You are currently viewing a new version of our website. To view the old version click .
MDPIMDPI
Search all articles
Journal of Clinical Medicine
Download PDF
  • Review
  • Open Access

10 November 2025

Therapeutic Drug Monitoring in Special Circumstances in Inflammatory Bowel Disease

,
,
,
and
1
Department of Gastroenterology, St George’s University Hospital NHS Foundation Trust, London SW17 0QT, UK
2
Department of Gastroenterology, Saint-Etienne University Hospital, 42055 Saint-Etienne, France
3
Department of Gastroenterology, Center for Inflammatory Bowel Diseases, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
4
School of Immunology and Microbial Sciences, King’s College London, London SE1 9RT, UK
J. Clin. Med.2025, 14(22), 7956;https://doi.org/10.3390/jcm14227956
This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases: 2nd Edition
Version Notes
Order Reprints

Abstract

Inflammatory bowel disease, encompassing ulcerative colitis and Crohn’s disease, is characterised by chronic immune-mediated inflammation and variable treatment response. Loss of drug efficacy due to underexposure, pharmacokinetic variability, and immunogenicity remains a key challenge. Therapeutic drug monitoring, using drug levels and anti-drug antibody measurements, is an important strategy for optimising the treatment of inflammatory bowel disease. It helps ensure adequate dosing and can distinguish between pharmacokinetic and mechanistic drug failure. Most evidence pertains to infliximab and adalimumab. Multiple factors influence drug pharmacokinetics, affecting both target drug levels and the doses required to achieve them. These include inflammatory burden, bodyweight, age, disease phenotype, and route of administration, all of which are important considerations for individualising treatment in inflammatory bowel disease. This narrative review explores how special clinical situations—acute severe ulcerative colitis, perianal fistulising Crohn’s disease, hypoalbuminaemia, extremes of body composition, pregnancy, paediatrics, and advanced age—alter drug pharmacokinetics and influence the utility and interpretation of therapeutic drug monitoring in inflammatory bowel disease.

1. Introduction

Inflammatory bowel disease (IBD) is a collective term for a group of lifelong, immune-mediated inflammatory diseases, broadly comprising ulcerative colitis (UC) and Crohn’s disease (CD) [,]. Treatment for IBD is often hampered by poor drug persistence, with approximately one third of patients needing to change their advanced therapy after a year []. Suboptimal persistence reflects a mix of underexposure, pharmacokinetic (PK) variability, and immunogenicity, which collectively drive loss of response and treatment failure. Therapeutic drug monitoring (TDM), including drug levels and anti-drug antibody (ADA) assessment, is established for infliximab (IFX), adalimumab (ADM), and thiopurines to extend treatment durability and prevent avoidable relapse from underdosing or ADA formation to anti-tumour necrosis factor alpha (TNFα) drugs [,]. TDM helps distinguish PK failure (amenable to dose optimisation or immunomodulator co-therapy) from mechanistic failure (prompting a switch out of class), enabling more rational, cost-based decisions and reducing unnecessary drug cycling.
In clinical practice, TDM can be applied reactively, when primary non-response or secondary loss of response is suspected, or proactively, with scheduled measurement of trough concentrations to maintain targets associated with remission. Some evidence supports a proactive versus reactive approach to TDM [,], although several studies were not designed to directly answer this question and methodological limitations temper certainty [,]. Beyond thiopurines and anti-TNFα agents, the evidence base for TDM remains contentious and not part of routine practice at present []. The PANTS study showed that low drug concentrations at week 14 were the only independent risk factor for primary non-response to IFX and ADM in CD, with remission associated with drug levels of 7 mg/L and 12 mg/L, respectively []. Major societies endorse TDM for IFX, ADM, and thiopurines; uniquely, ESPGHAN currently recommends early proactive TDM in paediatric CD, while others deem evidence insufficient to prefer it over reactive use [,,,,]. Regardless of strategy, practical barriers still impede TDM implementation [].
Multiple patient variables influence drug levels and targets and include disease phenotype, disease severity, body composition, pregnancy, age, and administration route [,]. Evidence around these factors continues to evolve, reshaping how TDM is applied and how targets are set in specific clinical contexts. This narrative review synthesises current evidence across these scenarios and highlights evidence gaps and research priorities to advance routine, patient-centred TDM.

2. Methods

In August 2025, MEDLINE (via PubMed) was searched using the following terms: “therapeutic drug monitoring” AND (“inflammatory bowel disease” OR “ulcerative colitis” OR “Crohn’s disease”). Additional searches included: “acute severe ulcerative colitis,” “albumin,” “fistula,” “perianal,” “body composition,” “weight,” “obesity,” “adipose,” “pregnancy,” “paediatric,” “age,” “elderly,” and “subcutaneous.” Reference lists of included studies were hand-searched for further articles. We included randomised controlled trials (RCTs), post hoc analyses of RCTs, meta-analyses, retrospective and prospective cohort studies, cross-sectional studies, and population pharmacokinetic studies. Narrative and systematic review articles were also accepted and their reference lists searched for further studies.

3. Disease Severity and Phenotype

3.1. Acute Severe Ulcerative Colitis

Acute severe ulcerative colitis (ASUC) is a life-threatening manifestation of UC, classically defined by Truelove and Witts criteria (≥6 bloody stools/day plus systemic toxicity), requiring urgent inpatient management. The biologic era ushered in by IFX, one of only two therapies repeatedly showing efficacy in ASUC (the other is ciclosporin), has markedly reduced colectomy rates, particularly in the short term [,]. Despite this, up to 20% of patients require colectomy during their first admission, which increases on subsequent admissions [,]. Consequently, optimisation of inpatient medical rescue therapy is still needed. To date, optimal dosing regimens and the role of TDM in this situation have not clearly been demonstrated. In patients with moderate to severe UC, post hoc analysis of the landmark ACT1 and ACT2 trials showed that patients in the lowest quartile for serum IFX concentration were less likely to achieve clinical response, remission, and mucosal healing, irrespective of the IFX dose given []. Increased IFX clearance also predicts colectomy in ASUC []. This supports a target-concentration approach to overcome increased drug clearance and improve outcomes.
One barrier to achieving therapeutic IFX exposure in ASUC is the multiple mechanisms which increase drug clearance (Figure 1) []. Inflamed mucosa express high levels of TNFα which bind the circulating IFX, thereby depleting circulating levels and acting as an “anti-TNFα sink” []. Severe epithelial disruption increases faecal IFX loss, and higher early faecal loss correlates with primary non-response []. Furthermore, the high numbers of mononuclear cells degrade large amounts of IFX through phagocytosis [], as well as increasing proteolysis of infliximab []. Neonatal Fc receptor-mediated recycling of IFX, a pathway that usually prolongs the drug’s half-life by circumventing usual lysosomal degradation, is also reduced as a result of colonic epithelial damage, as well as increased receptor saturation in high inflammatory states []. These reductions in circulating drug can also heighten immunogenicity and predispose to anti-drug antibody formation [].
Figure 1. Mechanisms of infliximab clearance. In disease states with a high inflammatory burden, there is increased damage of the intestinal epithelium, leading to increased faecal loss of infliximab (IFX) and albumin, which is associated with low IFX levels. There is also increased tumour necrosis factor alpha (TNFα) in the tissue, which then binds and neutralises a greater proportion of IFX, acting as a ‘TNFα sink’. Through increased intestinal epithelial cell damage, there is also reduced neonatal Fc receptor availability, thus reducing the recycling of IFX to circumvent lysosomal proteolysis, resulting in increased degradation. Finally, with increased immune cell activity, there is increased IFX proteolysis and phagocytosis. In obesity, particularly with visceral adipose tissue, there is increased TNFα, which also acts as a ‘TNFα sink’. There is also increased systemic proteolytic activity, which increases IFX degradation.
The impact of a high inflammatory burden on IFX exposure is exemplified C-reactive protein (CRP) data, where values >50 mg/L are independently associated with lower drug levels []. The PREDICT-UC randomised trial evaluated intensified and accelerated induction to overcome these mechanisms of increased IFX drug clearance. Although neither 10 mg/kg nor accelerated dosing achieved statistically significant superiority over standard care, a numerically higher response was seen with 10 mg/kg among patients with CRP ≥50 mg/L []. Early PKs were prognostic as day 3 IFX concentrations ≤53.6 μg/mL predicted day 14 treatment failure and ≤57.9 μg/mL predicted 3-month colectomy, and greater faecal IFX loss between days 1 and 7 correlated with better response to 10 mg/kg versus 5 mg/kg []. Taken together, faecal IFX clearance appears promising for personalised dosing selection, and current signals support consideration of intensified or accelerated regimens in selected patients. Pharmacokinetic models have attempted to assess personalised dosing strategies of IFX over standard-of-care 5 mg/kg dosing in ASUC. Whilst TITRATE did not meet its primary endpoint, other promising models are being developed and await prospective validation [,].

3.2. Albumin

Hypoalbuminaemia is distinct from, but often accompanies, severe disease activity. There are several reasons that may explain this. First, albumin is a negative acute-phase reactant with hepatic synthesis suppressed by pro-inflammatory cytokines. In health, approximately 10% of albumin turnover occurs via the gastrointestinal tract, but mucosal inflammation markedly increases this loss []. Second, the neonatal Fc receptor normally recycles albumin to prevent degradation, but in highly active disease, this mechanism is impaired, increasing albumin clearance. Finally, patients with active disease often have a worse nutritional status, with reduced intake of amino acids, despite having an increased requirement due to acquired tissue damage, leading to decreased albumin production. These effects are partially counterbalanced by a stimulus for albumin production, often via muscle catabolism, to maintain oncotic pressure [].
Population PK studies for patients with both CD and UC have demonstrated that higher IFX clearance is associated with low albumin []. Trough IFX levels robustly correlate with albumin levels []. In moderate–severe UC, albumin <35 g/L associates with lower week 6 IFX levels [], and in CD, albumin <30 g/L predicts primary non-response (PNR) to anti-TNFα therapy []. PREDICT-UC also suggested a numerically higher response to 10 mg/kg (vs 5 mg/kg) among ASUC patients with albumin <25 g/L []. The mechanism through which albumin influences infliximab clearance is most likely indirect. Very little infliximab is albumin-bound. Instead, albumin often reflects the degree of mucosal injury, which leads to increased drug clearance, as described in the previous section. Similar effects of albumin levels on ADM PKs have been demonstrated [].
This is also true for vedolizumab (VDZ), for which population PK studies have shown higher drug clearance with hypoalbuminaemia and states of higher disease activity, such as endoscopic activity or CRP. However, albumin appears to be the strongest covariate affecting PKs []. As such, albumin is also included in the clinical decision support tool which can help predict response in CD []. This is likely through increased faecal drug loss in active disease []. Conversely, whilst population PK studies in ustekinumab, mirikizumab, and risankizumab show a similar direction of effect with albumin and disease activity, the effect size is small to be considered not clinically relevant [,,,,]. Janus kinase inhibitors (JAKis), such as upadacitinib, show no effect of albumin [] or baseline disease severity [] in PKs. There are no data on the effect of albumin or baseline disease severity on the PK of sphingosine-1-phosphate receptor modulator (S1P) drugs such as ozanimod or etrasimod.
Patients with high inflammatory burden and low albumin may require intensified dosing to achieve therapeutic IFX exposure. Specific criteria for identifying such patients remain poorly defined, and early IFX level or faecal clearance monitoring is not yet practical in routine care. In severe cases, particularly with hypoalbuminaemia, 10 mg/kg dosing and accelerated induction should be considered, especially if early symptom recurrence suggests rapid drug clearance.

