Optimizing Therapies Using Therapeutic Drug Monitoring: Current Strategies and Future Perspectives

Therapeutic drug monitoring (TDM) has emerged as a strategy for treatment optimization in inflammatory bowel diseases to maximize benefit and to reach more stringent, objective end points. Optimal drug concentrations in inflammatory bowel disease vary according to treatment target, disease phenotype, inflammatory burden, and timing of sampling during the treatment cycle. This review provides an update on TDM with biologic and oral small molecules, evaluates the role of reactive vs proactive TDM, and identifies the gaps in current evidence. In the future, adaptations to how we use TDM may contribute further to the goal of personalized treatment in patients with IBD. Therapeutic drug monitoring (TDM) has emerged as a strategy for treatment optimization in inflammatory bowel diseases to maximize benefit and to reach more stringent, objective end points. Optimal drug concentrations in inflammatory bowel disease vary according to treatment target, disease phenotype, inflammatory burden, and timing of sampling during the treatment cycle. This review provides an update on TDM with biologic and oral small molecules, evaluates the role of reactive vs proactive TDM, and identifies the gaps in current evidence. In the future, adaptations to how we use TDM may contribute further to the goal of personalized treatment in patients with IBD. Krisztina B. GecseView Large Image Figure ViewerDownload Hi-res image Download (PPT) The introduction of anti-tumor necrosis factor (TNF) drugs revolutionized the medical management of inflammatory bowel diseases (IBD). Since then, the expanding treatment armamentarium has allowed treatment targets to evolve from symptomatic disease control to objective targets, such as endoscopic and biomarker end points, which have been associated with improved long-term outcomes.1Turner D. Ricciuto A. Lewis A. et al.STRIDE-II: an update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD.Gastroenterology. 2021; 160: 1570-1583Abstract Full Text Full Text PDF PubMed Scopus (910) Google Scholar The rationale for therapeutic drug monitoring (TDM) is based on, on one hand, exposure-response studies that demonstrate association between higher drug or metabolite concentrations and improved therapeutic outcomes, and on the other hand, studies that assess the utility of TDM in clinical practice. While the former generally derive from post hoc analysis of randomized controlled trials (RCTs), the latter group mostly includes retrospective studies, but also includes a handful of RCTs and prospective studies. Based on these data, TDM has emerged as a strategy for treatment optimization, although several challenges still remain. Firstly, optimal cutoffs for drug levels remain uncertain and dependent on treatment targets.2Vermeire S. Dreesen E. Papamichael K. et al.How, when, and for whom should we perform therapeutic drug monitoring?.Clin Gastroenterol Hepatol. 2020; 18: 1291-1299Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Secondly, the turnover of the results is currently prone to cause a lag between testing and dose adaptation. Thirdly, pharmacokinetics (PK) is dependent on several patient-related as well as disease-related factors such as inflammatory burden or disease phenotype.3Hindryckx P. Novak G. Vande Casteele N. et al.Review article: dose optimisation of infliximab for acute severe ulcerative colitis.Aliment Pharmacol Ther. 2017; 45: 617-630Crossref PubMed Scopus (67) Google Scholar The aim of this review is to provide an update on the evidence behind TDM, to identify gaps in the evidence that drives use of TDM, and to consider the future of TDM. Much of the understanding of TDM for thiopurines comes from a time when thiopurine monotherapy was common. While in much of the world azathioprine and mercaptopurine are largely now used only in combination with anti-TNF agents, there remains a role for TDM when using thiopurines both as monotherapy and as combination therapy. Indeed, much