scholarly journals Letter to Dreesen et al. on their article “Modelling of the Relationship Between Infliximab Exposure, Faecal Calprotectin, and Endoscopic Remission in Patients With Crohn's Disease”—A comprehensive review of infliximab population pharmacokinetic modelling publications

2020 ◽  
Author(s):  
Olivier Le Tilly ◽  
Theodora Bejan‐Angoulvant ◽  
Gilles Paintaud ◽  
David Ternant
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Modelling ◽  
Faecal Calprotectin ◽  
Comprehensive Review ◽  
Population Pharmacokinetic Modelling ◽  
Endoscopic Remission ◽  
The Relationship

scholarly journals P307 Modelling of the relationship between ustekinumab exposure, faecal calprotectin and endoscopic outcomes in patients with Crohn’s disease

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S335-S336
Author(s):  
Z Wang ◽  
B Verstockt ◽  
S Vermeire ◽  
J Sabino ◽  
M Ferrante ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Serum Albumin ◽  
Modelling And Simulation ◽  
Population Pharmacokinetic ◽  
Real World Data ◽  
Faecal Calprotectin ◽  
Indirect Response ◽  
Endoscopic Remission ◽  
Dose Optimisation

Abstract Background In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn’s disease (CD) on ustekinumab achieved endoscopic response and 10.9% achieved endoscopic remission at week (w)44. We aimed to investigate if improved endoscopic outcomes can be achieved through dose optimisation based on a population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis. Methods Real-world data were obtained from 83 patients with moderate-to-severe CD (94% multi-refractory) enrolled in a prospective cohort study receiving ustekinumab 6 mg/kg induction and every eight-week (q8w) 90 mg maintenance therapy. Ustekinumab serum concentrations were measured at mid-dose (w4) and trough (w8, w16, w24). Faecal calprotectin (fCal) was measured at baseline and at w4, w8, w16, w24. Endoscopic response (≥50% decrease in simple endoscopic score for CD [SES-CD]) and endoscopic remission (SES-CD ≤2) were assessed at w24. Modelling and simulation were performed using NONMEM 7.4. Results Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fCal, and a logistic regression popPD model linking fCal at w8 to endoscopic outcomes at w24 (Figure 1). Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. The terminal half-life of ustekinumab in a median patient (bodyweight 65 kg, serum albumin 42.7 g/L) was 20.4 days. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1,800 μg/g to 694 μg/g (Figure 2a) The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1,800 μg/g to 214 μg/g (Figure 2b).The results from the simulation-based comparison of q8w and q4w maintenance dosing are shown in Table 1. Dose doubling (180 mg q8w), as opposed to interval halving (90 mg q4w), was predicted to result in a ustekinumab trough concentration of 2.4 μg/mL instead of 4.8 μg/mL. Conclusion The developed model can guide clinical trial design and support model-informed dose optimisation to improve endoscopic outcome rates. Although our analyses showed that q4w dosing resulted in higher ustekinumab and lower fCal concentrations, the proportion of patients achieving endoscopic remission was limited.

Week 6 Calprotectin Best Predicts Likelihood of Long-term Endoscopic Healing in Crohn’s Disease: A Post-hoc Analysis of the UNITI/IM-UNITI Trials

2020 ◽  
Author(s):  
Neeraj Narula ◽  
Emily C L Wong ◽  
Parambir S Dulai ◽  
John K Marshall ◽  
Jean-Frederic Colombel ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Predictive Performance ◽  
Drug Level ◽  
Symptom Improvement ◽  
Faecal Calprotectin ◽  
Post Hoc Analysis ◽  
Post Hoc ◽  
The Relationship