3.3. Perianal Fistulising Crohn’s Disease

Perianal fistulising CD is challenging to treat and is associated with substantial morbidity and a poor quality of life []. Optimising drug exposure is central; anti-TNFα therapy, particularly IFX, remains the standard of care []. Cross-sectional data show significantly higher median IFX levels in patients with fistula healing versus active fistulas (15.8 vs. 4.4 µg/mL; p < 0.0001), with ≥10.1 µg/mL best associated with healing and a further numerical benefit at ≥20.2 µg/mL []. A post hoc analysis of ACCENT-II [], a multicentre, double-blind, randomised, placebo-control trial of IFX in fistulising CD, demonstrated that higher week 14 IFX levels were independently associated with fistula response. They also defined thresholds with combined maximal sensitivity and specificity for week 14 composite remission of ≥20.2 μg/mL at week 2, ≥15 μg/mL at week 6, and ≥7.2 μg/mL at week 14 []. These higher targets may result from the increased local expression of matrix metalloproteinases (MMPs) in perianal fistulae [], which may cleave and inactivate IFX and ADM [], resulting in higher serum levels required to overcome this. Accordingly, proactively targeting IFX troughs of at least 7.2 µg/mL is recommended, with higher targets often warranted in complex perianal disease. Similar evidence exists for ADM, where ~12.1 µg/mL optimally associates with complete fistula healing []. Whilst for other drugs, such as ustekinumab, drug levels correlating with fistula response have been measured to attempt to define target levels, there is significant heterogeneity between the indicated target levels in different studies in CD, and thus no clear target levels can be set [,,]. There is no data to support different targets or dosing strategies for other drugs.

4. Body Composition

4.1. Obesity

Bodyweight, body composition, and obesity have long been linked to IBD natural history and treatment effectiveness, including PKs. This is of particular interest as 15–40% of IBD patients are now obese []. The widespread use of GLP-1 receptor agonists introduces a modifiable variable: intentional weight loss and shifts in fat/lean mass may alter drug exposure, particularly for weight-dependent dosing and subcutaneous biologics, potentially prompting a re-assessment of TDM targets and strategies [].
Some evidence suggests that IBD follows a milder natural history in obesity [], whereas other studies report that obese patients treated with IFX are both more likely to relapse, and do so earlier in their treatment course, than non-obese patients []. However, meta-analyses of the pivotal IFX trials (ACCENT-1, SONIC, ACT-1, ACT-2) found no association between obesity and IFX response []. Similarly, whilst bodyweight has been associated with higher IFX clearance [], body mass index (BMI) is not always a reliable predictor of IFX [].
When considering the mechanism through which obesity might affect IFX drug levels, volume of distribution is one factor to consider. Whilst the weight-based dosing of IFX might be expected to overcome this, there is evidence that the volume of distribution in the peripheral compartment decreases with increasing body mass []. This would predict a potential overcompensation of dosing in higher-bodyweight individuals and an undercompensation in lower-bodyweight individuals based on weight-based IFX dosing. However, both weight and BMI are inherently poor ways of defining obesity, as they take no account of the differential effect of body composition, where fat and muscle mass may be more important for the specific effect of obesity.
The effect of BMI and bodyweight is more straightforward in ADM. A prospective cohort analysis nested within the COMBINE trial of anti-TNF monotherapy vs. combination therapy with oral methotrexate in paediatric CD demonstrated patients with BMI > 1 standard deviation above mean had lower drug concentrations compared to patients with normal BMI (median 5.8 vs. 12.8 mg/mL, p = 0.02), but this effect was not seen with IFX []. In adults, a higher bodyweight was also an independent covariate predicting lower ADM levels in a population PK model developed from data from the SERENE CD and UC trials [].
One mechanism through which increased biologic drug clearance may occur in obesity is due to increased proteolysis, which is seen in obese individuals [,]. Adipose tissue, particularly in obesity, overexpresses TNFα due to macrophage accumulation, creating an “anti-TNFα sink” analogous to ASUC (Figure 1) [,]. Site-specific effects are relevant as mesenteric adipocytes produce more TNFα than subcutaneous adipocytes, and patients with CD exhibit a higher intra-abdominal-to-total abdominal fat ratio []. “Creeping fat,” a mesenteric fat subtype encasing the bowel, is characteristic of ileal CD, correlates with transmural inflammation, fibrosis, muscular hypertrophy, and stricture formation, and is present in approximately 20% of patients [,]. Anti-TNFα outcomes appear worse at both extremes of visceral adipose tissue (VAT) volume (≥3000 cm3 and <1500 cm3) [].
Poor response in the patient group with very low visceral adipose tissue volume likely parallels adverse outcomes seen with sarcopenia, where myopenia itself predicts primary non-response to anti-TNFα, malnutrition both worsens outcomes and reflects advanced disease, and low bodyweight leads to increased volume of distribution of IFX in the peripheral compartment [,,]. Whether targeted TDM can offset the adverse impact of high visceral adipose tissue is uncertain. However, non-linear data suggest different trough requirements by very low visceral adipose tissue—steroid-free deep remission and endoscopic remission were associated with 3.9 µg/mL in the lowest two quartiles versus 15.3 µg/mL in the highest two quartiles [].
Extremes of bodyweight are a significant predictor of PKs in vedolizumab, although the clinical relevance of this is uncertain []. Similarly, a post hoc analysis of IM-UNITI investigating ustekinumab in CD demonstrated a BMI ≥ 30 kg/m2 significantly predicts lower drug levels but does not predict clinical response []. In contrast, thiopurines show no clear relationship between 6-thioguanine (TGN) levels and body composition metrics, including adiposity and total weight []. Similarly, although there is a detectable effect of weight on PKs of mirikizumab, risankizumab, JAKis, and S1Ps, the effect size is too small to be deemed clinically relevant [,,,,,].
Integration of tissue volumetrics into treatment target algorithms may be achievable in time. For now, in patients with obesity, targeting higher trough concentrations, or deferring a declaration of treatment failure until higher thresholds are reached, may be guided by clinical assessment of body composition rather than weight or BMI alone.

4.2. Pregnancy

Physiological adaptations in pregnancy alter PKs by expanding volume of distribution and modifying metabolic–catabolic pathways []. As disease relapse during pregnancy increases the risk of perinatal complications, including pre-term birth and low neonatal birthweight [,], appropriate dosing across all trimesters is essential and hinges on how drug levels change over gestation (Figure 2).
Figure 2. Graphical representation of drug level trends in pregnancy. Throughout pregnancy, infliximab (IFX) levels rise. Adalimumab (ADM) and ustekinumab (UST) levels remain static. Vedolizumab (VDZ) levels reduce throughout pregnancy, correlated with increasing patient weight. 6-thioguanine (6-TGN) levels reduce from baseline to their lowest point in the 2nd trimester before returning towards, but not quite back to, normal. 6-methylmercaptopurine (6-MMP) levels rise during pregnancy, peaking in the 2nd trimester before returning towards, but not quite back to, normal in the 3rd trimester.
IFX levels appear to increase throughout pregnancy trimesters, which remains true even when accounting for the variable changes in BMI, albumin, and CRP, suggesting decreased drug clearance during pregnancy [,]. The increase has been calculated as 0.16 µg/mL/week, or 6.4 µg/mL over a 40-week pregnancy []. This may be because of increased neonatal Fc receptor expression during pregnancy, which enhances IFX recycling []. By contrast, adalimumab shows little change through pregnancy [,]. Thiopurines display a different pattern, with 6-TGN levels falling and 6-methylmercaptopurine (MMP) levels increasing in the second trimester before returning back towards pre-pregnancy levels in the third trimester []. This has implications for potentially increased hepatotoxicity with reduced drug efficacy during pregnancy. Ustekinumab levels appear stable throughout pregnancy [,], whereas vedolizumab levels tend to decline in association with weight gain; the clinical significance is uncertain [,]. There is a lack of evidence for the effect of pregnancy on mirikizumab and risankizumab PKs. Whilst the small molecules tofacitinib, filgotinib, upadacitinib, ozanimod, and etrasimod are contraindicated during pregnancy due to teratogenicity, major societies strongly recommend continuing anti-TNFα drugs and thiopurines during pregnancy, as well as other non-anti-TNFα biologics, particularly if active or historically difficult-to-treat disease is present [,]. This is because of their well-documented safety in pregnancy, with any detectable risk outweighed by the risk to mother and child of flare after drug discontinuation [,,,,].

5. Age

5.1. Elderly

Ageing IBD cohorts are expanding; in 2010–2014, adults >65 years accounted for 26% of index IBD admissions in the USA []. This reflects compounding prevalence—incidence has stabilised, but improved outcomes and survival increase the number of older adults living with IBD []. Modelling from Canada, Denmark, and Scotland projects continued growth in the older IBD population through 2023–2043 [].
Older patients face unique challenges: comorbidities, polypharmacy, frailty, and altered PKs all influence drug disposition and treatment outcomes. Thiopurines and JAKis carry higher risks of adverse events, including infections, cytopenias, and malignancies, particularly in patients over 60 [,]. Yet dosing and monitoring data for advanced therapies in this group are sparse because older patients are underrepresented in trials; from 2011 to 2018, those ≥75 years comprised only 1.3% of IBD trial participants [,]. Observational studies are therefore the main source of guidance, but heterogeneity in design and reporting limits certainty.
For IFX, available evidence indicates a similar exposure–response relationship in patients ≥65 and younger adults, while serious adverse events and malignancy rise with age independent of IFX exposure []. This implies that the same TDM targets can be applied in elderly patients, but interpretation should be set against a higher background risk of adverse events. PK studies of ustekinumab in adult trials suggest no effect of age within the studied range (18–64) []. There is no evidence of age affecting PKs of mirikizumab, risankizumab, vedolizumab, JAKis, or S1Ps within studied age ranges of adults. Whilst polypharmacy does not appear to be an issue affecting the PK of biologic drugs, small molecules, which include JAKis and S1Ps, are typically metabolised by Cytochrome P450 (CYP) enzymatic pathways and thus subject to drug–drug interactions. Etrasimod and ozanimod are metabolised by CYP2C8 and thus their levels are increased by CYP2C8 inhibitors, including clopidogrel and gemfibrozil, whilst conversely rifampicin may reduce their levels. Upadacitinib and tofacitinib are metabolised by CYP3A4, and thus their levels are potentiated by inhibitors including ciprofloxacin, clarithromycin, diltiazem, fluconazole, and verapamil. Conversely, carbamazepine, phenytoin, and rifampicin reduce their levels. Filgotinib, however, is an exception that is not metabolised predominantly through CYP enzymatic pathways and thus not subject to drug–drug interactions [,].
Future studies could examine whether frailty, sarcopenia, and altered body composition modify PKs in the elderly, and whether higher trough levels carry a different balance of risk and benefit in this population. Defining optimal TDM thresholds in the elderly will likely require pragmatic registry studies that incorporate outcomes such as adverse and serious adverse events, including hospitalisation and functional decline. Until then, application of standard TDM targets in older adults remains reasonable, provided decisions are contextualised within individual comorbidity profiles and vigilant clinical surveillance.