of the interest in TDM in IBD has probably been driven by our desire to optimize thiopurine use when alternative treatments were limited. Thiopurines are pro-drugs that undergo metabolism through a number of enzymatic steps, resulting in 2 main metabolites of interest, the active metabolites, the thioguanine nucleotides (TGNs) and the methylated metabolites (methylmercaptopurine [MMP]), which are implicated in adverse effects. Azathioprine undergoes conversion to mercaptopurine after absorption, which is then further metabolized through 1 of 3 pathways, 1 of which, the salvage pathway, results in the production of the active metabolites collectively known as the TGNs.4Dart R.J. Irving P.M. Optimising use of thiopurines in inflammatory bowel disease.Expert Rev Clin Immunol. 2017; 13: 877-888Crossref PubMed Scopus (15) Google Scholar However, the greatest regulation of mercaptopurine metabolism depends on the activity of thiopurine S-methyltransferase, which results in the production of MMPs. High activity increases MMP production, which is associated with an increased risk of hepatotoxicity and also results in low levels of TGNs and hence lack of efficacy. Conversely, low activity of thiopurine S-methyltransferase is associated with greater metabolism towards TGN and hence an increased risk of myelotoxicity. The ability to measure both TGNs and MMPs in red blood cells resulted in studies investigating the association of these metabolites with therapeutic response as well as with adverse effects.5Dubinsky M.C. Lamothe S. Yang H.Y. et al.Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease.Gastroenterology. 2000; 118: 705-713Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar Meta-analyses confirmed the association between TGN concentration and therapeutic effect, with 1 study describing a 3-fold increase rate of clinical remission in patients with levels >230 to 260 pmol/8 × 108 erythrocytes (odds ratio [OR], 3.15; 95% confidence interval [CI], 2.41–4.11) and another identifying a cutoff of 397 pmol/8 × 108 erythrocytes for mucosal healing in Crohn's disease (CD) (OR, 3.3; 95% CI, 1.3–8.0; P = .009).6Osterman M.T. Kundu R. Lichtenstein G.R. et al.Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis.Gastroenterology. 2006; 130: 1047-1053Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar, 7Moreau A.C. Paul S. Del Tedesco E. et al.Association between 6-thioguanine nucleotides levels and clinical remission in inflammatory disease: a meta-analysis.Inflamm Bowel Dis. 2014; 20: 464-471Crossref PubMed Scopus (78) Google Scholar, 8Mao R. Guo J. Luber R. et al.6-Thioguanine nucleotide levels are associated with mucosal healing in patients with Crohn's disease.Inflamm Bowel Dis. 2018; 24: 2621-2627Crossref PubMed Google Scholar Publications describing associations between drug levels and therapeutic response abound in IBD, yet high-quality studies that investigate TDM-driven interventions are rare. Observational studies provide support for dose optimization of thiopurines in IBD and real-world retrospective analyses of the benefits of measuring TGNs support these findings.9Smith M. Blaker P. Patel C. et al.The impact of introducing thioguanine nucleotide monitoring into an inflammatory bowel disease clinic.Int J Clin Pract. 2013; 67: 161-169Crossref PubMed Scopus (47) Google Scholar, 10Wright S. Sanders D.S. Lobo A.J. et al.Clinical significance of azathioprine active metabolite concentrations in inflammatory bowel disease.Gut. 2004; 53: 1123-1128Crossref PubMed Scopus (124) Google Scholar, 11Hindorf U. Lyrenas E. Nilsson A. et al.Monitoring of long-term thiopurine therapy among adults with inflammatory bowel disease.Scand J Gastroenterol. 