Abstract Objectives There is need for biomarkers as predictors of outcome of medical treatment in Crohn’s disease. The purpose of this study was to evaluate the predictive performance of faecal calprotectin for short- and long-term clinical and endoscopic outcomes. Methods This post-hoc analysis of the UNITI/IM-UNITI studies [NCT01369329, NCT01369342, and NCT01369355; YODA #2019–4026] included 677 patients to evaluate the relationship of Week 6 calprotectin cut-offs and changes from baseline assessments in calprotectin for prediction of outcomes at Weeks 8, 32, and 52, using receiver operating characteristic curves with comparisons of areas under the curve [AUC]. The relationship between clinical and biomarker assessments at Week 6 and endoscopic remission [ER] at Week 52 was evaluated using multivariate logistic regression models adjusted for confounders. Results A Week 6 calprotectin <250 mg/kg demonstrated a significant ability to predict Week 52 ER (AUC 0.709, 95% confidence interval [CI] 0.566–0.852, p = 0.014) with fair accuracy, and performed better than other calprotectin cut-offs and deltas from baseline for prediction of Week 52 ER. When adjusted for covariates, patients with a Week 6 faecal calprotectin <250 mg/kg had 3.48 times [95% CI 1.31–9.28, p = 0.013] increased odds of Week 52 ER. No other Week 6 clinical assessment [clinical remission or clinical response] or biomarker [CRP <5 or drug level] had an association with Week 52 ER. Conclusions In summary, the results of this post-hoc analysis suggest that Week 6 calprotectin levels < 250 mg/kg can be predictive of future endoscopic healing and may be more informative than clinical symptom improvement. Podcast This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast

scholarly journals P497 The value of endoscopic healing index monitoring for guiding infliximab dosing in patients with Crohn’s disease

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S481-S483
Author(s):  
W Kantasiripitak ◽  
R Mathôt ◽  
B Oldenburg ◽  
A Buisson ◽  
M Ferrante ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Time Course ◽  
Population Pharmacokinetic ◽  
Roc Curve Analysis ◽  
Mobility Shift ◽  
Faecal Calprotectin ◽  
Healing Index ◽  
Poppk Model ◽  
Dose Optimisation

Abstract Background The endoscopic healing index (EHI) is a novel multi-protein serum biomarker test developed and validated to assess endoscopic disease activity in patients with Crohn’s disease (CD). Evidence for the use of EHI to guide decision-making during infliximab (IFX) treatment remains scarce. Therefore, we aimed to characterise the relationships between IFX dose, serum IFX concentrations, EHI, and endoscopic remission (ER). Methods Data were obtained from 118 biologic naïve adult patients with CD enrolled in the phase 4 TAILORIX trial (EudraCT 2011 003038 14). All patients had confirmed active CD at baseline based on clinical, biological, and endoscopic criteria. IFX and EHI (scores ranging from 0–100) were measured using a homogenous mobility shift assay (HMSA) and immunoassay, respectively (Prometheus Laboratories). First, the previously published population pharmacokinetic (popPK) model of the TAILORIX study population was revisited to describe the HMSA data. The effect of EHI, faecal calprotectin (FC), C-reactive protein (CRP), and serum albumin (ALB) on IFX clearance was evaluated. Next, a minimal continuous-time Markov model was developed to describe the time course of EHI within patients. EHI was considered as a three-stage ordinal variable (scores 0–19, 20–49, and 50–100) with the lowest score stage (0–19) indicative of ER. The course-modifying effect of IFX on EHI was assessed. Finally, a generalised linear model was used to describe the relationship between EHI and the probability of attaining ER (Simple Endoscopic Score for CD [SES-CD] ≤2). The predictive ability of EHI for ER was compared with that of FC, CRP, ALB, and IFX using a receiver operating characteristic (ROC) curve analysis. Results The revisited two-compartment popPK model described the IFX data with adequate descriptive and predictive accuracies. EHI, FC, CRP, and ALB at week (w)0 were not found to explain interpatient variability in IFX clearance. In contrast, higher IFX at w14 was associated with a higher probability of achieving EHI <20 at w14 (Figure 1). The probability of attaining EHI <20 at w14 was predicted to increase more than four-fold when IFX at w14 was targeted at 10 mg/L instead of 5 mg/L (Table 1). EHI and FC equally well predicted the probability of attaining ER at the same time point (Figure 2, Table 2). Conclusion EHI, FC, ALB, and CRP at w0 should not be considered for a priori IFX dose optimisation. Nevertheless, a posteriori IFX dose optimisation (based on IFX concentrations measurements) towards a predefined IFX concentration at w14 may lead to lower post-induction EHI scores and thus improved ER rates. An IFX target of 10 mg/L at w14 is associated with four-fold higher normalisation of EHI as compared to the commonly used target of 5 mg/L.