5.2. Paediatrics

Paediatric guidelines predate adult guidance and, unlike most adult recommendations, endorse proactive TDM rather than reactive use alone [,]. The PAILOT study demonstrated that, when using ADM in paediatric patients with CD, proactive TDM was superior to reactive TDM in achieving steroid free clinical remission []. Concentration targets broadly mirror adult targets; PANTS, which included patients ≥6 years, associated remission with 7 μg/mL for IFX and 12 μg/mL for ADM [].
As in adults, higher IFX targets in perianal fistulising CD have also been suggested, with week 14 trough levels of 12.7 μg/mL seen in responders versus 5.4 μg/mL in the active disease group []. Children <10 years appear more prone to subtherapeutic troughs and to require escalation and intensified regimens despite similar baseline characteristics []. This may in part be due to increased volume of distribution in the peripheral compartment with low bodyweights []. This supports consideration of upfront intensified dosing and/or more frequent proactive TDM in this age group. For ustekinumab, PKs appeared to be related to bodyweight, with patients <40 kg more likely to have lower trough levels despite bespoke weight-based dosing regimens []. Other drugs are either not licenced in paediatric populations or have no evidence to suggest altered PKs.
IFX clearance is emerging as an additional TDM metric in paediatrics. In ASUC, higher IFX clearance at baseline and week 26 is predictive of colectomy. Higher IFX induction may overcome this—a median 9.9 mg/kg induction resulted in a 1-year colectomy rate of 2.7% compared to 52% with previous the 5 mg/kg standard-of-care induction [,]. Similarly, in CD there is a strong negative association between early IFX clearance and subsequent remission []. This is driven in part by ADA formation, which increases IFX clearance even at lower levels. Lower overall (area under the curve) IFX exposure between weeks 0 and 14 predicts ADA development and low-level ADA formation and thus higher IFX clearance may be reversed with dose intensification []. Taken together, early assessment of IFX clearance may additionally guide early treatment escalation. Alternatively, more pragmatic upfront intensive dosing strategies may prevent pharmacokinetic and immunogenicity failures with IFX.
Models have also been developed based on population PK studies to inform early IFX dose intensification in both UC and CD, with multi-model approaches appearing to provide incremental benefit over single model approaches in retrospective data sets [,]. The upcoming REMODEL-CD clinical trial will prospectively assess standard of-care IFX dosing regimens in paediatric CD versus a novel precision dosing platform which determines the starting dose based on covariates including weight, albumin, and ESR and then sets personalised doses and drug level targets according to the most recent measured drug trough level, CRP, faecal calprotectin (fCal), and disease activity score [].

6. Administration

6.1. Thiopurines: Monotherapy or Combination

When used as monotherapy, 6-TGN levels of 235–450 pmol/8 × 108 red blood cells (RBCs) correlate best with response, conferring 3-fold higher remission rates; this range is therefore the standard monotherapy target. Thiopurines are increasingly employed as immunomodulators to curb anti-TNFα immunogenicity, particularly with IFX, a major cause of treatment failure []. Observational data suggest that, in combination therapy, lower 6-TGN targets, around 125 pmol/8 × 108 RBCs, adequately predict higher IFX levels and lack of ADA development [,]. Targeting a lower level may enable reduced exposure to unnecessary burden of immunosuppression or thiopurine toxicity []. Other retrospective data suggest traditional 6-TGN target levels of 235–450 pmol/8×108 RBCs are required to prevent IFX ADA formation []. Much larger observational data also suggests higher thiopurine analogue doses (azathioprine ≥2.2 mg/kg, mercaptopurine ≥1.1 mg/kg) may be required to reduce the chance of anti-TNFα loss of response in CD []. However, a randomised drug withdrawal trial for IBD patients in remission showed that halving the azathioprine dose had no significant effect on IFX trough levels []. Neither of these trials defined 6-TGN targets. In summary, evidence for a specific combination-therapy 6-TGN target is mixed; requirements are likely less stringent than for monotherapy, but no consensus target is established.

6.2. Route: Subcutaneous or Intravenous

With intravenous (IV) IFX, serum levels fluctuate widely over the dosing interval (peaks often >100 µg/mL), so true trough sampling is essential for valid TDM []. In contrast, subcutaneously (SC) administered ADM displays very minimal drug level variation throughout the treatment cycle such that TDM can be performed at any time []. The recent availability of SC IFX provides patients with greater flexibility in administration, reduces the burden on infusion units and associated healthcare costs, and, given its comparable immunogenicity profile to IV IFX in combination with immunomodulators, raises the possibility of monotherapy [,,]. The MINIMISE study is expected to clarify whether SC IFX monotherapy is a viable strategy [].
Like ADM, SC IFX achieves stable serum concentrations throughout its biweekly dosing interval, meaning TDM can reliably be performed at any time []. Serum stability is also seen when switching to biweekly SC VDZ from IV administration []. When switching from a median IV IFX dose of 500 mg every 8 weeks to SC IFX 120 mg every 2 weeks, trough levels increase from 8.2 ± 4.5 µg/mL to steady-state levels of 14.5 ± 6.0 µg/mL, without a significant change in steroid-free remission rates []. Standard SC IFX dosing has also been shown to maintain remission in patients previously escalated to IV IFX regimens up to 10 mg/kg every 6 weeks []. Another study in patients switching to SC who at baseline were receiving a range of IV IFX dosing regimens from 5 mg/kg 8-weekly (52%) to >5 mg/kg 4-weekly (5%) showed a median increase in measured levels from 5.25 µg/mL to between 15.1 and 15.4 µg/mL at week 12–52 post-switch. This study suggested optimal SC IFX targets for clinical and biochemical remission based on receiver operating characteristic analysis of 12.2 μg/mL at week 12 and 13.2 μg/mL week 56 for UC and CD []. Different treatment endpoints may require different threshold drug levels in SC IFX, as with IV dosing []. A cross-sectional study of UC and CD patients predicted targeting IFX levels ≥12 μg/mL to achieve clinical remission alone, ≥16 μg/mL for combined clinical remission and CRP <5 mg/L, and to achieve deep remission (combined clinical remission, CRP <5 mg/L, and fCal <250 μg/g), targeting ≥20 μg/mL was required. These thresholds are higher than those suggested for IV IFX and should be taken into account when interpreting drug levels following a switch to SC administration.

7. Conclusions and Future Directions

TDM is increasingly recognised as a key tool in the precision management of IBD, providing a structured approach to optimise drug exposure, prolong treatment durability, and improve outcomes. Beyond simply guiding dose adjustments, TDM distinguishes PK from mechanistic failure, reduces unnecessary drug cycling, and supports safer, more cost-effective use of anti-TNFα drugs. For thiopurines, metabolite monitoring not only mitigates toxicity but also enhances anti-TNFα persistence by reducing immunogenicity.
Although much of the current evidence remains retrospective or observational, this review highlights patient-, disease-, and treatment-specific factors that shape PKs (Table 1) and target concentrations, with direct implications for clinical practice (Table 2).
Table 1. Summary of factors affecting pharmacokinetics.
Table 2. Summary of therapeutic drug monitoring and drug dosing recommendations.
States of high inflammatory burden may require higher anti-TNFα doses to counter accelerated clearance []. In acute care, TDM utility is limited by long assay turnaround times, particularly outside specialist centres. Hence, upfront accelerated or intensified IFX dosing may be more pragmatic given the favourable safety profile of intensified regimens. Targeting higher trough levels of anti-TNFα may be required in perianal fistulising CD to promote fistula healing [,,]. Similarly, higher trough levels may also be required in patients with higher visceral adipose tissue [], although the most appropriate metrics to measure and the most practical way to assess this are still to be clearly defined. With increasing obesity in IBD cohorts, prospective trials in this area, particularly for anti-TNFα drugs, would be welcomed. Anti-TNFα levels appear stable during pregnancy; by contrast, thiopurine metabolism shifts in the second trimester (falling 6-TGN and rising 6-MMP) may reduce efficacy and increase toxicity [,]. Paediatric patients are less likely to achieve target anti-TNFα drug levels [], and proactive TDM is well supported [], warranting vigilant monitoring and consideration of early intensive dosing within the paediatric population.
Further progress in TDM for special situations should be derived from studies that explore context-specific exposure targets. ASUC, perianal fistulising CD, pregnancy, paediatrics, and obesity or body composition are the settings where standard targets most often fall short. Here, prospective work should relate early PKs, including faecal infliximab in ASUC, to hard outcomes such as colectomy-free survival, fistula healing on MRI, and steroid-free remission. Subcutaneous infliximab also needs clear induction and maintenance targets, with practical rules for adjustment after switching from IV, so that any time sampling can translate into confident dose changes.
Evidence for non-anti-TNFα therapies remains uneven, and concentration response relationships are weaker. Vedolizumab saturates α4β7 receptors at very low drug levels [], and different studies suggest very different thresholds, limiting their applicability [,,]. Whilst an exposure–response relationship is well documented for ustekinumab [], the inability to recapture response after dose optimisation in CD questions the utility of TDM here []. There is limited data regarding TDM in mirikizumab and risankizumab to date. Whilst there is a clear dose–response relationship for JAKis, plasma concentrations do not appear to be related to response [,]. Ozanimod and etrasimod also do not have a clearly defined exposure–response relationship.
Assay harmonisation is also important, with drug-tolerant ADA methods, cross-platform calibration, and clear reporting of sampling timing all needed to allow results to be compared reliably across centres. Turnaround times must be shortened through point-of-care testing, home sampling, and integration with electronic records, so that results can inform same visit decisions in both specialist and non-specialist settings. Clinical utility will also depend on the development of dosing tools that combine routine clinical variables such as albumin, CRP, phenotype, route, body composition, co-therapy, and prior levels to suggest adjustments and highlight risk of immunogenicity or loss of response. Pragmatic trials with cost–benefit analyses are also needed to establish which proactive, reactive, or hybrid approaches to TDM deliver the greatest benefit and value across different healthcare systems. Ultimately, the goal is a comprehensive PK dashboard or model-informed precision dosing tool that integrates patient characteristics, disease features, route and co-therapy, and treatment intent to define both starting doses and subsequent TDM targets. Although recent prospective trials have not achieved their primary endpoints [], whilst further trials are awaited, recognition of the individual factors influencing PKs can already support more personalised, case-by-case decision making in UC and CD.

Author Contributions

Conceptualization, S.H.; writing—original draft preparation, S.P.; writing—review and editing, S.P., K.P. (Kamal Patel), X.R., K.P. (Konstantinos Papamichael) and S.H.; supervision, S.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

No new data were created or analysed in this study. Data sharing is not applicable to this article.

Acknowledgments

During the preparation of this manuscript, Sebastian Povlsen used BioRender for the creation of Figure 1 (created in BioRender. Povlsen, S. (2025) https://BioRender.com/aceelq5) and Figure 2 (Created in BioRender. Povlsen, S. (2025) https://BioRender.com/egsr9mg).

