Reverse metabolomics for the discovery of chemical structures from humans.

Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis1,2, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4+ T cells3 and agonism of the pregnane X receptor4. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.

Noninvasive Targeted Crohn Disease Management by Combining Endoscopic Healing Index and Therapeutic Drug Monitoring.

Background and Aims: Therapeutic drug monitoring (TDM) with measurement of serum drug and antidrug antibody concentrations is used to optimize tumor necrosis factor antagonists (anti-TNF). The endoscopic healing index (EHI) is a validated serum-based assay to measure mucosal inflammation in adults with Crohn disease (CD). Our objectives were to evaluate the relationship between EHI and TDM results and to determine the anti-TNF concentration range associated with EHI <20 (consistent with endoscopic remission). Methods: Adult and pediatric patients with CD (N = 1731) were selected retrospectively from a clinical laboratory cohort. Patients were selected if they had an ICD-10 code for CD and if results for EHI and TDM were available within 30 days of each other. The relationship between EHI and TDM results was examined and the anti-TNF concentration range associated with EHI <20 vs >50 was evaluated. Results: Median anti-TNF concentration was higher in patients with EHI <20 vs >50 for infliximab (N = 796): 11.1 vs 3.4 µg/mL and for adalimumab (N = 935): 9.2 vs 5.0 µg/mL (P < 0.0001 both drugs). Patients with antibodies to infliximab (12.8%) or adalimumab (14.9%) had lower anti-TNF concentrations (P < 0.001 both drugs) and higher EHI (P < 0.01 both drugs). The concentration range for infliximab: 5-15 µg/mL (5-9 µg/mL in pediatric patients) and for adalimumab: 5-10 µg/mL (8 µg/mL in pediatric patients) best discriminated EHI <20 vs >50. Conclusions: We report the anti-TNF concentration range associated with EHI <20. Combined testing of EHI and TDM is proposed as a noninvasive approach for treat-to-target management which could improve the ability to monitor disease and optimize anti-TNF therapy.

Baseline Clearance of Infliximab Is Associated With Requirement for Colectomy in Patients With Acute Severe Ulcerative Colitis.

BACKGROUND & AIMS: Hospitalized patients with acute severe ulcerative colitis (ASUC) often require surgery. Although the tumor necrosis factor antagonist infliximab is an effective salvage therapy to prevent colectomy in patients with ASUC, optimal dosing is unclear. Calculated infliximab clearance has been associated with important outcomes in patients with ulcerative colitis, but its utility in patients with ASUC has not been established. We assessed the relationship between calculated the baseline infliximab clearance before infliximab salvage therapy and the requirement for colectomy in patients hospitalized for ASUC. METHODS: We obtained data from hospitalized patients with ASUC who initiated infliximab therapy. We then calculated the baseline infliximab drug clearance in these patients based on an existing formula. The primary aim was to compare clearance between patients who required colectomy 6 months later and patients who did not require colectomy. Receiver operating characteristic curve analyses evaluated clearance thresholds for colectomy. Multivariable logistic regression analysis evaluated factors associated with colectomy. RESULTS: In 39 patients with ASUC, the median baseline calculated clearance was higher in patients requiring colectomy at 6 months than in patients without colectomy (0.733 vs 0.569 L/d; P = .005). An infliximab clearance threshold of 0.627 L/d identified patients who required colectomy with 80.0% sensitivity and 82.8% specificity (area under the curve, 0.80). A higher proportion of patients with infliximab clearance of 0.627 L/d or more underwent colectomy within 6 months (61.5%) than patients with lower infliximab clearance values (7.7%) (P = .001). Multivariable analysis identified baseline infliximab clearance as the only factor associated with colectomy. The infliximab dose in the hospital was higher in patients who required colectomy. Results were similar at 30 days and 1 year. CONCLUSIONS: In patients hospitalized with ASUC, higher values of calculated infliximab clearance before infliximab administration is associated with higher rates of colectomy. Although patients who required colectomies received higher doses, data on infliximab concentrations are lacking. Infliximab pharmacokinetic models are needed for patients with ASUC to allow comparative trials on clearance-based vs standard dosing.

Clinical Pharmacology in Adult and Pediatric Inflammatory Bowel Disease.

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.

Clinical Pharmacokinetics and Pharmacodynamics of Infliximab in the Treatment of Inflammatory Bowel Disease.

Infliximab was the first monoclonal antibody to be approved for the treatment of pediatric and adult patients with moderately to severely active Crohn's disease (CD) and ulcerative colitis (UC). It has been shown to induce and maintain both clinical remission and mucosal healing in pediatric and adult patients with inflammatory bowel disease (IBD) who are unresponsive or refractory to conventional therapies. The administration of infliximab is weight-based and the drug is administered intravenously. The volume of distribution of infliximab is low and at steady state ranges from 4.5 to 6 L. Therapeutic monoclonal antibodies, such as immunoglobulins, are cleared from the circulation primarily by catabolism. Median infliximab half-life is approximately 14 days. Infliximab concentration-time data in patients with CD and UC have been shown to be highly variable within an individual patient over time and between individuals by multiple population pharmacokinetic models. Covariates that have been identified to account for a part of the observed inter- and intra-individual variability in clearance are the presence of antidrug antibodies, use of concomitant immunomodulators, degree of systemic inflammation, serum albumin concentration, and body weight, which can affect the pharmacodynamic response. This article provides a comprehensive review of the clinical pharmacokinetics and pharmacodynamics of infliximab, as well as the role of therapeutic drug monitoring in the treatment of IBD.