2004; 39: 1105-1112Crossref PubMed Scopus (55) Google Scholar, 12Gupta P. Gokhale R. Kirschner B.S. 6-mercaptopurine metabolite levels in children with inflammatory bowel disease.J Pediatr Gastroenterol Nutr. 2001; 33: 450-454Crossref PubMed Scopus (85) Google Scholar, 13Roblin X. Serre-Debeauvais F. Phelip J.M. et al.6-tioguanine monitoring in steroid-dependent patients with inflammatory bowel diseases receiving azathioprine.Aliment Pharmacol Ther. 2005; 21: 829-839Crossref PubMed Scopus (54) Google Scholar To date, however, only 2 studies have assessed the use of dose optimization in a prospective, controlled manner.14Reinshagen M. Schutz E. Armstrong V.W. et al.6-thioguanine nucleotide-adapted azathioprine therapy does not lead to higher remission rates than standard therapy in chronic active Crohn disease: results from a randomized, controlled, open trial.Clin Chem. 2007; 53: 1306-1314Crossref PubMed Scopus (96) Google Scholar,15Dassopoulos T. Dubinsky M.C. Bentsen J.L. et al.Randomised clinical trial: individualised vs weight-based dosing of azathioprine in Crohn's disease.Aliment Pharmacol Ther. 2014; 39: 163-175Crossref PubMed Scopus (66) Google Scholar Neither showed benefit of dose optimization, yet both had methodologic issues that limited their findings.4Dart R.J. Irving P.M. Optimising use of thiopurines in inflammatory bowel disease.Expert Rev Clin Immunol. 2017; 13: 877-888Crossref PubMed Scopus (15) Google Scholar It is a shame that high-quality studies have failed to define the use of thiopurine metabolite testing; however, perhaps in the current therapeutic climate, there are more relevant questions to answer. Nevertheless, thiopurines play an important role in preventing loss of response to anti-TNF therapy16Colombel J.F. Sandborn W.J. Reinisch W. et al.Infliximab, azathioprine, or combination therapy for Crohn's disease.N Engl J Med. 2010; 362: 1383-1395Crossref PubMed Scopus (2633) Google Scholar and can both prevent immunogenicity to a second anti-TNF agent as well as reverse immunogenicity once it develops.17Roblin X. Williet N. Boschetti G. et al.Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial.Gut. 2020; 69: 1206-1212Crossref PubMed Scopus (96) Google Scholar, 18Ungar B. Kopylov U. Engel T. et al.Addition of an immunomodulator can reverse antibody formation and loss of response in patients treated with adalimumab.Aliment Pharmacol Ther. 2017; 45: 276-282Crossref PubMed Scopus (97) Google Scholar, 19Ben-Horin S. Waterman M. Kopylov U. et al.Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease.Clin Gastroenterol Hepatol. 2013; 11: 444-447Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar While anti-TNF agents are no longer the only advanced therapy available, they remain the most widely used, and with the advent of vastly cheaper biosimilars, will continue to be used in IBD for some time. Accordingly, the role of TGN monitoring in patients on combination therapy is still relevant. Several studies have examined the relationship between TGN concentration and infliximab (IFX) levels. It is also noteworthy that the prospective Personalised Anti-TNF in Crohn's Disease (PANTS) study, which recruited approximately 1600 patients initiating anti-TNF therapy, showed a dose-response relationship between thiopurine dose and immunogenicity, at least for IFX; TGN testing, however, was not performed in this study.20Kennedy N.A. Heap G.A. Green H.D. et al.Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study.Lancet Gastroenterol Hepatol. 2019; 4: 341-353Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar Where the relationship between TGN concentration and anti-TNF drug levels has been explored, some, but not all, studies have suggested that a lower therapeutic threshold may apply; a cutoff of 125 pmol/8 × 108 erythrocytes (area under [AU] receiver operating characteristic [ROC] curve [AUROC], 0.86; P < .001) has been suggested.21Kariyawasam V.C. Ward M.G. Blaker P.A. et al.Thiopurines dosed to a therapeutic 6-thioguanine level in combination with adalimumab are more effective than subtherapeutic thiopurine-based combination therapy or adalimumab monotherapy during induction and maintenance in patients with long-standing Crohn's disease.Inflamm Bowel Dis. 2017; 23: 1555-1565PubMed Google Scholar, 22Luber R.P. Dawson L. Munari S. et al.Thiopurines and their optimization during infliximab induction and maintenance: a retrospective study in Crohn's disease.J Gastroenterol Hepatol. 