Conflicts of Interest

S.P. has no conflicts to declare. K.P. (Kamal Patel) has received honoraria for educational meetings and speaker fees from Abbvie, Janssen, Takeda, Dr. Falk Pharma, PredictImmune, Pfizer, and Ferring and has received advisory board fees from Abbvie, Galapagos, Pfizer, and Janssen. He has also received a grant from AbbVie to support research. X.R. served as a speaker, a consultant, and/or an advisory board member for MSD, Pfizer, Janssen, Takeda, Abbvie, Amgen, Biogen, Galapagos, Roche, Theradiag, and Celltrion. K.P. (Konstantinos Papamichael) received lecture/speaker fees from Physicians Education Resource LLC and Grifols; scientific advisory board fees from ProciseDx Inc and Scipher Medicine Corporation; and serves as a consultant for Prometheus Laboratories Inc. S.H. served as a speaker, a consultant, and an advisory board member or has received grants from Pfizer, Janssen, AbbVie, Takeda, J&J, Alfasigma, Ferring, Lilly, Pharmacosmos, and Banook Group.

Abbreviations

The following abbreviations are used in this manuscript:
ADMAdalimumab
ASUCAcute severe ulcerative colitis
CRPC-reactive protein
CYPCytochrome P450
fCalFaecal calprotectin
GLP-1Glucagon-like peptide-1
IVIntravenous
mAbMonoclonal antibody
PKPharmacokinetic
RBCRed blood cell
SCSubcutaneous
TDMTherapeutic drug monitoring
TNFαTumour necrosis factor alpha
USTUstekinumab
VDZVedolizumab
6-MMP6-Methylmercaptopurine
6-TGN6-Thioguanine