scholarly journals Ustekinumab Exposure-outcome Analysis in Crohn’s Disease Only in Part Explains Limited Endoscopic Remission Rates

2019 ◽  
Vol 13 (7) ◽  
pp. 864-872 ◽  
Author(s):  
Bram Verstockt ◽  
Erwin Dreesen ◽  
Maja Noman ◽  
An Outtier ◽  
Nathalie Van den Berghe ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Remission ◽  
Real Life ◽  
Outcome Analysis ◽  
Faecal Calprotectin ◽  
Exposure Response ◽  
Patient Reported ◽  
Endoscopic Remission ◽  
Remission Rates

Abstract Background and Aims Ustekinumab, an anti-IL12/23p40 monoclonal antibody, has been approved for Crohn’s disease [CD]. Real-life data in CD patients receiving ustekinumab intravenously [IV] during induction, followed by subcutaneous [SC] maintenance, are lacking. We assessed efficacy of ustekinumab and studied exposure-response correlations. Methods We performed a prospective study in 86 CD patients predominantly refractory or intolerant to anti-tumour necrosis factor agents and/or vedolizumab. All received ustekinumab 6 mg/kg IV induction, with 90 mg SC every 8 weeks thereafter. Endoscopic response (50% decrease in Simple Endoscopic Score for CD [SES-CD] at Week 24), endoscopic remission [SES-CD ≤2], and clinical remission [daily stool frequency ≤2.8 and abdominal pain score ≤1] were assessed at weeks 4,8,16, and 24. Further serial analyses included patient-reported outcomes [PRO2], faecal calprotectin [fCal], and ustekinumab serum levels. Results SES-CD decreased from 11.5 [8.0–18.0] at baseline to 9.0 [6.0–16.0] at week [w]24 [p = 0.0009], but proportions of patients achieving endoscopic response [20.5%] or endoscopic remission [7.1%] were low. Clinical remission rates were 39.5% at w24. After IV induction, fCal dropped from baseline [1242.9 μg/g] to w4 [529.0 μg/g] and w8 [372.2 μg/g], but increased again by w16 [537.4 μg/g] and w24 [749.0 μg/g]. A clear exposure-response relationship was observed, both during induction and during maintenance therapy, with different thresholds depending on the targeted outcome. Conclusions In this cohort of refractory CD patients, ustekinumab showed good clinical remission rates but limited endoscopic remission after 24 weeks. Our data suggest that higher doses may be required to achieve better endoscopic outcomes.

scholarly journals DOP14 Modelling of the relationship between infliximab exposure, faecal calprotectin, and endoscopic remission in patients with Crohn’s disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S052-S053 ◽  
Author(s):  
E Dreesen ◽  
S Berends ◽  
D Laharie ◽  
G D’Haens ◽  
S Vermeire ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Activity Index ◽  
Simulated Patients ◽  
Dose Escalation Study ◽  
Faecal Calprotectin ◽  
Indirect Response ◽  
Flat Dose ◽  
Biomarker Response ◽  
Endoscopic Remission