2021; 36: 990-998Crossref PubMed Scopus (4) Google Scholar, 23Roblin X. Boschetti G. Williet N. et al.Azathioprine dose reduction in inflammatory bowel disease patients on combination therapy: an open-label, prospective and randomised clinical trial.Aliment Pharmacol Ther. 2017; 46: 142-149Crossref PubMed Scopus (101) Google Scholar, 24Yarur A.J. Kubiliun M.J. Czul F. et al.Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy.Clin Gastroenterol Hepatol. 2015; 13: 1118-1124.e3Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar Like thiopurines, the role for methotrexate in IBD is now largely limited to prevention of immunogenicity to anti-TNF agents. Interesting observational data regarding the measurement of methotrexate polyglutamates in patients with IBD have yet to be tested in clinical trials, which are, in reality, unlikely to happen in the current era.25Morrow R. Funk R. Becker M. et al.Potential role of methotrexate polyglutamates in therapeutic drug monitoring for pediatric inflammatory bowel disease.Pharmaceuticals (Basel). 2021; 14: 463Crossref PubMed Scopus (4) Google Scholar,26Brooks A.J. Begg E.J. Zhang M. et al.Red blood cell methotrexate polyglutamate concentrations in inflammatory bowel disease.Ther Drug Monit. 2007; 29: 619-625Crossref PubMed Scopus (45) Google Scholar Therefore, perhaps the only role for TDM of methotrexate will be in the identification of poor adherence.27Taylor K.M. Irving P.M. Optimization of conventional therapy in patients with IBD.Nat Rev Gastroenterol Hepatol. 2011; 8: 646-656Crossref PubMed Scopus (70) Google Scholar Tofacitinib, a nonselective Janus kinase inhibitor licensed in ulcerative colitis (UC), is characterized by a dose-response relationship both in terms of efficacy and adverse effects. Population PK analysis in patients with moderate to severe UC has been performed based on the phase 2 and 3 development program.28Vong C. Martin S.W. Deng C. et al.Population pharmacokinetics of tofacitinib in patients with moderate to severe ulcerative colitis.Clin Pharmacol Drug Dev. 2021; 10: 229-240Crossref PubMed Scopus (8) Google Scholar The study concluded that dose adjustment was not required based on weight, sex, age, race, prior TNF exposure, or baseline disease activity. Similar PK findings were seen in patients with rheumatoid arthritis, suggesting that unlike for biologics, colonic inflammation does not influence tofacitinib PK, although intriguing data derived from animal experiments suggest that colonic inflammation increases plasma tofacitinib concentrations.29Texler B. Zollner A. Reinstadler V. et al.Tofacitinib-induced modulation of intestinal adaptive and innate immunity and factors driving cellular and systemic pharmacokinetics.Cell Mol Gastroenterol Hepatol. 2021; 13: 383-404Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Plasma concentrations of tofacitinib were not, however, related to response in the phase 2 and 3 studies, and patients with low plasma levels did not demonstrate loss of response to treatment.30Mukherjee A. Hazra A. Smith M.K. et al.Exposure-response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis: Results from a dose-ranging phase 2 trial.Br J Clin Pharmacol. 2018; 84: 1136-1145Crossref PubMed Scopus (27) Google Scholar In addition, given that tofacitinib metabolites account for only 10% of radioactivity identified after receiving radiolabeled tofacitinib, it also seems unlikely that they will emerge as a useful tool in terms of TDM.31Dowty M.E. Lin J. Ryder T.F. et al.The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans.Drug Metab Dispos. 2014; 42: 759-773Crossref PubMed Scopus (177) Google Scholar Similarly, in the SELECTION ((Study to Evaluate the Efficacy and Safety of Filgotinib in the Induction and Maintenance of Remission in Adults With Moderately to Severely Active Ulcerative Colitis ) registration trial of filgotinib for UC, drug exposures overlapped between patients who achieved the primary end point of the study (clinical remission) and those who did not.32Feagan B.G. Danese S. Loftus Jr., E.V. et al.Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial.Lancet. 2021; 397: 2372-2384Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar Overall, therefore, while formal studies have not been performed, the role for TDM using plasma levels for Janus kinase inhibitors seems likely to be limited other than, perhaps, as a mechanism for identifying poor adherence. Ozanimod, a selective sphingosine-1-phosphate receptor modulator, has a dose-dependent effect both on the reduction of circulating total peripheral lymphocytes, and also with adverse effects.33Tran J.Q. Hartung J.P. Peach R.J. et al.Results from the first-in-human study with ozanimod, a novel, selective sphingosine-1-phosphate receptor modulator.J Clin Pharmacol. 2017; 57: 988-996Crossref PubMed Scopus (70) Google Scholar Ozanimod is metabolized by 3 primary pathways to 14 different metabolites, the major active metabolite being CC112273.34Surapaneni S. Yerramilli U. Bai A. et al.Absorption, metabolism, and excretion, in vitro pharmacology, and clinical pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor modulator.Drug Metab Dispos. 2021; 49: 405-419Crossref PubMed Scopus (37) Google Scholar To date an exposure-response relationship has not been identified for the drug or its main metabolite in UC. In 2017, the American Gastroenterological Association published guidance on TDM in IBD. Therapeutic targets during maintenance treatment were identified for IFX (5 μg/mL), adalimumab (ADA; 7.5 μg/mL) and certolizumab pegol (20 μg/mL).35Feuerstein J.D. Nguyen G.C. Kupfer S.S. et al.American Gastroenterological Association institute guideline on therapeutic drug monitoring in inflammatory bowel disease.Gastroenterology. 2017; 153: 827-834Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar The evidence at the time was too sparse to recommend a cutoff for golimumab, although subsequent studies have reinforced a therapeutic level of 2.4 to 3.2 μg/mL during maintenance treatment.36Adedokun O.J. Xu Z. Marano C.W. et al.Pharmacokinetics and exposure-response relationship of golimumab in patients with moderately-to-severely active ulcerative colitis: results from phase 2/3 PURSUIT induction and maintenance studies.J Crohns Colitis. 2017; 11: 35-46Crossref PubMed Scopus (92) Google Scholar, 37Samaan M.A. Cunningham G. Tamilarasan A.G. et al.Therapeutic thresholds for golimumab serum concentrations during induction and maintenance therapy in ulcerative colitis: results from the GO-LEVEL study.Aliment Pharmacol Ther. 2020; 52: 292-302Crossref PubMed Scopus (16) Google Scholar, 38Dreesen E. Kantasiripitak W. Detrez I. et al.A population pharmacokinetic and exposure-response model of golimumab for targeting endoscopic remission in patients with ulcerative colitis.Inflamm Bowel Dis. 2020; 26: 570-580PubMed Google Scholar These guidelines highlighted the many difficulties with recommending therapeutic cutoffs for biologics, as acknowledged by the authors and as further discussed below. The evidence behind therapeutic cutoffs in luminal CD and UC is well covered elsewhere.2Vermeire S. Dreesen E. Papamichael K. et al.How, when, and for whom should we perform therapeutic drug monitoring?.Clin Gastroenterol Hepatol. 2020; 18: 1291-1299Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar,39Ma C. Battat R. Jairath V. et al.Advances in therapeutic drug monitoring for small-molecule and biologic therapies in inflammatory bowel disease.Curr Treat Options Gastroenterol. 2019; 17: 127-145Crossref PubMed Google Scholar,40Papamichael K. Cheifetz A.S. Melmed G.Y. et al.Appropriate therapeutic drug monitoring of biologic agents for patients with inflammatory bowel diseases.Clin Gastroenterol Hepatol. 