References

  1. Berre, C.L.; Honap, S.; Peyrin-Biroulet, L. Ulcerative colitis. Lancet 2023, 402, 571–584. [Google Scholar] [CrossRef]
  2. Dolinger, M.; Torres, J.; Vermeire, S. Crohn’s disease. Lancet 2024, 403, 1177–1191. [Google Scholar] [CrossRef]
  3. Zhao, M.; Sall Jensen, M.; Knudsen, T.; Kelsen, J.; Coskun, M.; Kjellberg, J.; Burisch, J. Trends in the use of biologicals and their treatment outcomes among patients with inflammatory bowel diseases—A Danish nationwide cohort study. Aliment. Pharmacol. Ther. 2022, 55, 541–557. [Google Scholar] [CrossRef]
  4. Papamichael, K.; Cheifetz, A.S.; Melmed, G.Y.; Irving, P.M.; Vande Casteele, N.; Kozuch, P.L.; Raffals, L.E.; Baidoo, L.; Bressler, B.; Devlin, S.M.; et al. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients with Inflammatory Bowel Diseases. Clin. Gastroenterol. Hepatol. 2019, 17, 1655–1668.e3. [Google Scholar] [CrossRef]
  5. Cheifetz, A.S.; Abreu, M.T.; Afif, W.; Cross, R.K.; Dubinsky, M.C.; Loftus, E.V.; Osterman, M.T.; Saroufim, A.; Siegel, C.A.; Yarur, A.J.; et al. A Comprehensive Literature Review and Expert Consensus Statement on Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease. Am. J. Gastroenterol. 2021, 116, 2014–2025. [Google Scholar] [CrossRef] [PubMed]
  6. Assa, A.; Matar, M.; Turner, D.; Broide, E.; Weiss, B.; Ledder, O.; Guz-Mark, A.; Rinawi, F.; Cohen, S.; Topf-Olivestone, C.; et al. Proactive Monitoring of Adalimumab Trough Concentration Associated with Increased Clinical Remission in Children with Crohn’s Disease Compared with Reactive Monitoring. Gastroenterology 2019, 157, 985–996.e2. [Google Scholar] [CrossRef] [PubMed]
  7. Papamichael, K.; Juncadella, A.; Wong, D.; Rakowsky, S.; Sattler, L.A.; Campbell, J.P.; Vaughn, B.P.; Cheifetz, A.S. Proactive Therapeutic Drug Monitoring of Adalimumab Is Associated with Better Long-term Outcomes Compared with Standard of Care in Patients with Inflammatory Bowel Disease. J. Crohns Colitis 2019, 13, 976–981. [Google Scholar] [CrossRef]
  8. Nguyen, N.H.; Solitano, V.; Vuyyuru, S.K.; MacDonald, J.K.; Syversen, S.W.; Jørgensen, K.K.; Crowley, E.; Ma, C.; Jairath, V.; Singh, S. Proactive Therapeutic Drug Monitoring Versus Conventional Management for Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis. Gastroenterology 2022, 163, 937–949.e2. [Google Scholar] [CrossRef] [PubMed]
  9. Sethi, S.; Dias, S.; Kumar, A.; Blackwell, J.; Brookes, M.J.; Segal, J.P. Meta-analysis: The efficacy of therapeutic drug monitoring of anti-TNF-therapy in inflammatory bowel disease. Aliment. Pharmacol. Ther. 2023, 57, 1362–1374. [Google Scholar] [CrossRef] [PubMed]
  10. Irving, P.M.; Gecse, K.B. Optimizing Therapies Using Therapeutic Drug Monitoring: Current Strategies and Future Perspectives. Gastroenterology 2022, 162, 1512–1524. [Google Scholar] [CrossRef]
  11. Kennedy, N.A.; Heap, G.A.; Green, H.D.; Hamilton, B.; Bewshea, C.; Walker, G.J.; Thomas, A.; Nice, R.; Perry, M.H.; Bouri, S.; 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, 341–353. [Google Scholar] [CrossRef] [PubMed]
  12. Van Rheenen, P.F.; Aloi, M.; Assa, A.; Bronsky, J.; Escher, J.C.; Fagerberg, U.L.; Gasparetto, M.; Gerasimidis, K.; Griffiths, A.; Henderson, P.; et al. The Medical Management of Paediatric Crohn’s Disease: An ECCO-ESPGHAN Guideline Update. J. Crohn’s Colitis 2021, 15, 171–194. [Google Scholar] [CrossRef] [PubMed]
  13. Gordon, H.; Minozzi, S.; Kopylov, U.; Verstockt, B.; Chaparro, M.; Buskens, C.; Warusavitarne, J.; Agrawal, M.; Allocca, M.; Atreya, R.; et al. ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment. J. Crohn’s Colitis 2024, 18, 1531–1555. [Google Scholar] [CrossRef]
  14. Lichtenstein, G.R.; Loftus, E.V.; Afzali, A.; Long, M.D.; Barnes, E.L.; Isaacs, K.L.; Ha, C.Y. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am. J. Gastroenterol. 2025, 120, 1225–1264. [Google Scholar] [CrossRef]
  15. Moran, G.W.; Gordon, M.; Sinopolou, V.; Radford, S.J.; Darie, A.-M.; Vuyyuru, S.K.; Alrubaiy, L.; Arebi, N.; Blackwell, J.; Butler, T.D.; et al. British Society of Gastroenterology guidelines on inflammatory bowel disease in adults: 2025. Gut 2025, 74, s1–s101. [Google Scholar] [CrossRef]
  16. Raine, T.; Bonovas, S.; Burisch, J.; Kucharzik, T.; Adamina, M.; Annese, V.; Bachmann, O.; Bettenworth, D.; Chaparro, M.; Czuber-Dochan, W.; et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J. Crohn’s Colitis 2022, 16, 2–17. [Google Scholar] [CrossRef]
  17. Papamichael, K.; Afif, W.; Drobne, D.; Dubinsky, M.C.; Ferrante, M.; Irving, P.M.; Kamperidis, N.; Kobayashi, T.; Kotze, P.G.; Lambert, J.; et al. Therapeutic drug monitoring of biologics in inflammatory bowel disease: Unmet needs and future perspectives. Lancet Gastroenterol. Hepatol. 2022, 7, 171–185. [Google Scholar] [CrossRef]
  18. Barrau, M.; Roblin, X.; Andromaque, L.; Rozieres, A.; Faure, M.; Paul, S.; Nancey, S. What Should We Know about Drug Levels and Therapeutic Drug Monitoring during Pregnancy and Breastfeeding in Inflammatory Bowel Disease under Biologic Therapy? J. Clin. Med. 2023, 12, 7495. [Google Scholar] [CrossRef]
  19. Honap, S.; Jairath, V.; Sands, B.E.; Dulai, P.S.; Danese, S.; Peyrin-Biroulet, L. Acute severe ulcerative colitis trials: The past, the present and the future. Gut 2024, 73, 1763–1773. [Google Scholar] [CrossRef] [PubMed]
  20. Festa, S.; Scribano, M.L.; Pugliese, D.; Bezzio, C.; Principi, M.; Ribaldone, D.G.; Allocca, M.; Mocci, G.; Bodini, G.; Spagnuolo, R.; et al. Long-term outcomes of acute severe ulcerative colitis in the rescue therapy era: A multicentre cohort study. UEG J. 2021, 9, 507–516. [Google Scholar] [CrossRef]
  21. Sebastian, S.; Walker, G.J.; Kennedy, N.A.; Conley, T.E.; Patel, K.V.; Subramanian, S.; Kent, A.J.; Segal, J.P.; Brookes, M.J.; Bhala, N.; et al. Assessment, endoscopy, and treatment in patients with acute severe ulcerative colitis during the COVID-19 pandemic (PROTECT-ASUC): A multicentre, observational, case-control study. Lancet Gastroenterol. Hepatol. 2021, 6, 271–281. [Google Scholar] [CrossRef]
  22. Adedokun, O.J.; Sandborn, W.J.; Feagan, B.G.; Rutgeerts, P.; Xu, Z.; Marano, C.W.; Johanns, J.; Zhou, H.; Davis, H.M.; Cornillie, F.; et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology 2014, 147, 1296–1307.e5. [Google Scholar] [CrossRef]
  23. Battat, R.; Hemperly, A.; Truong, S.; Whitmire, N.; Boland, B.S.; Dulai, P.S.; Holmer, A.K.; Nguyen, N.H.; Singh, S.; Vande Casteele, N.; et al. Baseline Clearance of Infliximab Is Associated with Requirement for Colectomy in Patients with Acute Severe Ulcerative Colitis. Clin. Gastroenterol. Hepatol. 2021, 19, 511–518.e6. [Google Scholar] [CrossRef]
  24. Hindryckx, P.; Novak, G.; Vande Casteele, N.; Laukens, D.; Parker, C.; Shackelton, L.M.; Narula, N.; Khanna, R.; Dulai, P.; Levesque, B.G.; et al. Review article: Dose optimisation of infliximab for acute severe ulcerative colitis. Aliment. Pharmacol. Ther. 2017, 45, 617–630. [Google Scholar] [CrossRef] [PubMed]
  25. Yarur, A.J.; Jain, A.; Sussman, D.A.; Barkin, J.S.; Quintero, M.A.; Princen, F.; Kirkland, R.; Deshpande, A.R.; Singh, S.; Abreu, M.T. The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: The ATLAS study. Gut 2016, 65, 249–255. [Google Scholar] [CrossRef]
  26. Brandse, J.F.; van den Brink, G.R.; Wildenberg, M.E.; van der Kleij, D.; Rispens, T.; Jansen, J.M.; Mathôt, R.A.; Ponsioen, C.Y.; Löwenberg, M.; D’Haens, G.R.A.M. Loss of Infliximab into Feces Is Associated with Lack of Response to Therapy in Patients with Severe Ulcerative Colitis. Gastroenterology 2015, 149, 350–355.e2. [Google Scholar] [CrossRef]
  27. Ordás, I.; Mould, D.R.; Feagan, B.G.; Sandborn, W.J. Anti-TNF monoclonal antibodies in inflammatory bowel disease: Pharmacokinetics-based dosing paradigms. Clin. Pharmacol. Ther. 2012, 91, 635–646. [Google Scholar] [CrossRef] [PubMed]
  28. Biancheri, P.; Brezski, R.J.; Di Sabatino, A.; Greenplate, A.R.; Soring, K.L.; Corazza, G.R.; Kok, K.B.; Rovedatti, L.; Vossenkämper, A.; Ahmad, N.; et al. Proteolytic cleavage and loss of function of biologic agents that neutralize tumor necrosis factor in the mucosa of patients with inflammatory bowel disease. Gastroenterology 2015, 149, 1564–1574.e3. [Google Scholar] [CrossRef]
  29. Brandse, J.F.; Mathôt, R.A.; van der Kleij, D.; Rispens, T.; Ashruf, Y.; Jansen, J.M.; Rietdijk, S.; Löwenberg, M.; Ponsioen, C.Y.; Singh, S.; 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, 251–258.e2. [Google Scholar] [CrossRef] [PubMed]
  30. Choy, M.C.; Li Wai Suen, C.F.D.; Con, D.; Boyd, K.; Pena, R.; Burrell, K.; Rosella, O.; Proud, D.; Brouwer, R.; Gorelik, A.; et al. Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): An open-label, multicentre, randomised controlled trial. Lancet Gastroenterol. Hepatol. 2024, 9, 981–996. [Google Scholar] [CrossRef] [PubMed]
  31. Li Wai Suen, C.F.D.; Choy, M.C.; Con, D.; Cheng, K.; Nigro, J.; Breheney, K.; Boyd, K.; Pena, R.; Burrell, K.; Rosella, O.; et al. Early infliximab levels and clearance predict outcomes after infliximab rescue in acute severe ulcerative colitis: Results from PREDICT-UC. Gastroenterology 2025, in press. [CrossRef]
  32. Gecse, K.; Van Oostrom, J.; Rietdijk, S.; Frigstad, S.O.; Doherty, G.; Irving, P.; Laharie, D.; De Voogd, F.; Hammersboen Bjorlykke, K.; Mould, D.R.; et al. DOP056 TDM-Based Dose-Intensification of Infliximab is not Superior to Standard Dosing in Patients with Acute Severe Ulcerative Colitis: Results from the TITRATE Study. J. Crohn’s Colitis 2025, 19, i194–i195. [Google Scholar] [CrossRef]
  33. Niyigena, E.; Hoffert, Y.; Peyrin-Biroulet, L.; Afif, W.; Roblin, X.; Hanžel, J.; Papamichael, K.; Kobayashi, T.; Wang, Z.; Verstockt, B.; et al. P0643 Development of a personalized infliximab dosing algorithm for Acute Severe Ulcerative Colitis: Results of a multi-center pharmacometrics analysis. J. Crohn’s Colitis 2025, 19, i1263–i1265. [Google Scholar] [CrossRef]
  34. Braamskamp, M.J.A.M.; Dolman, K.M.; Tabbers, M.M. Clinical practice: Protein-losing enteropathy in children. Eur. J. Pediatr. 2010, 169, 1179–1185. [Google Scholar] [CrossRef]
  35. Cameron, K.; Nguyen, A.L.; Gibson, D.J.; Ward, M.G.; Sparrow, M.P.; Gibson, P.R. Review Article: Albumin and Its Role in Inflammatory Bowel Disease: The Old, the New, and the Future. J. Gastro Hepatol. 2025, 40, 808–820. [Google Scholar] [CrossRef]
