Pharmacokinetic review of janus kinase inhibitors and its clinical implications for the management of rheumatoid arthritis

ABSTRACT

Introduction

In the realm of autoimmune rheumatic diseases, understanding JAK inhibitors (JAKi) nuances is vital. Baricitinib, tofacitinib, upaacitinib, filgotinib, and peficitinib exhibit subtle yet impactful pharmacokinetic (PK) and pharmacodynamic (PD) variations.

Areas covered

This narrative review critically assesses PK and PD distinctions among globally approved JAKi for rheumatoid arthritis, which primarily guide clinical decisions in autoimmune diseases, particularly rheumatoid arthritis. It explores the intricate JAK-STAT signaling pathway, offering insights into JAKs’ roles in inflammation, hematopoiesis, and immune homeostasis. Emphasis on PK parameters, including absorption, distribution, metabolism, and excretion, along with CYP3A4 drug interactions, is highlighted. The review underscores integrating PK and PD properties, considering patient-specific factors like hepatic and renal clearance, for judicious JAKi selection in RA and related autoimmune conditions. The literature has been collected from all available databases based on the review question.

Expert opinion

Integrating PK and PD properties with patient-specific factors is pivotal for judicious JAKi selection. Recognizing disparities in PK and PD across diseases, ethnicities, and environmental factors is crucial for personalized JAKi choices. This expert opinion underscores the significance of a second compartment analysis, elucidating the interplay between PK and PD and its impact on JAKi efficacy.

KEYWORDS:

• Baricitinib
• tofacitinib
• upadacitinib
• filgotinib
• and peficitinib
• JAKi

Article highlights

• This review explores the PK and PD characteristics of JAKi critical for the management of RA and related autoimmune conditions.

• The article examines the subtle differences in affinity and molecular domains of globally approved JAKi (baricitinib, tofacitinib, upadacitinib, filgotinib, peficitinib), which have significant impact on their clinical effects and adverse event profiles.

• PK parameters including absorption, distribution, metabolism, and excretion (ADME), alongside CYP3A4 drug interactions, are highlighted as key determinants of JAKi efficacy and safety in RA treatment.

• Integrating PK and PD properties with patient-specific factors such as hepatic and renal clearance is imperative for informed and judicious selection of JAKi in RA and other autoimmune diseases.

• The review addresses the significance of ethnic variability in PK profiles, guiding personalized JAKi choices and dosage adjustments to optimize treatment outcomes in diverse patient populations.

• The article underscores the need for further research to elucidate JAKi disparities across diseases, ethnicities, and environmental factors, to customize treatment strategies and enhance therapeutic efficacy in autoimmune diseases.

Declaration of interest

The author has no 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

One reviewer received honoraria: Pfizer, Astellas Pharma Inc, AbbVie, Bristol-Myers Squibb, Eli lilly Japan K.K, Eisai Pharma and Gilead G.K.

Additional information

Funding

This paper was not funded.