A Gastroenterologist's guide to drug interactions of small molecules for inflammatory bowel disease.

Small molecule drugs are becoming increasingly used in the treatment of inflammatory bowel diseases (IBD). However, unlike monoclonal antibody drugs, which have few interactions with other medications, the pharmacokinetics of small molecule drugs are complex and may be influenced by a myriad of drug-drug interactions (DDI) as well as by patient characteristics and food intake. This review aims to provide a concise practical guide to small molecule drug interactions for the use of IBD physicians. It starts with a brief overview of the main metabolizing enzymes and transporters involved in drug interactions and the Food and Drug Administration's (FDA) approach to determining drug-interaction hazard thresholds. It is then followed by a more detailed review of the pharmacokinetics of five novel small molecules approved in IBD: Tofacitinib, Upadacitinib, Filgotinib, Ozanimod, and Etrasimod, including their known interactions and specific warnings. This review will also inform readers on challenges in determining the actual magnitude of interactions and their clinical relevance, including the arbitrary nature of some hazard thresholds, the inference of the impact on metabolizing enzymes and transporters from single-drug assays which may not reflect poly-pharmaceutical regimens, and other challenges in this field which the IBD physician needs to be cognizant of. In practice, before administering a small molecule drug, it is advisable to evaluate any potential interactions with other medications the patient is receiving. An increased awareness by health care professionals and patients, may reduce the possible risks associated with DDI of small molecule IBD drugs.

Prospective Observational Evaluation of the Time-Dependency of Adalimumab Immunogenicity and Drug Concentration in Ulcerative Colitis Patients: the POETIC II Study.

BACKGROUND AND AIMS: Home self-injection of the human anti-tumour necrosis alpha [anti-TNFα] monoclonal adalimumab complicates prospective serial-sampling studies. Although a recent study examined adalimumab levels and immunogenicity in Crohn's disease [CD] patients, prospective real-world data from ulcerative colitis [UC] patients are lacking. METHODS: A three-monthly home-visit programme from induction was established prospectively for UC patients. Clinical scores were determined at each visit, and sera were obtained for assessment of drug and anti-adalimumab antibody levels. Calprotectin was measured using a smartphone-based app. This cohort was compared to a parallel prospective cohort of adalimumab-treated CD patients [POETIC1]. RESULTS: Fifty UC patients starting adalimumab [median follow-up 28 weeks] were compared to 98 adalimumab-treated CD patients [median follow-up 44 weeks]. Only 11/50 UC patients [22%] continued treatment to the end of the follow-up compared with 50/98 [51%] CD patients (odds ratio [OR] = 0.27, p = 0.001). Loss of response was significantly more common in UC patients [OR = 3.2, p = 0.001]. Seventeen patients [34%] in the UC cohort developed anti-adalimumab antibodies, 9/17 [52.9%] as early as week 2. There was no difference between patient cohorts in the overall development of anti-adalimumab antibodies [34% vs 30.6%, respectively, OR = 1.67, p = 0.67], nor was there a difference in early immunogenicity [OR = 1.39, p = 0.35]. There was no difference in low drug levels [<3 µg/mL] between the two cohorts [OR = 0.87, p = 0.83]. CONCLUSIONS: Loss of response to adalimumab therapy was significantly more common in the UC compared to the CD cohort and was driven by a higher rate of non-immunogenic, pharmacodynamic parameters.

Distal Fecal Wash Host Transcriptomics Identifies Inflammation Throughout the Colon and Terminal Ileum.

BACKGROUND & AIMS: Noninvasive modalities for assessing active endoscopic and histologic inflammation in Crohn's disease and ulcerative colitis patients are critically needed. Fecal wash host shed-cell transcriptomics has been shown to be a robust classifier of endoscopic and histologic inflammation in inflammatory bowel disease patients with distal colitis. Whether such fecal washes can inform on inflammatory processes occurring in more proximal intestinal segments is currently unknown. METHODS: Fifty-nine inflammatory bowel disease patients and 50 controls were prospectively enrolled. Biopsy specimens and fecal washes from the distal colon, proximal colon, and terminal ileum were compared. Host transcriptomics were performed on the biopsy specimens and fecal washes obtained during colonoscopy at predefined locations throughout the colon and terminal ileum and results were associated with concurrent clinical, endoscopic, and histologic parameters. RESULTS: We found that host transcriptomics of distal fecal washes robustly classify histologic inflammation in ileal and proximal colonic Crohn's disease, even without distal colonic involvement (area under the receiver operating characteristic curve, 0.94 ± 0.09). We further found that fecal washes consist of modules of co-expressed genes of immune, stromal, and epithelial origin that are indicative of endoscopic disease severity. Fecal wash host transcriptomics also captures expression of gene modules previously associated with a lack of response to biological therapies. CONCLUSIONS: Our study establishes the accuracy of distal colonic fecal washes for identifying and scoring inflammatory processes throughout the entire ileal-colonic axis.