4.4 Article

Predictors of Infliximab Trough Concentrations in Inflammatory Bowel Disease Patients Using a Repeated-Measures Design

Journal

THERAPEUTIC DRUG MONITORING
Volume 42, Issue 1, Pages 102-110

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FTD.0000000000000669

Keywords

infliximab; pharmacokinetics; inflammatory bowel disease

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Background and aims: Treating patients based on a treat-to-trough approach has been shown to be a cost-effective strategy for inflammatory bowel disease (IBD) patients who have become unresponsive to infliximab (IFX). However, the documented evidence for this is limited, and some controversy remains regarding the use of routine proactive therapeutic drug monitoring (TDM). To support routine TDM of IFX and regimen optimization in IBD patients, more in-depth knowledge of the covariates that affect the pharmacokinetic (PK) variability of IFX is needed. The aim of this study was to identify the characteristics of the patient, disease, and treatments that influence IFX PK and exposure in our cohort of IBD patients using a repeated-measures design. Methods: We performed a prospective observational study of adult IBD patients who received IFX between July 2013 and March 2017. We obtained repeated IFX trough concentration (C-min) measurements and implemented a previously described population pharmacokinetic model to estimate individual clearance (CL). From the individual primary parameters, the area under the curve (AUC), half-life (t(1/2)), and central elimination rate constant (K-10) were estimated. We performed a repeated-measures analysis to evaluate whether patient characteristics, disease status, concomitant immunosuppressive therapy, and immunogenicity are associated with IFX C-min and PK parameters. Results: We collected 429 C-min measurements from 112 patients. The median of the C-min values was 3.62 mg/L (1.47-6.02). Antibodies to IFX (ATI) were detected in 14 patients. The predicted median AUC was 28,421 mg/h/L (22,336-36,903). The median individual predicted CL, K-10, and t(1/2) values were 4.77 mL/kg/day (3.88-5.90), 0.09 days(-1) (0.08-0.12), and 12.22 days (9.49-14.87), respectively. IFX C-min, AUC, CL, and K-10 were significantly influenced by ATI and serum albumin concentrations. Moreover, body weight was significantly associated with AUC, CL, and K-10. Patients receiving concurrent immunosuppressive therapy had higher C-min and AUC values and lower CL and K-10 values than those treated with IFX monotherapy. We also observed high intrapatient variability in C-min values during the study period. Conclusions: In this repeated-measures study in a population of IBD patients, we observed significant associations between ATI, serum albumin concentration, concomitant immunosuppressive therapy, body weight and gender, and IFX C-min, and CL. The high PK variability observed in this study supports the need for proactive TDM to optimize the use of IFX as early as possible in IBD patients.

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