Pharmacogenomics of TNF inhibitors

Abstract

Tumor necrosis factor alpha inhibitors (TNFi) are biologic drugs that target TNFα, a key pro-inflammatory cytokine, to suppress disease activity and alleviate symptoms of various autoimmune diseases, including inflammatory bowel disease. This review focuses on the five US FDA-approved TNFi including the monoclonal antibodies Infliximab, Adalimumab, Golimumab, Certolizumab pegol and the soluble TNFα receptor fusion protein Etanercept, with a brief mention of other available biosimilars to TNFi. The review aims to summarize the recent evidence on the pharmacokinetics, pharmacodynamics, and pharmacogenomics of TNFi with a particular focus on Human Leukocyte Antigen (HLA) variants in terms of their genetic contribution to the response to TNFi. HLA variants have been linked to heterogeneity in the efficacy and safety of TNFi among patients. Building on the summarized evidence, the last part of the review discusses the potential clinical utility of testing for pharmacogenetic variants that are linked to the response to TNFi prior to the drug prescription, and it also addresses the future directions to achieve personalized treatment for TNFi users.

Keywords: TNF inhibitors; drug efficacy and safety; genetic variants; human leukocyte antigen; pharmacogenomics.

Figure 1

Timeline of the development and approval of TNF inhibitors along with the structure of TNFα. 1990s: In 1999, Infliximab was approved to treat Crohn’s disease (CD), later it was used for Rheumatoid Arthritis (RA), Ankylosing Spondylitis, and other autoimmune diseases. 2000-05: In 2002, Adalimumab was approved by the FDA to treat RA. Later, it was also used for CD, Psoriatic Arthritis, Juvenile Idiopathic and other diseases. 2006-10: In 2009, Golimumab was approved by the FDA to treat RA and used in combination with methotrexate, which was also later approved for Ankylosing Spondylitis, Ulcerative colitis, and Psoriatic arthritis treatment. 2011-15: In 2011, Infliximab was approved by the FDA for pediatric Ulcerative Colitis treatment, followed by Adalimumab and Golimumab; Adalimumab for CD. 2016-20: In 2018, Certolizumab pegol was used to treat RA, Psoriatic arthritis, CD, Ankylosing Spondylitis, and Psoriatic Arthritis. 2021-22: Ozoralizumab (TS-152) developed by Taisho research institute to treat RA.

Figure 2

Factors influencing the pharmacokinetics of TNFi. BMI, Body Mass Index; SC, Subcutaneous; IMS, Immunosuppressants; FcRn, Neonatal Fc receptor; ↑: increases; ↓: decreases.

Figure 3

Pharmacokinetics and pharmacodynamics of TNF inhibitors. Infliximab is injected intravenously while other TNFi such as Adalimumab, Golimumab, Etanercept, and Certolizumab pegol are given intravenously and subcutaneously. All TNFi circulate via the lymphatic system and absorb into the body by endocytosis. Absorption occurs through different mechanisms, including receptor-mediated endocytosis, fluid phase pinocytosis, phagocytosis, and transcytosis. Metabolism occurs in the liver, while elimination takes place from the body via three different ways: 1) Peripheral tissues, 2) Biliary & Fc-receptor 3) Renal.