Clinical Pharmacology in Adult and Pediatric Inflammatory Bowel Disease

Abstract

This review describes the clinical pharmacology of the major drugs used for the treatment of patients with inflammatory bowel disease (IBD). Pharmacokinetics, drug metabolism, mechanism of action, efficacy, and safety profile are discussed. Some small molecules were developed to act systemically (eg, ozanimod) or locally (eg, aminosalicylates) and thus have disparate pharmacokinetic properties. In addition, locally acting compounds have been optimized to mitigate systemic exposure-eg, budesonide, which undergoes extensive first-pass metabolism-thereby reducing systemic bioavailability and side effects. Other small molecules such as thiopurines are precursors of their active metabolites and differences in genotype or phenotype of metabolizing enzymes may affect efficacy and safety, requiring therapeutic drug monitoring (TDM). Monoclonal antibodies (MAs) are large molecules administered parenterally, and their pharmacokinetics may be influenced not only by the general immunoglobulin (Ig) G metabolism and recycling pathways but also by antigen properties such as antigen distribution and antigen concentration. In addition, antibody structure, host factors, concurrent medications, and immunogenicity may contribute to the substantial inter- and intrapatient variability in drug exposure and response observed for MAs. Current guidelines recommend reactive TDM of tumor necrosis factor antagonists at the time of loss of response. Evidence for proactive TDM and for the role of TDM for biologics with a different mechanism of action is emerging. Although small molecules offer potential benefits over biologics with oral administration and lack of immunogenicity, there may be risk for more systemic side effects due to off-target binding. Understanding drug metabolism, pharmacokinetic characteristics, and mechanism of action are important in selecting the right drug at the right time at the right dose for patients with IBD.10.1093/ibd/izy189_video1izy189.video15786062223001.

Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases

“…Filgotinib has been shown to improve other diseases such as moderate to severe CD (Ananthakrishnan, 2017; Fiorino et al, 2018). Clinical efficacy of filgotinib was shown in a Phase II study in CD (FITZROY; Danese, Fiorino, & Peyrin‐Biroulet, 2017; Hemperly, Sandborn, & Vande Casteele, 2018; Kish, 2018). Following the FITZROY study, clinical remission, improved quality of life and a notable decrease in pSTAT3 levels were observed (Vermeire et al, 2016a, 2016b; Vermeire, De Hertogh, et al, 2017).…”

“…In addition, treatment with filgotinib after 10 weeks, global histology activity score (GHAS) was significantly improved and macroscopic changes were seen in colonic simplified endoscopic score for CD (CSES‐CD; Christopher, Vipul, Niels, & Gastroenterology, 2019; Reinisch et al, 2018). However, JAK1 inhibitor filgotinib demonstrated serious adverse events compared with placebo at 75% versus 67%, respectively (Fiorino et al, 2018; Hemperly et al, 2018).…”

Targeting Cytokine Signaling and Lymphocyte Traffic via Small Molecules in Inflammatory Bowel Disease: JAK Inhibitors and S1PR Agonists

“…More recently, antibodies with a different mechanism of action (MOA), such as anti-integrin α4β7 (vedolizumab) and anti-IL12/IL23 (ustekinumab), became available for clinical use (Olivera et al, 2016). However, mAbs have limitations in terms of safety, cost, and sustained efficacy (Hemperly et al, 2018). In fact, around 10–30% of patients treated with anti-TNF are primary non-responders to therapy, and 23–46% are secondary non-responders (Hemperly et al, 2018).…”

“…However, mAbs have limitations in terms of safety, cost, and sustained efficacy (Hemperly et al, 2018). In fact, around 10–30% of patients treated with anti-TNF are primary non-responders to therapy, and 23–46% are secondary non-responders (Hemperly et al, 2018). For these reasons, novel orally available drugs are still in great need and are being developed to treat IBD.…”

Clinical Pharmacology of Janus Kinase Inhibitors in Inflammatory Bowel Disease

“… 2 , 3 Conventional therapy for IBD includes aminosalicylates, glucocorticoids, and immunomodulators. 4 Although various agents are effective for inducing and maintaining remission, about 20% of patients are treatment-refractory and require surgery. 5 Immunosuppressive therapy includes antibody-based biologics, which are administered parenterally and are often associated with adverse effects [AEs] and/or loss of response to therapy, due to immunogenicity.…”