  36. Dotan, I.; Ron, Y.; Yanai, H.; Becker, S.; Fishman, S.; Yahav, L.; Ben Yehoyada, M.; Mould, D.R. Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: A population pharmacokinetic study. Inflamm. Bowel Dis. 2014, 20, 2247–2259. [Google Scholar] [CrossRef]
  37. Yarur, A.J.; Kanagala, V.; Stein, D.J.; Czul, F.; Quintero, M.A.; Agrawal, D.; Patel, A.; Best, K.; Fox, C.; Idstein, K.; et al. Higher infliximab trough levels are associated with perianal fistula healing in patients with Crohn’s disease. Aliment. Pharmacol. Ther. 2017, 45, 933–940. [Google Scholar] [CrossRef] [PubMed]
  38. Ding, N.S.; Malietzis, G.; Lung, P.F.C.; Penez, L.; Yip, W.M.; Gabe, S.; Jenkins, J.T.; Hart, A. The body composition profile is associated with response to anti-TNF therapy in Crohn’s disease and may offer an alternative dosing paradigm. Aliment. Pharmacol. Ther. 2017, 46, 883–891. [Google Scholar] [CrossRef] [PubMed]
  39. Marquez-Megias, S.; Nalda-Molina, R.; Más-Serrano, P.; Ramon-Lopez, A. Population Pharmacokinetic Model of Adalimumab Based on Prior Information Using Real World Data. Biomedicines 2023, 11, 2822. [Google Scholar] [CrossRef] [PubMed]
  40. Rosario, M.; Dirks, N.L.; Gastonguay, M.R.; Fasanmade, A.A.; Wyant, T.; Parikh, A.; Sandborn, W.J.; Feagan, B.G.; Reinisch, W.; Fox, I. Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn’s disease. Aliment. Pharmacol. Ther. 2015, 42, 188–202. [Google Scholar] [CrossRef]
  41. Alric, H.; Amiot, A.; Kirchgesner, J.; Tréton, X.; Allez, M.; Bouhnik, Y.; Beaugerie, L.; Carbonnel, F.; Meyer, A. Vedolizumab Clinical Decision Support Tool Predicts Efficacy of Vedolizumab but Not Ustekinumab in Refractory Crohn’s Disease. Inflamm. Bowel Dis. 2022, 28, 218–225. [Google Scholar] [CrossRef] [PubMed]
  42. Samaan, M.A.; Cunningham, G.; Lim, S.H.; Dawson, P.; Kottoor, S.H.; Bheekhun, Z.; Lee, E.; Anderson, S.H.; Mawdsley, J.; Ray, S.; et al. Faecal loss of vedolizumab is associated with UC severity, lower serum vedolizumab levels and rates of clinical response: Results from the FAVOUR study. J. Crohns Colitis 2025, 19, jjaf159. [Google Scholar] [CrossRef] [PubMed]
  43. Adedokun, O.J.; Xu, Z.; Marano, C.; O’Brien, C.; Szapary, P.; Zhang, H.; Johanns, J.; Leong, R.W.; Hisamatsu, T.; Van Assche, G.; et al. Ustekinumab Pharmacokinetics and Exposure Response in a Phase 3 Randomized Trial of Patients With Ulcerative Colitis. Clin. Gastroenterol. Hepatol. 2020, 18, 2244–2255.e9. [Google Scholar] [CrossRef]
  44. Adedokun, O.J.; Xu, Z.; Gasink, C.; Kowalski, K.; Sandborn, W.J.; Feagan, B. Population Pharmacokinetics and Exposure–Response Analyses of Ustekinumab in Patients with Moderately to Severely Active Crohn’s Disease. Clin. Ther. 2022, 44, 1336–1355. [Google Scholar] [CrossRef]
  45. Chua, L.; Otani, Y.; Lin, Z.; Friedrich, S.; Durand, F.; Zhang, X.C. Mirikizumab Pharmacokinetics and Exposure-Response in Patients with Moderately-To-Severely Active Crohn’s Disease: Results from Two Randomized Studies. Clin. Transl. Sci. 2025, 18, e70320. [Google Scholar] [CrossRef]
  46. Suleiman, A.A.; Goebel, A.; Bhatnagar, S.; D’Cunha, R.; Liu, W.; Pang, Y. Population Pharmacokinetic and Exposure-Response Analyses for Efficacy and Safety of Risankizumab in Patients with Active Crohn’s Disease. Clin. Pharmacol. Ther. 2023, 113, 839–850. [Google Scholar] [CrossRef]
  47. Deyhim, T.; Cheifetz, A.S.; Papamichael, K. Drug Clearance in Patients with Inflammatory Bowel Disease Treated with Biologics. J. Clin. Med. JCM 2023, 12, 7132. [Google Scholar] [CrossRef] [PubMed]
  48. Bhatnagar, S.; Schlachter, L.; Eckert, D.; Stodtmann, S.; Liu, W.; Lacerda, A.P.; Mohamed, M.-E.F. Pharmacokinetics and Exposure-Response Analyses to Support Dose Selection of Upadacitinib in Crohn’s Disease. Clin. Pharmacol. Ther. 2024, 116, 1240–1251. [Google Scholar] [CrossRef]
  49. Ponce-Bobadilla, A.V.; Stodtmann, S.; Eckert, D.; Zhou, W.; Liu, W.; Mohamed, M.-E.F. Upadacitinib Population Pharmacokinetics and Exposure-Response Relationships in Ulcerative Colitis Patients. Clin. Pharmacokinet. 2023, 62, 101–112. [Google Scholar] [CrossRef]
  50. Tsai, L.; McCurdy, J.D.; Ma, C.; Jairath, V.; Singh, S. Epidemiology and Natural History of Perianal Crohn’s Disease: A Systematic Review and Meta-Analysis of Population-Based Cohorts. Inflamm. Bowel Dis. 2022, 28, 1477–1484. [Google Scholar] [CrossRef]
  51. Sands, B.E.; Anderson, F.H.; Bernstein, C.N.; Chey, W.Y.; Feagan, B.G.; Fedorak, R.N.; Kamm, M.A.; Korzenik, J.R.; Lashner, B.A.; Onken, J.E.; et al. Infliximab Maintenance Therapy for Fistulizing Crohn’s Disease. N. Engl. J. Med. 2004, 350, 876–885. [Google Scholar] [CrossRef]
  52. Papamichael, K.; Vande Casteele, N.; Jeyarajah, J.; Jairath, V.; Osterman, M.T.; Cheifetz, A.S. Higher Postinduction Infliximab Concentrations Are Associated with Improved Clinical Outcomes in Fistulizing Crohn’s Disease: An ACCENT-II Post Hoc Analysis. Am. J. Gastroenterol. 2021, 116, 1007–1014. [Google Scholar] [CrossRef] [PubMed]
  53. Kirkegaard, T. Expression and localisation of matrix metalloproteinases and their natural inhibitors in fistulae of patients with Crohn’s disease. Gut 2004, 53, 701–709. [Google Scholar] [CrossRef]
  54. Papamichael, K.; Centritto, A.; Guillo, L.; Hier, J.; Sherman, Z.; Cheifetz, A.S.; International Consortium of Therapeutic Drug Monitoring (Spectrum). Higher Adalimumab Concentration Is Associated with Complete Fistula Healing in Patients with Perianal Fistulizing Crohn’s Disease. Clin. Gastroenterol. Hepatol. 2024, 22, 2134–2136.e2. [Google Scholar] [CrossRef]
  55. Yao, J.; Zhang, H.; Su, T.; Peng, X.; Zhao, J.; Liu, T.; Wang, W.; Hu, P.; Zhi, M.; Zhang, M. Ustekinumab Promotes Radiological Fistula Healing in Perianal Fistulizing Crohn’s Disease: A Retrospective Real-World Analysis. J. Clin. Med. 2023, 12, 939. [Google Scholar] [CrossRef]
  56. Straatmijer, T.; Biemans, V.B.C.; Moes, D.J.A.R.; Hoentjen, F.; Ter Heine, R.; Maljaars, P.W.J.; Theeuwen, R.; Pierik, M.; Duijvestein, M.; van der Meulen-de Jong, A.E.; et al. Ustekinumab Trough Concentrations Are Associated with Biochemical Outcomes in Patients with Crohn’s Disease. Dig. Dis. Sci. 2023, 68, 2647–2657. [Google Scholar] [CrossRef] [PubMed]
  57. Hirayama, H.; Morita, Y.; Imai, T.; Takahashi, K.; Yoshida, A.; Bamba, S.; Inatomi, O.; Andoh, A. Ustekinumab trough levels predicting laboratory and endoscopic remission in patients with Crohn’s disease. BMC Gastroenterol. 2022, 22, 195. [Google Scholar] [CrossRef]
  58. Singh, S.; Dulai, P.S.; Zarrinpar, A.; Ramamoorthy, S.; Sandborn, W.J. Obesity in IBD: Epidemiology, pathogenesis, disease course and treatment outcomes. Nat. Rev. Gastroenterol. Hepatol. 2017, 14, 110–121. [Google Scholar] [CrossRef]
  59. Colwill, M.; Povlsen, S.; Pollok, R.; Patel, K.; Goodhand, J.; Ahmad, T.; Honap, S. Glucagon-Like Peptide (GLP-1) Receptor Agonists in Inflammatory Bowel Disease: Mechanisms, Clinical Implications, and Therapeutic Potential. J. Crohns Colitis 2025, 19, jjaf167. [Google Scholar] [CrossRef]
  60. Flores, A.; Burstein, E.; Cipher, D.J.; Feagins, L.A. Obesity in Inflammatory Bowel Disease: A Marker of Less Severe Disease. Dig. Dis. Sci. 2015, 60, 2436–2445. [Google Scholar] [CrossRef] [PubMed]
  61. Harper, J.W.; Sinanan, M.N.; Zisman, T.L. Increased body mass index is associated with earlier time to loss of response to infliximab in patients with inflammatory bowel disease. Inflamm. Bowel Dis. 2013, 19, 2118–2124. [Google Scholar] [CrossRef] [PubMed]
  62. Singh, S.; Proudfoot, J.; Xu, R.; Sandborn, W.J. Obesity and Response to Infliximab in Patients with Inflammatory Bowel Diseases: Pooled Analysis of Individual Participant Data from Clinical Trials. Am. J. Gastroenterol. 2018, 113, 883–889. [Google Scholar] [CrossRef]
  63. Bond, A.; Asher, R.; Jackson, R.; Sager, K.; Martin, K.; Kneebone, A.; Philips, S.; Taylor, W.; Subramanian, S. Comparative analysis of the influence of clinical factors including BMI on adalimumab and infliximab trough levels. Eur. J. Gastroenterol. Hepatol. 2016, 28, 271–276. [Google Scholar] [CrossRef]
  64. Fasanmade, A.A.; Adedokun, O.J.; Ford, J.; Hernandez, D.; Johanns, J.; Hu, C.; Davis, H.M.; Zhou, H. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur. J. Clin. Pharmacol. 2009, 65, 1211–1228. [Google Scholar] [CrossRef]
  65. Ebach, D.R.; Jester, T.W.; Galanko, J.A.; Firestine, A.M.; Ammoury, R.; Cabrera, J.; Bass, J.; Minar, P.; Olano, K.; Margolis, P.; et al. High Body Mass Index and Response to Anti-Tumor Necrosis Factor Therapy in Pediatric Crohn’s Disease. Am. J. Gastroenterol. 2024, 119, 1110–1116. [Google Scholar] [CrossRef]
  66. Ponce-Bobadilla, A.V.; Stodtmann, S.; Chen, M.-J.; Winzenborg, I.; Mensing, S.; Blaes, J.; Haslberger, T.; Laplanche, L.; Dreher, I.; Mostafa, N.M. Assessing the Impact of Immunogenicity and Improving Prediction of Trough Concentrations: Population Pharmacokinetic Modeling of Adalimumab in Patients with Crohn’s Disease and Ulcerative Colitis. Clin. Pharmacokinet. 2023, 62, 623–634. [Google Scholar] [CrossRef] [PubMed]
  67. Kurnool, S.; Nguyen, N.H.; Proudfoot, J.; Dulai, P.S.; Boland, B.S.; Vande Casteele, N.; Evans, E.; Grunvald, E.L.; Zarrinpar, A.; Sandborn, W.J.; et al. High body mass index is associated with increased risk of treatment failure and surgery in biologic-treated patients with ulcerative colitis. Aliment. Pharmacol. Ther. 2018, 47, 1472–1479. [Google Scholar] [CrossRef]
  68. Jensen, M.D.; Haymond, M.W. Protein metabolism in obesity: Effects of body fat distribution and hyperinsulinemia on leucine turnover. Am. J. Clin. Nutr. 1991, 53, 172–176. [Google Scholar] [CrossRef]
  69. Hotamisligil, G.S.; Arner, P.; Caro, J.F.; Atkinson, R.L.; Spiegelman, B.M. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J. Clin. Investig. 1995, 95, 2409–2415. [Google Scholar] [CrossRef]
  70. Weisberg, S.P.; McCann, D.; Desai, M.; Rosenbaum, M.; Leibel, R.L.; Ferrante, A.W. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Investig. 2003, 112, 1796–1808. [Google Scholar] [CrossRef] [PubMed]
  71. Desreumaux, P.; Ernst, O.; Geboes, K.; Gambiez, L.; Berrebi, D.; Müller-Alouf, H.; Hafraoui, S.; Emilie, D.; Ectors, N.; Peuchmaur, M.; et al. Inflammatory alterations in mesenteric adipose tissue in Crohn’s disease. Gastroenterology 1999, 117, 73–81. [Google Scholar] [CrossRef]
  72. Sheehan, A.L.; Warren, B.F.; Gear, M.W.; Shepherd, N.A. Fat-wrapping in Crohn’s disease: Pathological basis and relevance to surgical practice. Br. J. Surg. 1992, 79, 955–958. [Google Scholar] [CrossRef]