Abstract Background Less than 50% of patients with Crohn’s disease (CD) starting infliximab (IFX) therapy achieve endoscopic remission (ER). Evidence for the benefits of pharmacokinetic (PK) and pharmacodynamic (PD) monitoring remains scarce. We aimed to develop a population (pop)PK/PD model to characterise the IFX dose-exposure-biomarker-response (faecal calprotectin [fCal] and ER) relationship in patients with CD. Methods Analyses were performed using data of a phase 4 dose-escalation study (TAILORIX). Patients started standard 5 mg/kg IFX induction therapy at weeks [w]0, 2 and 6. From w14 through w54, the IFX dose could be irreversibly doubled based on one of the three monitoring algorithms.1 Endoscopies were performed at w0, 12 and 54. Three sequential models were developed: A 2-compartment popPK model linking IFX dose to exposure, an indirect response popPK-PD model describing the inhibitory effect of IFX exposure on fCal, and a first-order Markov popPD model linking fCal to transitions between states of ER (CD endoscopic index of severity <3), no ER and dropout (Figure 1). All modelling and simulation were performed using NONMEM 7.4. Results The study included 116/122 (95%) patients with CD enrolled in TAILORIX who had ≥1 detectable IFX serum concentration. In the developed models, it was shown that IFX clearance increased with increasing fCal, decreasing albumin, increasing CD activity index and presence of antibodies to IFX (transiently). Baseline fCal increased with increasing CRP and decreasing platelet count. Lower fCal increased probability of attaining ER and decreased probability of losing ER. Probability of dropping out given an earlier state of absence of ER increased with elapsing time. Simulations of 150 000 patients receiving 5, 7.5 or 10 mg/kg IFX (1:1:1) resulted in a flat dose–response curve due to large interindividual variability in PK and PD (Figure 2, top panels). The predicted fraction of patients achieving ER at w12 was 45.1% [30.3–60.5] (median [IQR]) when on 5 mg/kg IFX (~46.4% observed in data). However, simulations of 10 mg/kg IFX induction doses predicted only a slight increase in the fraction of patients achieving ER at w12 to 47.5% [32.0–62.6]. This minor benefit at the population level argues against systematic 10 mg/kg induction dosing in all patients. A similar observation was done during maintenance therapy, where 70.8% [62.6–75.5] of all simulated patients maintained ER at w54 (~72.2% observed in data) (Figure 2, right panels). Conclusion Model-informed infliximab dose optimisation towards a predefined fCal concentration—while accounting for PK and PD variability—may improve the effectiveness of infliximab therapy (eg. 64% chance of ER at w12 ~100 μg/g fCal at w6). Reference

scholarly journals P537 Real-world long-term effectiveness of ustekinumab in Crohn’s disease: Results from the ENEIDA registry

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S458-S460
Author(s):  
M I Iborra Colomino ◽  
B Beltrán ◽  
A Fernández-Clotet ◽  
E Iglesias Flores ◽  
P Navarro ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Real World ◽  
Clinical Remission ◽  
Poor Response ◽  
Faecal Calprotectin ◽  
The Real ◽  
Reactive Protein ◽  
Endoscopic Remission

Abstract Background There are limited data of long-term ustekinumab administered according to the doses recommended in the UNITI studies. The objective of this study was to assess the real-world, long-term effectiveness of ustekinumab in refractory Crohn’s disease (CD) (LONG-CROHNUSK Study). Methods Multicentre study of CD patients starting ustekinumab at the recommended dose based on weight ~6 mg/kg IV week 0, 90 mg SC week 8 and maintenance 90 mg SC every 8 or 12 weeks and with 1 year of follow-up. Values for Harvey-Bradshaw Index (HBI), endoscopic activity, C reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at weeks 26 and 52. Demographic and clinical data, previous treatments, adverse events (AEs), surgeries and hospitalisations were documented. Potential predictors of clinical and endoscopic remission were examined. Results Four hundred and seven patients were analysed (Table 1). For the maintenance dose, ustekinumab 90 mg was administered SC every 12, 8 and 4 weeks in 56 (14%), 318 (84.5%) and 7 (1.5%) patients, respectively. An interval reduction was applied for 118 patients (29%). Before 52 weeks, treatment discontinuation occurred in 71 patients (17%). At baseline, 295 (72%) had an HBI >4 points. Of these, 169 (57%) and 190 (64%) achieved clinical remission at weeks 26 and 52, respectively. FC levels returned to normal (<250 μg/g) in the 44% and 54% of the patients at weeks 26 and 52, respectively. CRP returned to normal (<3 mg/l) in 36% and 37% of the patients at weeks 26 and 52 respectively. HBI, FC, and CRP values over time are shown in Figure 1. Of the 159 patients with endoscopy at 52 weeks, 25 (16%) were in remission and 58 (36%) presented mild activity. Thirty-eight (9.3%) patients worsened extra-intestinal manifestations and 33 (8%) their perianal disease. AEs were recorded in 54 patients, 73 were hospitalised and 53 had surgery. An association was shown for fewer previous anti-TNF agents and ileal localisation with clinical remission, and for endoscopic severity at baseline with poor response. No factors correlated with endoscopic remission. Conclusion This is the first study to show the real-world long-term effectiveness, endoscopic improvement and safety of ustekinumab administered according to the recommended induction regimen in a cohort of highly refractory CD patients.

scholarly journals End of Induction Patient Reported Outcomes Predict Clinical Remission but not Endoscopic Remission in Crohn’s Disease

