Modeling Immunization To Infliximab in Children With Crohn’s Disease Using Population Pharmacokinetics: A Pilot Study

Petitcollin, Antoine; Leuret, O.; Tron, Camille; Lemaître, F.; Verdier, Marie‐Clémence; Paintaud, Gilles; Bouguen, Guillaume; Willot, S.; Ternant, David

doi:10.1093/ibd/izy129

Cited by 20 publications

(19 citation statements)

References 27 publications

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“…The logit-risk model used here to describe the fast changes in infliximab clearance was already tested in a cohort of children with IBD and is useful to describe immunizations to infliximab as well as transient periods of higher clearance, for example, during the induction phase. 12 Of note, in the present study, only one patient tested positive for ADA. In this patient, the logit-risk model detected a clearance increase of 1.9fold prior to ADA positivity, indicating that the model described the immunization process well in this patient.…”

Section: Discussioncontrasting

confidence: 44%

“…The majority of the remaining concentrations that were not well predicted were properly described after the addition a logit‐risk model, as previously described, with a decrease of Akaike's information criterion of −64. Of note, only one sample was tested positive for antidrug antibodies (ADAs) and, thus, the effect of this covariate was not assessed.…”

Section: Resultsmentioning

confidence: 60%

“…These results support our hypothesis that measuring infliximab clearance could be of interest to improve the monitoring of the treatment. 12 A higher volume of distribution was also associated with lower relapse rates. This was unexpected as a higher volume of distribution would result in lower circulating concentrations.…”

Section: Discussionmentioning

confidence: 94%

“…Therefore, a logit model was used to detect and describe the clearance variations that were not explained by the aforementioned time-varying model, as we previously reported. 12 Briefly, this model is constituted of a linear risk function of time which is logit-transformed as follows:…”

Section: Modeling Of the Time-varying Clearance Of Infliximabmentioning

confidence: 99%

“…Identifying these pharmacokinetic characteristics seems an appealing approach because they are closely linked to the activity of the disease, and recent data suggest that monitoring of infliximab clearance along with the concentrations may be superior to concentrations alone in predicting the success of the treatment. 12 Moreover, the long-term pharmacokinetics of infliximab has never been described in patients with IBD with sustained remission who underwent a de-escalation, although infliximab pharmacokinetics may be different in this population compared with patients with an active disease, with a direct impact on the modalities of dose adjustments. The use of population pharmacokinetic modeling can help address these questions and refine the exploration of the predictive factors of relapse at de-escalation.…”

mentioning

confidence: 99%

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Pharmacokinetic Parameters of Infliximab Influence the Rate of Relapse After De‐Escalation in Adults With Inflammatory Bowel Diseases

Petitcollin

Brochard

Siproudhis

et al. 2019

Clin Pharma and Therapeutics

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This study aimed at exploring the link among individual concentrations, pharmacokinetic parameters, and the probability of relapse after de‐escalation in a real‐world prospective cohort of patients with inflammatory bowel disease (IBD) who underwent infliximab treatment de‐escalation. Ninety‐one patients were included. A time‐varying compartment model was used to estimate individual pharmacokinetic parameters and trough concentrations. A Cox model was implemented to explore the parameters influencing the probability of relapse after de‐escalation. Volume, clearance, and trough before and after de‐escalation were linked to the relapse risk at the univariate step. Independent predictors of relapse were tobacco use and/or ulcerative colitis (P = 0.0093), a higher C‐reactive protein (CRP; P = 0.00064), and an infliximab trough < 2.4 μg/mL after de‐escalation (P = 0.0001). Patients with trough > 5.7 μg/mL are eligible to de‐escalation, but infliximab pharmacokinetics is highly variable in time. Therefore, drug monitoring is mandatory after de‐escalation to maintain trough > 2.4 μg/mL. Clearance monitoring seems an appealing approach for patient selection and relapse prediction.