  73. Althoff, P.; Schmiegel, W.; Lang, G.; Nicolas, V.; Brechmann, T. Creeping Fat Assessed by Small Bowel MRI Is Linked to Bowel Damage and Abdominal Surgery in Crohn’s Disease. Dig. Dis. Sci. 2019, 64, 204–212. [Google Scholar] [CrossRef]
  74. Gu, P.; Chhabra, A.; Chittajallu, P.; Chang, C.; Mendez, D.; Gilman, A.; Fudman, D.I.; Xi, Y.; Feagins, L.A. Visceral Adipose Tissue Volumetrics Inform Odds of Treatment Response and Risk of Subsequent Surgery in IBD Patients Starting Antitumor Necrosis Factor Therapy. Inflamm. Bowel Dis. 2022, 28, 657–666. [Google Scholar] [CrossRef]
  75. Liu, S.; Ding, X.; Maggiore, G.; Pietrobattista, A.; Satapathy, S.K.; Tian, Z.; Jing, X. Sarcopenia is associated with poor clinical outcomes in patients with inflammatory bowel disease: A prospective cohort study. Ann. Transl. Med. 2022, 10, 367. [Google Scholar] [CrossRef] [PubMed]
  76. Yarur, A.J.; Abreu, M.T.; Deepak, P.; Beniwal-Patel, P.; Papamichael, K.; Vaughn, B.; Bruss, A.; Sekhri, S.; Moosreiner, A.; Gu, P.; et al. Patients with Inflammatory Bowel Diseases and Higher Visceral Adipose Tissue Burden May Benefit from Higher Infliximab Concentrations to Achieve Remission. Am. J. Gastroenterol. 2023, 118, 2005–2013. [Google Scholar] [CrossRef] [PubMed]
  77. Wong, E.C.L.; Marshall, J.K.; Reinisch, W.; Narula, N. Body Mass Index Does Not Impact Clinical Efficacy of Ustekinumab in Crohn’s Disease: A Post Hoc Analysis of the IM-UNITI Trial. Inflamm. Bowel Dis. 2021, 27, 848–854. [Google Scholar] [CrossRef] [PubMed]
  78. Holt, D.Q.; Strauss, B.J.; Moore, G.T. Weight and Body Composition Compartments Do Not Predict Therapeutic Thiopurine Metabolite Levels in Inflammatory Bowel Disease. Clin. Transl. Gastroenterol. 2016, 7, e199. [Google Scholar] [CrossRef]
  79. Shen, J.; Tatosian, D.; Sid-Otmane, L.; Teuscher, N.; Chen, L.; Zhang, P.; Tirucherai, G.; Chitkara, D.; Marta, C. Population Pharmacokinetics of Ozanimod and Active Metabolite Cc112273 in Patients with Ulcerative Colitis. Gastroenterology 2022, 162, S17–S18. [Google Scholar] [CrossRef]
  80. Teasdale, S.; Morton, A. Changes in biochemical tests in pregnancy and their clinical significance. Obstet. Med. 2018, 11, 160–170. [Google Scholar] [CrossRef]
  81. Nielsen, O.H.; Gubatan, J.M.; Kolho, K.-L.; Streett, S.E.; Maxwell, C. Updates on the management of inflammatory bowel disease from periconception to pregnancy and lactation. Lancet 2024, 403, 1291–1303. [Google Scholar] [CrossRef]
  82. Rottenstreich, A.; Fridman Lev, S.; Rotem, R.; Mishael, T.; Grisaru Granovsky, S.; Koslowsky, B.; Goldin, E.; Bar-Gil Shitrit, A. Disease flare at prior pregnancy and disease activity at conception are important determinants of disease relapse at subsequent pregnancy in women with inflammatory bowel diseases. Arch. Gynecol. Obstet. 2020, 301, 1449–1454. [Google Scholar] [CrossRef]
  83. Seow, C.H.; Leung, Y.; Vande Casteele, N.; Ehteshami Afshar, E.; Tanyingoh, D.; Bindra, G.; Stewart, M.J.; Beck, P.L.; Kaplan, G.G.; Ghosh, S.; et al. The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease. Aliment. Pharmacol. Ther. 2017, 45, 1329–1338. [Google Scholar] [CrossRef]
  84. Flanagan, E.; Gibson, P.R.; Wright, E.K.; Moore, G.T.; Sparrow, M.P.; Connell, W.; Kamm, M.A.; Begun, J.; Christensen, B.; De Cruz, P.; et al. Infliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure. Aliment. Pharmacol. Ther. 2020, 52, 1551–1562. [Google Scholar] [CrossRef] [PubMed]
  85. Lozano, N.A.; Lozano, A.; Marini, V.; Saranz, R.J.; Blumberg, R.S.; Baker, K.; Agresta, M.F.; Ponzio, M.F. Expression of FcRn receptor in placental tissue and its relationship with IgG levels in term and preterm newborns. Am. J. Rep. Immunol. 2018, 80, e12972. [Google Scholar] [CrossRef]
  86. Flanagan, E.; Wright, E.K.; Hardikar, W.; Sparrow, M.P.; Connell, W.R.; Kamm, M.A.; De Cruz, P.; Brown, S.J.; Thompson, A.; Greenway, A.; et al. Maternal thiopurine metabolism during pregnancy in inflammatory bowel disease and clearance of thiopurine metabolites and outcomes in exposed neonates. Aliment. Pharmacol. Ther. 2021, 53, 810–820. [Google Scholar] [CrossRef]
  87. Prentice, R.; Flanagan, E.; Wright, E.K.; Gibson, P.R.; Rosella, S.; Rosella, O.; Begun, J.; An, Y.-K.; Lawrance, I.C.; Kamm, M.A.; et al. Vedolizumab and Ustekinumab Levels in Pregnant Women with Inflammatory Bowel Disease and Infants Exposed In Utero. Clin. Gastroenterol. Hepatol. 2025, 23, 124–133.e7. [Google Scholar] [CrossRef]
  88. Rowan, C.R.; Cullen, G.; Mulcahy, H.E.; Keegan, D.; Byrne, K.; Murphy, D.J.; Sheridan, J.; Doherty, G.A. Ustekinumab Drug Levels in Maternal and Cord Blood in a Woman with Crohn’s Disease Treated Until 33 Weeks of Gestation. J. Crohn’s Colitis 2018, 12, 376–378. [Google Scholar] [CrossRef]
  89. Torres, J.; Chaparro, M.; Julsgaard, M.; Katsanos, K.; Zelinkova, Z.; Agrawal, M.; Ardizzone, S.; Campmans-Kuijpers, M.; Dragoni, G.; Ferrante, M.; et al. European Crohn’s and Colitis Guidelines on Sexuality, Fertility, Pregnancy, and Lactation. J. Crohn’s Colitis 2023, 17, 1–27. [Google Scholar] [CrossRef] [PubMed]
  90. Chugh, R.; Long, M.D.; Jiang, Y.; Weaver, K.N.; Beaulieu, D.B.; Scherl, E.J.; Mahadevan, U. Maternal and Neonatal Outcomes in Vedolizumab- and Ustekinumab-Exposed Pregnancies: Results from the PIANO Registry. Am. J. Gastroenterol. 2024, 119, 468–476. [Google Scholar] [CrossRef] [PubMed]
  91. Mahadevan, U.; Long, M.D.; Kane, S.V.; Roy, A.; Dubinsky, M.C.; Sands, B.E.; Cohen, R.D.; Chambers, C.D.; Sandborn, W.J. Pregnancy and Neonatal Outcomes After Fetal Exposure to Biologics and Thiopurines Among Women with Inflammatory Bowel Disease. Gastroenterology 2021, 160, 1131–1139. [Google Scholar] [CrossRef] [PubMed]
  92. Long, M.D.; Kane, S.; Beaulieu, D.; Abraham, B.; Zhang, X.; Mahadevan, U. Use of Biosimilars to Infliximab During Pregnancy in Women with Inflammatory Bowel Disease: Results from the Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes Study. Clin. Transl. Gastroenterol. 2024, 15, e00795. [Google Scholar] [CrossRef]
  93. Mahadevan, U.; Long, M. Low Placental Transfer Rates of Risankizumab Among Pregnant Women with Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2024, 30, 2240–2241. [Google Scholar] [CrossRef]
  94. Luu, M.; Benzenine, E.; Doret, M.; Michiels, C.; Barkun, A.; Degand, T.; Quantin, C.; Bardou, M. Continuous Anti-TNFα Use Throughout Pregnancy: Possible Complications for the Mother but Not for the Fetus. A Retrospective Cohort on the French National Health Insurance Database (EVASION). Am. J. Gastroenterol. 2018, 113, 1669–1677. [Google Scholar] [CrossRef]
  95. Ng, S.C.; Shi, H.Y.; Hamidi, N.; Underwood, F.E.; Tang, W.; Benchimol, E.I.; Panaccione, R.; Ghosh, S.; Wu, J.C.Y.; Chan, F.K.L.; et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies. Lancet 2017, 390, 2769–2778. [Google Scholar] [CrossRef]
  96. Kaplan, G.G.; Windsor, J.W. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 56–66. [Google Scholar] [CrossRef]
  97. Hracs, L.; Windsor, J.W.; Gorospe, J.; Cummings, M.; Coward, S.; Buie, M.J.; Quan, J.; Goddard, Q.; Caplan, L.; Markovinović, A.; et al. Global evolution of inflammatory bowel disease across epidemiologic stages. Nature 2025, 642, 458–466. [Google Scholar] [CrossRef]
  98. Honap, S.; Agorogianni, A.; Colwill, M.J.; Mehta, S.K.; Donovan, F.; Pollok, R.; Poullis, A.; Patel, K. JAK inhibitors for inflammatory bowel disease: Recent advances. Frontline Gastroenterol. 2024, 15, 59–69. [Google Scholar] [CrossRef] [PubMed]
  99. Calafat, M.; Mañosa, M.; Cañete, F.; Ricart, E.; Iglesias, E.; Calvo, M.; Rodríguez-Moranta, F.; Taxonera, C.; Nos, P.; Mesonero, F.; et al. Increased risk of thiopurine-related adverse events in elderly patients with IBD. Aliment. Pharmacol. Ther. 2019, 50, 780–788. [Google Scholar] [CrossRef]
  100. Ruiter, R.; Burggraaf, J.; Rissmann, R. Under-representation of elderly in clinical trials: An analysis of the initial approval documents in the Food and Drug Administration database. Br. J. Clin. Pharmacol. 2019, 85, 838–844. [Google Scholar] [CrossRef] [PubMed]
  101. Johnson, C.; Barnes, E.L.; Zhang, X.; Long, M.D. Trends and Characteristics of Clinical Trials Participation for Inflammatory Bowel Disease in the United States: A Report from IBD Partners. Crohn’s Colitis 360 2020, 2, otaa023. [Google Scholar] [CrossRef]
  102. Kantasiripitak, W.; Verstockt, B.; Alsoud, D.; Lobatón, T.; Thomas, D.; Gils, A.; Vermeire, S.; Ferrante, M.; Dreesen, E. The effect of aging on infliximab exposure and response in patients with inflammatory bowel diseases. Br. J. Clin. Pharmacol. 2021, 87, 3776–3789. [Google Scholar] [CrossRef]
  103. Harnik, S.; Ungar, B.; Loebstein, R.; Ben-Horin, S. A Gastroenterologist’s guide to drug interactions of small molecules for inflammatory bowel disease. United Eur. Gastroenterol. J. 2024, 12, 627–637. [Google Scholar] [CrossRef]
  104. Sands, B.E.; Schreiber, S.; Blumenstein, I.; Chiorean, M.V.; Ungaro, R.C.; Rubin, D.T. Clinician’s Guide to Using Ozanimod for the Treatment of Ulcerative Colitis. J. Crohns Colitis 2023, 17, 2012–2025. [Google Scholar] [CrossRef]
  105. Turner, D.; Ruemmele, F.M.; Orlanski-Meyer, E.; Griffiths, A.M.; De Carpi, J.M.; Bronsky, J.; Veres, G.; Aloi, M.; Strisciuglio, C.; Braegger, C.P.; et al. Management of Paediatric Ulcerative Colitis, Part 1: Ambulatory Care—An Evidence-based Guideline From European Crohn’s and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J. Pediatr. Gastroenterol. Nutr. 2018, 67, 257–291. [Google Scholar] [CrossRef] [PubMed]
  106. El-Matary, W.; Walters, T.D.; Huynh, H.Q.; deBruyn, J.; Mack, D.R.; Jacobson, K.; Sherlock, M.E.; Church, P.; Wine, E.; Carroll, M.W.; et al. Higher Postinduction Infliximab Serum Trough Levels Are Associated with Healing of Fistulizing Perianal Crohn’s Disease in Children. Inflamm. Bowel Dis. 2019, 25, 150–155. [Google Scholar] [CrossRef] [PubMed]
  107. Jongsma, M.M.E.; Winter, D.A.; Huynh, H.Q.; Norsa, L.; Hussey, S.; Kolho, K.-L.; Bronsky, J.; Assa, A.; Cohen, S.; Lev-Tzion, R.; et al. Infliximab in young paediatric IBD patients: It is all about the dosing. Eur. J. Pediatr. 2020, 179, 1935–1944. [Google Scholar] [CrossRef] [PubMed]
