pharmacokinetics of upadacitinib as induction and maintenance therapy for CD.

Expert opinion

The approval of newer targeted small molecules drug, including JAK inhibitors, marked a significant advancement in terms of effectiveness. In fact, the oral administration, the rapid absorption, the excellent bioavailability and the short serum time of maximum concentration are some of the advantages compared to biologics. The selective inhibition of JAK1 by upadacitinib allows for high efficacy while maintaining a reliable safety profile.

KEYWORDS:

• Upadacitinib
• Crohn’s disease
• pharmacokinetics
• targeted small molecules
• inflammatory bowel disease

Article highlights

• Upadacitinib is an oral selective inhibitor of Janus Kinase 1.

• Upadacitinib exhibits a rapid mechanism of action, with a time to reach maximal concentration of 1 to 3 hours.

• Upadacitinib can be administered regardless of food intake, and dosage adjustment is not necessary in cases of renal or liver impairment.

• PK analyses showed that clinical and endoscopic remission rates increased with higher upadacitinib plasma exposure.

• Upadacitinib was discontinued in only 5-10% of cases due to adverse events, and serious adverse events were rare.

• Insufficient data exists on the use and pharmacokinetics of upadacitinib in elderly, pregnant, post-surgery, and pediatric populations that requires further investigation.

Declaration of interest

F D’Amico has served as a speaker for Sandoz, Janssen, Galapagos, and Omega Pharma; he also served as an advisory board member for Abbvie, Ferring, Galapagos, and Nestlè. M Allocca has received consulting fees from Nikkiso Europe, Mundipharma, Janssen, AbbVie, Ferring, and Pfizer. F Furfaro received consulting fees from Amgen, AbbVie and lecture fees from Janssen and Pfizer. G Fiorino received consultancy fees from Ferring, MSD, AbbVie, Takeda, Janssen, Amgen, Sandoz, Samsung Bioepis, and Celltrion. Laurent Peyrin-Biroulet declares personal fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSE Immunotherapeutics, Enthera, Theravance, Pandion Therapeutics, Gossamer Bio, Viatris and Thermo Fisher, grants from Abbvie, MSD, Takeda and Fresenius Kabi, and stock options from CTMA. S Danese has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson and Johnson, Millenium Takeda, MSD, Nikkiso Europe GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma and Vifor. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.