2019; 17: 1655-1668.e3Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar It is largely derived from retrospective studies and post hoc analyses of large registration trials that have identified associations between various definitions of therapeutic response and trough concentrations of anti-TNF agents. Several themes emerge from these studies. First, the harder the end point examined, the higher the associated trough concentration of the biologic. Papamichael et al,40Papamichael K. Cheifetz A.S. Melmed G.Y. et al.Appropriate therapeutic drug monitoring of biologic agents for patients with inflammatory bowel diseases.Clin Gastroenterol Hepatol. 2019; 17: 1655-1668.e3Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar for example, summarized the studies investigating clinical, biochemical (fecal calprotectin [FCal]), endoscopic, and histologic end points and demonstrated an increasing serum level associated with each of these outcomes for IFX and ADA (Table 1).Table 1Association Between Different End Points and Trough Levels of Infliximab and Adalimumab at Varying Times After InductionVariableInfliximabAdalimumabMedian (IQR), μg/mLMedian (IQR), μg/mLBiological remission2.8 (2.2-3.4)5.9 (5.8-6.6)Biochemical remission4.4 (2.5-6.1)…Endoscopic remission4.8 (3.3-7.6)7.7 (7.4-8.7)Histologic remission10.2 (10.0-10.3)10 (8.9-11.1)Clinical remission4.1 (2.1-5.1)6.2 (5.9-7.0)NOTE: Biological remission indicates normalization of CRP. Biochemical remission indicates normalization of FCal. Clinical remission indicates varying time points after induction. Data derived from Papamichael et al.40Papamichael K. Cheifetz A.S. Melmed G.Y. et al.Appropriate therapeutic drug monitoring of biologic agents for patients with inflammatory bowel diseases.Clin Gastroenterol Hepatol. 2019; 17: 1655-1668.e3Abstract Full Text Full Text PDF PubMed Scopus (210) Google ScholarIQR, interquartile range. Open table in a new tab NOTE: Biological remission indicates normalization of CRP. Biochemical remission indicates normalization of FCal. Clinical remission indicates varying time points after induction. Data derived from Papamichael et al.40Papamichael K. Cheifetz A.S. Melmed G.Y. et al.Appropriate therapeutic drug monitoring of biologic agents for patients with inflammatory bowel diseases.Clin Gastroenterol Hepatol. 2019; 17: 1655-1668.e3Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar IQR, interquartile range. Second, other phenotypes and clinical scenarios, including fistulizing disease and acute severe UC (ASUC), may require a different TDM approach and are discussed in greater detail below. Third, interassay variability potentially limits our ability to translate findings from individual studies to clinical practice, where a variety of assays using different methodologies are in use.41Papamichael K. Clarke W.T. Vande Casteele N. et al.Comparison of assays for therapeutic monitoring of infliximab and adalimumab in patients with inflammatory bowel diseases.Clin Gastroenterol Hepatol. 2021; 19: 839-841.e2Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Finally, the interplay between IFX and ADA drug levels and anti-drug antibodies (ADAb) is complex but of great importance. In addition, the variability across assays when measuring ADAb is an order of magnitude greater than it is for drug levels, without even considering the relevance of antibodies detected in the presence of drug using drug-tolerant assays. It is clear, however, that formation of ADAb is a poor prognostic factor, is more common in IFX-treated than ADA-treated patients, is less common in the presence of concomitant immunomodulation, and is more common in patients who are carriers of HLA-DQA1∗05.42Sazonovs A. Kennedy N.A. Moutsianas L. et al.HLA-DQA1∗05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's disease.Gastroenterology. 2020; 158: 189-199Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar The development of subcutaneous IFX also has relevance in terms of TDM. Clearly, drug levels of IFX, which are usually measured at the end of an infusion cycle, need to be interpreted differently when the drug is delivered every two weeks by subcutaneous injection. Accordingly, the trough levels seen in the noninferiority study comparing a switch to subcutaneous IFX after induction, with ongoing intravenous treatment were, unsurprisingly, higher in the subcutaneous group (19.7 vs intravenous 2.4 μg/mL at week 22).43Schreiber S. Ben-Horin S. Leszczyszyn J. et al.Randomized controlled trial: subcutaneous vs intravenous infliximab CT-P13 maintenance in inflammatory bowel disease.Gastroenterology. 