  108. Rosh, J.R.; Turner, D.; Griffiths, A.; Cohen, S.A.; Jacobstein, D.; Adedokun, O.J.; Padgett, L.; Terry, N.A.; O’Brien, C.; Hyams, J.S. Ustekinumab in Paediatric Patients with Moderately to Severely Active Crohn’s Disease: Pharmacokinetics, Safety, and Efficacy Results from UniStar, a Phase 1 Study. J. Crohns Colitis 2021, 15, 1931–1942. [Google Scholar] [CrossRef]
  109. Whaley, K.G.; Xiong, Y.; Karns, R.; Hyams, J.S.; Kugathasan, S.; Boyle, B.M.; Walters, T.D.; Kelsen, J.; LeLeiko, N.; Shapiro, J.; et al. Multicenter Cohort Study of Infliximab Pharmacokinetics and Therapy Response in Pediatric Acute Severe Ulcerative Colitis. Clin. Gastroenterol. Hepatol. 2023, 21, 1338–1347. [Google Scholar] [CrossRef]
  110. Turner, D.; Mack, D.; Leleiko, N.; Walters, T.D.; Uusoue, K.; Leach, S.T.; Day, A.S.; Crandall, W.; Silverberg, M.S.; Markowitz, J.; et al. Severe Pediatric Ulcerative Colitis: A Prospective Multicenter Study of Outcomes and Predictors of Response. Gastroenterology 2010, 138, 2282–2291. [Google Scholar] [CrossRef]
  111. Chung, A.; Carroll, M.; Almeida, P.; Petrova, A.; Isaac, D.; Mould, D.; Wine, E.; Huynh, H. Early Infliximab Clearance Predicts Remission in Children with Crohn’s Disease. Dig. Dis. Sci. 2023, 68, 1995–2005. [Google Scholar] [CrossRef]
  112. Colman, R.J.; Xiong, Y.; Mizuno, T.; Hyams, J.S.; Noe, J.D.; Boyle, B.; D’Haens, G.R.; van Limbergen, J.; Chun, K.; Yang, J.; et al. Antibodies-to-infliximab accelerate clearance while dose intensification reverses immunogenicity and recaptures clinical response in paediatric Crohn’s disease. Aliment. Pharmacol. Ther. 2022, 55, 593–603. [Google Scholar] [CrossRef]
  113. Dubinsky, M.C.; Rabizadeh, S.; Panetta, J.C.; Spencer, E.A.; Everts-van Der Wind, A.; Dervieux, T. The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn’s Disease with Infliximab. Pharmaceutics 2023, 15, 2408. [Google Scholar] [CrossRef] [PubMed]
  114. Kantasiripitak, W.; Wicha, S.G.; Thomas, D.; Hoffman, I.; Ferrante, M.; Vermeire, S.; Van Hoeve, K.; Dreesen, E. A Model-Based Tool for Guiding Infliximab Induction Dosing to Maximize Long-term Deep Remission in Children with Inflammatory Bowel Diseases. J. Crohn’s Colitis 2023, 17, 896–908. [Google Scholar] [CrossRef] [PubMed]
  115. Minar, P.P.; Colman, R.J.; Zhang, N.; Mizuno, T.; Vinks, A.A. Precise infliximab exposure and pharmacodynamic control to achieve deep remission in paediatric Crohn’s disease (REMODEL-CD): Study protocol for a multicentre, open-label, pragmatic clinical trial in the USA. BMJ Open 2024, 14, e077193. [Google Scholar] [CrossRef]
  116. Yarur, A.J.; Kubiliun, M.J.; Czul, F.; Sussman, D.A.; Quintero, M.A.; Jain, A.; Drake, K.A.; Hauenstein, S.I.; Lockton, S.; Deshpande, A.R.; 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.e3. [Google Scholar] [CrossRef]
  117. Mogensen, D.V.; Brynskov, J.; Ainsworth, M.A.; Nersting, J.; Schmiegelow, K.; Steenholdt, C. A Role for Thiopurine Metabolites in the Synergism Between Thiopurines and Infliximab in Inflammatory Bowel Disease. J. Crohn’s Colitis 2018, 12, 298–305. [Google Scholar] [CrossRef]
  118. Luber, R.P.; Honap, S.; Cunningham, G.; Irving, P.M. Can We Predict the Toxicity and Response to Thiopurines in Inflammatory Bowel Diseases? Front. Med. 2019, 6, 279. [Google Scholar] [CrossRef]
  119. Phillips, J.; Leary, S.; Tyrrell-Price, J. Association between 6-thioguanine nucleotide levels and preventing production of antibodies to infliximab in patients with inflammatory bowel disease. BMJ Open Gastroenterol. 2023, 10, e001149. [Google Scholar] [CrossRef] [PubMed]
  120. Chanchlani, N.; Lin, S.; Bewshea, C.; Hamilton, B.; Thomas, A.; Smith, R.; Roberts, C.; Bishara, M.; Nice, R.; Lees, C.W.; et al. Mechanisms and management of loss of response to anti-TNF therapy for patients with Crohn’s disease: 3-year data from the prospective, multicentre PANTS cohort study. Lancet Gastroenterol. Hepatol. 2024, 9, 521–538. [Google Scholar] [CrossRef]
  121. Roblin, X.; Boschetti, G.; Williet, N.; Nancey, S.; Marotte, H.; Berger, A.; Phelip, J.M.; Peyrin-Biroulet, L.; Colombel, J.F.; Del Tedesco, E.; 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, 142–149. [Google Scholar] [CrossRef]
  122. Ungar, B.; Engel, T.; Yablecovitch, D.; Lahat, A.; Lang, A.; Avidan, B.; Har-Noy, O.; Carter, D.; Levhar, N.; Selinger, L.; et al. Prospective Observational Evaluation of Time-Dependency of Adalimumab Immunogenicity and Drug Concentrations: The POETIC Study. Am. J. Gastroenterol. 2018, 113, 890–898. [Google Scholar] [CrossRef]
  123. Smith, P.J.; Critchley, L.; Storey, D.; Gregg, B.; Stenson, J.; Kneebone, A.; Rimmer, T.; Burke, S.; Hussain, S.; Yi Teoh, W.; et al. Efficacy and Safety of Elective Switching from Intravenous to Subcutaneous Infliximab [CT-P13]: A Multicentre Cohort Study. J. Crohns Colitis 2022, 16, 1436–1446. [Google Scholar] [CrossRef] [PubMed]
  124. Harno-Tasihin, J.; Siregar, L.; Paajanen, M.; Arkkila, P.; Punkkinen, J. Switching from intravenous to subcutaneous infliximab and vedolizumab in patients with inflammatory bowel disease: Impact on trough levels, day hospital visits, and medical expenses. Scand. J. Gastroenterol. 2024, 59, 280–287. [Google Scholar] [CrossRef] [PubMed]
  125. D’Haens, G.; Reinisch, W.; Schreiber, S.; Cummings, F.; Irving, P.M.; Ye, B.D.; Kim, D.-H.; Yoon, S.; Ben-Horin, S. Subcutaneous Infliximab Monotherapy Versus Combination Therapy with Immunosuppressants in Inflammatory Bowel Disease: A Post Hoc Analysis of a Randomised Clinical Trial. Clin. Drug Investig. 2023, 43, 277–288. [Google Scholar] [CrossRef]
  126. Irving, P.; Irving, P.; Rahman, A. Investigating the Need to Continue Taking Immunomodulator Tablets for Patients with Inflammatory Bowel Disease, When Switching from Treatment with Intravenous Infliximab Infusions (Infliximab Given Directly into a Vein) to Subcutaneous Infliximab (Infliximab Given by an Injection Under the Skin). Available online: https://www.isrctn.com/ISRCTN95420128 (accessed on 5 November 2025).
  127. Hanauer, S.B.; Sands, B.E.; Schreiber, S.; Danese, S.; Kłopocka, M.; Kierkuś, J.; Kulynych, R.; Gonciarz, M.; Sołtysiak, A.; Smoliński, P.; et al. Subcutaneous Infliximab (CT-P13 SC) as Maintenance Therapy for Inflammatory Bowel Disease: Two Randomized Phase 3 Trials (LIBERTY). Gastroenterology 2024, 167, 919–933. [Google Scholar] [CrossRef] [PubMed]
  128. Wang, Z.; Verstockt, B.; Sabino, J.; Ferrante, M.; Vermeire, S.; Dreesen, E. Therapeutic Drug Monitoring Can Guide the Intravenous-to-Subcutaneous Switch of Infliximab and Vedolizumab: A Simulation Study. Clin. Gastroenterol. Hepatol. 2023, 21, 3188–3190.e2. [Google Scholar] [CrossRef]
  129. Chetwood, J.D.; Tran, Y.; Subramanian, S.; Smith, P.J.; Iborra, M.; Buisson, A.; Paramsothy, S.; Leong, R.W. Intravenous Versus Subcutaneous Infliximab in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J. Crohn’s Colitis 2024, 18, 1440–1449. [Google Scholar] [CrossRef]
  130. Iborra, M.; Caballol, B.; Garrido, A.; Huguet, J.M.; Mesonero, F.; Ponferrada, Á.; Arias García, L.; Boscá Watts, M.M.; Fernández Prada, S.J.; Brunet Mas, E.; et al. Subcutaneous Infliximab Cutoff Points in Patients with Inflammatory Bowel Disease: Data from the ENEIDA Registry. J. Crohn’s Colitis 2025, 19, jjae127. [Google Scholar] [CrossRef]
  131. Roblin, X.; Boschetti, G.; Duru, G.; Williet, N.; Deltedesco, E.; Phelip, J.M.; Peyrin-Biroulet, L.; Nancey, S.; Flourié, B.; Paul, S. Distinct Thresholds of Infliximab Trough Level Are Associated with Different Therapeutic Outcomes in Patients with Inflammatory Bowel Disease: A Prospective Observational Study. Inflamm. Bowel Dis. 2017, 23, 2048–2053. [Google Scholar] [CrossRef]
  132. Ungar, B.; Kopylov, U.; Yavzori, M.; Fudim, E.; Picard, O.; Lahat, A.; Coscas, D.; Waterman, M.; Haj-Natour, O.; Orbach-Zingboim, N.; et al. Association of Vedolizumab Level, Anti-Drug Antibodies, and α4β7 Occupancy with Response in Patients with Inflammatory Bowel Diseases. Clin. Gastroenterol. Hepatol. 2018, 16, 697–705.e7. [Google Scholar] [CrossRef] [PubMed]
  133. Steenholdt, C.; Lorentsen, R.D.; Petersen, P.N.; Widigson, E.S.; Kloft, C.; Klaasen, R.A.; Brynskov, J. Therapeutic drug monitoring of vedolizumab therapy in inflammatory bowel disease. J. Gastro Hepatol. 2024, 39, 1088–1098. [Google Scholar] [CrossRef] [PubMed]
  134. Seow, C.H.; Marshall, J.K.; Stewart, E.; Pettengell, C.; Ward, R.; Afif, W. The relationship among vedolizumab drug concentrations, biomarkers of inflammation, and clinical outcomes in a Canadian real-world study. J. Can. Assoc. Gastroenterol. 2024, 7, 290–298. [Google Scholar] [CrossRef]
  135. Yacoub, W.; Williet, N.; Pouillon, L.; Di-Bernado, T.; De Carvalho Bittencourt, M.; Nancey, S.; Lopez, A.; Paul, S.; Zallot, C.; Roblin, X.; et al. Early vedolizumab trough levels predict mucosal healing in inflammatory bowel disease: A multicentre prospective observational study. Aliment. Pharmacol. Ther. 2018, 47, 906–912. [Google Scholar] [CrossRef]
  136. Adedokun, O.J.; Xu, Z.; Gasink, C.; Jacobstein, D.; Szapary, P.; Johanns, J.; Gao, L.-L.; Davis, H.M.; Hanauer, S.B.; Feagan, B.G.; et al. Pharmacokinetics and Exposure Response Relationships of Ustekinumab in Patients with Crohn’s Disease. Gastroenterology 2018, 154, 1660–1671. [Google Scholar] [CrossRef]
  137. Bossuyt, P.; Rahier, J.F.; Baert, F.; Louis, E.; Macken, E.; Lobaton, T.; Busschaert, J.; Peeters, H.; Dewint, P.; Franchimont, D.; et al. OP35 Low remission recapture after ustekinumab dose optimization in Crohn’s disease: Results of the randomized placebo-controlled double-blind REScUE study. J. Crohn’s Colitis 2025, 19, i69–i70. [Google Scholar] [CrossRef]
  138. Feagan, B.G.; Danese, S.; Loftus, E.V.; Vermeire, S.; Schreiber, S.; Ritter, T.; Fogel, R.; Mehta, R.; Nijhawan, S.; Kempiński, R.; 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, 2372–2384. [Google Scholar] [CrossRef] [PubMed]
  139. Mukherjee, A.; Hazra, A.; Smith, M.K.; Martin, S.W.; Mould, D.R.; Su, C.; Niezychowski, W. 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, 1136–1145. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Article Metrics

Citations

Article Access Statistics

Journal Statistics
Multiple requests from the same IP address are counted as one view.
Download PDF
Nicotinamide and Pyruvate as Potential Therapeutic Interventions for Metabolic Dysfunction in Primary Open-Angle Glaucoma—A Narrative Review
Previous
Value of Percutaneous Transhepatic Gallbladder Drainage for Advanced Acute Cholecystitis as a Bridging Procedure: A Single-Center Retrospective Study
Next