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Section: Discussioncontrasting

confidence: 44%

Section: Resultsmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 94%

Section: Modeling Of the Time-varying Clearance Of Infliximabmentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetic Parameters of Infliximab Influence the Rate of Relapse After De‐Escalation in Adults With Inflammatory Bowel Diseases

Petitcollin

Brochard

Siproudhis

et al. 2019

Clin Pharma and Therapeutics

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SERENE ER Analysis Part 2 SERENE‐UC: Exposure‐response Analysis of Higher Versus Standard Adalimumab Dosing Regimens for Patients with Moderately to Severely Active Ulcerative Colitis

Stodtmann,

Chen,

Ponce‐Bobadilla

et al. 2024

Clinical Pharm in Drug Dev

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SERENE UC (NCT02065622) evaluated whether a higher adalimumab induction regimen improved patients with ulcerative colitis (UC) response, but a flat dose‐response relationship was found in the induction study. We investigated exposure‐response (ER) relationships in induction and maintenance studies considering patients’ baseline characteristics. Adalimumab exposures were simulated using the established population pharmacokinetic model. Multivariable logistic regressions were used to assess the efficacy endpoints (clinical remission, endoscopic remission, endoscopic improvement) at weeks 8 and 52. In the induction study, an increasing ER trend with heterogeneity between induction regimens was shown, suggesting average concentration (Cavg) had a significant impact on primary efficacy endpoints within each group. However, data were not described by a single ER curve. Using inverse effective clearance as the exposure metric described trends across induction regimens with a single curve. Patients with inherently lower effective adalimumab clearance responded better. The patient response rates at week 52 showed no heterogeneity. A short‐term increase in adalimumab dose did not drive better responses for induction, and apparent ER relationships were better explained by patient‐inherent lower clearance. Conversely, during maintenance up to week 52, increasing the concentration via dose translated to better responses more robustly. The ER findings for SERENE UC were consistent with SERENE CD.

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SERENE ER Analysis Part 1‐SERENE CD: Exposure‐Response Analysis of Higher Versus Standard Adalimumab Dosing Regimens for Patients With Moderately to Severely Active Crohn Disease

Chen,

Ponce‐Bobadilla,

Stodtmann

et al. 2024

Clinical Pharm in Drug Dev

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SERENE CD (NCT02065570) evaluated whether a higher adalimumab induction dose would improve patients with Crohn disease response and suggested a flat dose‐response relationship for efficacy in the induction study. We investigated exposure‐response relationships in induction and maintenance studies considering patients’ baseline characteristics. Adalimumab exposures were simulated using the established population pharmacokinetic model. Efficacy end points (clinical remission/endoscopic response) at Weeks 4, 12, and 56 were evaluated in exposure‐response analyses using multivariable logistic regression. Analyses showed an increasing trend with heterogeneity between induction regimens, which suggested that average concentration has an impact on coprimary efficacy end points within each group, but data did not fit a single‐response curve. Although higher concentrations within arms were associated with improved outcomes, increasing the concentration through a higher induction dose was not associated with increasing clinical remission/endoscopic response at Week 4/12. A model including inverse effective clearance eliminated heterogeneity and described trends across induction regimens with a single curve. In the maintenance study, the response rates at Week 56 showed no heterogeneity. In the induction study, patients with lower effective adalimumab clearance responded better, whereas in the maintenance study average concentration drove primary efficacy end points at Week 56. Research extending these findings to other indications is needed.

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Modeling Immunization To Infliximab in Children With Crohn’s Disease Using Population Pharmacokinetics: A Pilot Study

Cited by 20 publications

References 27 publications

Pharmacokinetic Parameters of Infliximab Influence the Rate of Relapse After De‐Escalation in Adults With Inflammatory Bowel Diseases

Pharmacokinetic Parameters of Infliximab Influence the Rate of Relapse After De‐Escalation in Adults With Inflammatory Bowel Diseases

SERENE ER Analysis Part 2 SERENE‐UC: Exposure‐response Analysis of Higher Versus Standard Adalimumab Dosing Regimens for Patients with Moderately to Severely Active Ulcerative Colitis

SERENE ER Analysis Part 1‐SERENE CD: Exposure‐Response Analysis of Higher Versus Standard Adalimumab Dosing Regimens for Patients With Moderately to Severely Active Crohn Disease

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