2021; 160: 2340-2353Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar There may, of course, be other PK benefits to subcutaneous dosing, including a more favorable exposure profile as measured using area under the curve analysis as well as a reduced risk of immunogenicity due to the avoidance of low trough drug levels, although whether low drug levels are driven by or occur as a result of immunogenicity (or perhaps a combination of the two) is unclear. In addition, whether the fixed dosing of subcutaneous IFX rather than the weight-based dosing of the intravenous preparation is of importance is not entirely clear; a recent population PK analysis of subcutaneous IFX identified that patients weighing >120 kg had lower drug exposure. It is to be hoped that ongoing studies will answer some of these important questions.44Hanzel J. Bukkems L.H. Gecse K.B. et al.Population pharmacokinetics of subcutaneous infliximab CT-P13 in Crohn's disease and ulcerative colitis.Aliment Pharmacol Ther. 2021; 54: 1309-1319Crossref PubMed Scopus (22) Google Scholar Therapeutic targets are generally based on large cohorts of people with a specific condition. Such an approach does not take into account variables that relate to differences in disease phenotype or treatment targets and intraindividual differences related to the disease course or disease activity. Evidence is mounting that an approach to TDM that takes some of these factors into account is superior to an unadjusted approach. The clearance of anti-TNF agents in ASUC is perpetuated by the high inflammatory burden. The abundance of TNF-α, increased proteolytic degradation of immune complexes, fecal loss due to the damaged mucosal barrier, decreased neonatal Fc receptor-mediated recycling of IFX, and as a result, low serum concentrations that may enhance immunogenicity, all influence PK.3Hindryckx P. Novak G. Vande Casteele N. et al.Review article: dose optimisation of infliximab for acute severe ulcerative colitis.Aliment Pharmacol Ther. 2017; 45: 617-630Crossref PubMed Scopus (67) Google Scholar,45Brandse J.F. Mathot R.A. van der Kleij D. et al.Pharmacokinetic features and presence of antidrug antibodies associate with response to infliximab induction therapy in patients with moderate to severe ulcerative colitis.Clin Gastroenterol Hepatol. 2016; 14 (e1–e2): 251-258Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 46Brandse J.F. van den Brink G.R. Wildenberg M.E. et al.Loss of infliximab into feces is associated with lack of response to therapy in patients with severe ulcerative colitis.Gastroenterology. 2015; 149: 350-355.e2Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 47Yarur A.J. Jain A. Sussman D.A. et al.The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study.Gut. 2016; 65: 249-255Crossref PubMed Scopus (182) Google Scholar, 48Seow C.H. Newman A. Irwin S.P. et al.Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis.Gut. 2010; 59: 49-54Crossref PubMed Scopus (478) Google Scholar Accordingly, an observational study showed that mean IFX trough levels at day 14 were significantly lower in patients with ASUC than in patients with moderately severe UC (7.1 vs 14.4 μg/mL, P = .007).49Ungar B. Mazor Y. Weisshof R. et al.Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis.Aliment Pharmacol Ther. 2016; 43: 1293-1299Crossref PubMed Scopus (69) Google Scholar The need for different dosing and perhaps different TDM targets was therefore identified in ASUC. Targets may need to be higher than the concentrations associated with mucosal healing in moderate-severe UC, such as those identified using an ROC curve analysis that identified IFX concentrations of 28.3 μg/mL (AUROC curve, 0.64), 15 μg/mL (AUROC curve, 0.69), and 2.1 μg/mL (AUROC curve, 0.78) at w