2020 ◽  
Author(s):  
Emily C L Wong ◽  
Elisa Buffone ◽  
So Jeong Lee ◽  
Parambir S Dulai ◽  
John K Marshall ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Remission ◽  
Patient Reported Outcomes ◽  
Post Induction ◽  
Patient Reported ◽  
Endoscopic Remission ◽  
One Year ◽  
The Relationship

Abstract Background and Aims It is unclear however whether early symptom improvement in Crohn’s disease (CD) provides any prognostic information for patients long-term. This paper aims to investigate the relationship between early patient reported outcomes (PROs) after completion of induction of infliximab and their relationship with long-term clinical remission (CR) and endoscopic remission (ER). Methods This post-hoc analysis (Clinicaltrials.gov: NCT02096861) used data from 220 CD patients to evaluate the relationship of week 6 and 14 PRO variables and week 54 clinical remission (CR) (CDAI < 150), PRO2 remission (mean score abdominal pain (AP) ≤ 1 and stool frequency (SF) ≤ 1.5), and endoscopic remission (SES-CD < 3). Multivariable logistic regression models adjusted for confounders were used to assess the relationships between post-induction PROs and outcomes of interest. Results Patients with moderate or severe AP after induction had reduced odds of achieving one-year CR and PRO2 remission compared to those with mild AP (aOR for CR 0.31, 95% CI 0.17-0.57, p=0.0002). Similarly, patients with moderate to severely elevated SF after induction had reduced odds of one-year CR and PRO2 remission compared to patients with less SF (aOR for CR 0.31, 95% CI 0.16-0.58, p=0.0003). No significant differences were found when comparing higher week 6 or 14 PRO scores of AP and/or SF to lower PRO scores in the odds of achieving one-year ER. Conclusions Post-induction PROs of AP and SF strongly predict likelihood of one-year CR but are not associated with one-year ER. Clinical symptoms alone should not be relied upon when assessing response to therapies for CD.

Outcomes of Passable and Non-passable Strictures in Clinical Trials of Crohn’s Disease: A Post-hoc Analysis

2021 ◽  
Author(s):  
Neeraj Narula ◽  
Emily C L Wong ◽  
Parambir S Dulai ◽  
John K Marshall ◽  
Jean-Frederic Colombel ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Activity Index ◽  
Disease Activity Index ◽  
Symptom Improvement ◽  
Logistic Regression Models ◽  
Post Hoc Analysis ◽  
Endoscopic Remission ◽  
Post Hoc ◽  
The Impact

Abstract Background and Aims There is paucity of evidence on the reversibility of Crohn’s disease [CD]-related strictures treated with therapies. We aimed to describe the clinical and endoscopic outcomes of CD patients with non-passable strictures. Methods This was a post-hoc analysis of three large CD clinical trial programmes examining outcomes with infliximab, ustekinumab, and azathioprine, which included data on 576 patients including 105 with non-passable strictures and 45 with passable strictures, as measured using the Simple Endoscopic Score for Crohn’s Disease [SES-CD]. The impact of non-passable strictures on achieving clinical remission [CR] and endoscopic remission [ER] was assessed using multivariate logistic regression models. CR was defined as a Crohn’s Disease Activity Index [CDAI] <150, clinical response as a CDAI reduction of ≥100 points, and ER as SES-CD score <3. Results After 1 year of treatment, patients with non-passable strictures demonstrated the ability to achieve passable or no strictures in 62.5% of cases, with 52.4% and 37.5% attaining CR and ER, respectively. However, patients with non-passable strictures at baseline were less likely to demonstrate symptom improvement compared with those with passable or no strictures, with reduced odds of 1-year CR (adjusted odds ratio [aOR] 0.17, 95% CI 0.03–0.99, p = 0.048). No significant differences were observed between patients with non-passable strictures at baseline and those with passable or no strictures in rates of ER [aOR 0.82, 95% CI 0.23–2.85, p = 0.751] at 1 year. Conclusions Patients with non-passable strictures can achieve symptomatic and endoscopic remission when receiving therapies used to treat CD, although they are less likely to obtain CR compared with patients without non-passable strictures. These findings support the importance of balancing the presence of non-passable strictures in trial arms.

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