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Abstract

We thank Dr Cui et al1Cui D. et al.Clin Gastroenterol Hepatol. 2016; 14: 1509-1510Scopus (1) Google Scholar for their letter. They allude to 2 concepts that could possibly impact the results observed2Ungar B. et al.Clin Gastroenterol Hepatol. 2016; 14: 550-557Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar; one concept is that of factors influencing anti–tumor necrosis factor (TNF) drug clearance, and the second relates to drug levels in tissue. For the first concept, we agree that clearance of infliximab is influenced by several factors such as weight, albumin, immunogenicity, and the degree of systemic inflammation that may impact clearance by target-mediated drug disposition.3Fasanmade A.A. et al.Eur J Clin Pharmacol. 2009; 65: 1211-1228Crossref PubMed Scopus (256) Google Scholar In addition, variable infliximab breakdown by metalloproteinases in tissue may also impact drug clearance.4Biancheri P. et al.Gastroenterology. 2015; 149: 1564-1574Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar However, these factors are primarily implicated in the clearance and pharmacokinetics of anti-TNFs, thereby influencing the levels of drug in the blood. Our study explored correlation between anti-TNF blood levels with the rate of mucosal healing at a colonoscopy performed in conjunction with drug level determination. In essence, drug levels are the outcome of the interplay between the various factors delineated by Cui et al.1Cui D. et al.Clin Gastroenterol Hepatol. 2016; 14: 1509-1510Scopus (1) Google Scholar This makes it less likely that factors accelerating clearance, such as fecal loss, will independently have effects on mucosal healing beyond their effects on the final drug level. Moreover, a recent pharmacokinetic modeling study concluded that drug level determination is significantly more accurate for drug-dosing prediction than any set of pre-identified factors including albumin, weight, and immunogenicity.5Dotan I. et al.Inflamm Bowel Dis. 2014; 20: 2247-2259Crossref PubMed Scopus (196) Google Scholar This implies that other unidentified factors may play a more important role in determining interindividual variability of infliximab and adalimumab pharmacokinetics. We agree with the second concept, namely that levels of drug in blood may not optimally reflect the drug level in tissue and the therapeutic effect of the drug in the target organ. Indeed, a model incorporating blood levels with tissue drug levels may aid in better tailoring of anti-TNF regimens to achieve optimal control of inflammation and clinical outcomes in the future. Such a model may need to also accommodate local tissue effects on drug such as local cleavage, complex formation, or neutralization, which mitigate the neutralization of TNF-alpha by the drug. Finally, we also caution once more against drawing causality inference from our work, which describes association between drug levels and inflammation outcomes. The inflammatory bowel disease community awaits interventional studies to examine the effect of drug levels on mucosal healing and inflammation control. Optimizing Therapeutic Drug Monitoring of Tumor Necrosis Factor-α Antagonists in Patients With Inflammatory Bowel DiseasesClinical Gastroenterology and HepatologyVol. 14Issue 10PreviewIt was with great interest that we read the Israeli population–based retrospective study of patients with inflammatory bowel disease treated with infliximab or adalimumab by Ungar et al.1 In this article, the correlation between tumor necrosis factor-α (TNF-α) antagonist levels and mucosal healing were evaluated, and serum levels of 6 to 10 mg/mL for infliximab and 8 to 12 mg/mL for adalimumab were required to achieve mucosal healing in 80% to 90% of patients with inflammatory bowel disease. We would like to share some comments and questions. Full-Text PDF