2017 - Budapest - Hungary

PAGE 2017: Drug/Disease modelling - Other topics
Ana-Marija Grisic

Towards understanding the loss of response to infliximab in patients with inflammatory bowel disease: A population PK modelling approach

Ana-Marija Grisic (1,2), Helena Edlund (1,2), Alexander Eser (3), Wilhelm Huisinga (4), Walter Reinisch (3), Charlotte Kloft (1)

1. Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany; 2. Graduate Research Training Program PharMetrX, Germany; 3. Dept. for Gastroenterology and Hepatology, Medical University of Vienna, Austria; 4. Institute of Mathematics, Universitaet Potsdam, Germany

Objectives: Infliximab (IFX) is an anti-tumour necrosis factor α monoclonal antibody (mAb) used in the treatment of inflammatory bowel disease (IBD). The biggest challenge with IFX therapy is loss of response over time observed in up to 60% of patients. The loss of response has been related to low IFX plasma concentrations [1]. The aim of the current study was to investigate the impact of patient and disease characteristics on IFX exposure in order to identify the subpopulations at risk of therapy failure.

Methods: A pharmacometric analysis was performed on data (npatients = 122) collected as a part of an investigator initiated trial at the outpatient clinic of the Medical University of Vienna. The IBD patients received 2-h IFX infusions of absolute doses between 100 and 1300 mg during induction and/or maintenance phase. The samples (nPK observations = 388) were collected mainly at minimum concentrations and approximately at the middle of dosing interval (0.6-12.4 weeks after last dose). The analysis was conducted using R (version 3.2.4), NONMEM (7.3.0), PsN and Pirana. Impact of covariates on interindividual variability (IIV) of CL was investigated.

Results: The data is best described by a 2-compartment model with linear elimination. Due to the sparse nature of the data, the model had to be reinforced with a previously published model by using the PRIOR functionality of NONMEM. All estimated parameters (CL, V1, V2, Q) were in the range of previously reported IFX values [2-7]. Estimated CL was comparable to values reported for non-specific mAb CL [8], indicating that target-mediated CL was negligible. An exponential IIV model revealed ~40 %CV in CL and residual variability (combined additive and proportional) was ~30 % ± ~0.3 µg/mL. As expected from data availability, shrinkage in IIV of both volumes of distribution was high (> 50%) and low for IIV of CL. Identified covariates with significant influence on CL were anti-IFX antibody status, disease activity, concomitant therapy with immunomodulators and body size. The model exhibited a good performance.

Conclusions: A population PK model on ambulatory data was successfully developed, identifying covariates influencing CL of IFX and contributing to identification of subpopulations at risk. The developed model will be used for PKPD modelling, with the final goal to explain and reduce the occurrence of the loss of response in patients with IBD.



References:
[1] Vande Casteele N et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterol. 148: 1320-1329 (2015).
[2] Fasanmade AA et al. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur. J. Clin. Pharmacol. 65: 1211-1228 (2009). 
[3] Fasanmade AA et al. Pharmacokinetic properties of infliximab in children and adults with Crohn’s disease: A retrospective analysis of data 2 phase III clinical trials. Clin. Ther. 33: 946-964 (2011).
[4] Dotan I et al. Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: A population pharmacokinetic study. Inflamm. Bowel Dis. 20: 2247-2259 (2014).
[5] Buurman DJ et al. Population pharmacokinetics of infliximab in patients with inflammatory bowel disease: Potential implication for dosing in clinical practice. Aliment. Pharmacol. Ther. 42: 529-539 (2015).
[6] Xu Z et al. Population pharmacokinetics of infliximab in patients with ankylosing spondylitis. J. Clin. Pharmacol. 48: 681-695 (2008).
[7] Edlund H et al. Magnitude of increased infliximab clearance imposed by anti-infliximab antibodies in Crohn’s disease is determined by their concentration. AAPS J. 19: 223-233 (2017).
[8] Dirks NL et al. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin. Pharmacokinet. 49: 633-659 (2010).


Reference: PAGE 26 (2017) Abstr 7315 [www.page-meeting.org/?abstract=7315]
Poster: Drug/Disease modelling - Other topics
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