Clinical relevance of albumin concentration in patients with Crohn’s disease treated with infliximab for recommendations on dosing regimen adjustments
H. Andersson (1,2), A. Keunecke (1), A. Eser (3), W. Reinisch (3), W. Huisinga (4), C. Kloft (1)
(1) Dept. of Clinical Pharmacy and Biochemistry, Freie Universitaet Berlin, Germany and (2) Graduate Research Training program PharMetrX, Germany. (3) Department for Gastroenterology and Hepatology, Medical University of Vienna, Austria. (4) Institute of Mathematics, Universitaet Potsdam, Germany.
Objectives: A high proportion of patients affected by Crohn’s disease (CD) lose response to infliximab (IFX) in the long-term. Patients with trough concentrations of IFX (Cmin) > 0.5 mg/L are more likely to exhibit maintained clinical remission [1]. Hypoalbuminaemia is seen in patients with severe disease status due to ulcerated mucosa, leading to loss of proteins as well as of IFX [2]. Based on the population pharmacokinetic model for IFX by Fasanmade et al. [3] and the clinical insight from [1, 2], we designed a simulation study to assess the clinical relevance of the serum albumin concentration (sALB) in patients with CD and establish recommendations for dose adjustments.
Methods: Concentration-time profiles of IFX were simulated in NONMEM using the model published in [3]. The covariates were sampled from realistic distributions in agreement with the observed population. The percentage of patients above the cut-off of 0.5 mg/L at steady state was calculated, both for the total population and for the two subpopulations with physiological (≥ 35 g/L) or low (< 35 g/L) sALB. New dosing regimens were simulated for the group with low sALB to achieve the same proportion of patients > 0.5 mg/L as in the group with physiological sALB. The sensitivity of using 0.5 mg/L is 86% [1], i.e., 86% of the patients with Cmin > 0.5 mg/L will truly exhibit maintained response.
Results: Application of the cut-off resulted in proportions of patients with maintained response similar to previous reports for IFX in CD [4]. The group with low sALB had a considerably smaller proportion of patients above the cut-off compared to the group with physiological sALB. Increasing the dose in these patients did not increase this proportion to a large extent but increased the maximal concentration (Cmax). Reducing the dosing interval, however, resulted in a larger increase of the proportion, without a high impact on Cmax.
Conclusions: A Cmin > 0.5 mg/L seems to be a good predictor for maintained response in patients with CD. Patients with low sALB exhibited lower Cmin than patients with physiological sALB. Shortening the dosing interval was preferred compared to increasing the dose. However, the variability in IFX clearance in this population is substantial. A model with covariates explaining more of the inter-individual variability is needed to be able to give more precise recommendations for dose adjustments.
References:
[1] Steenholdt et al. Scand J Gastroenterol 46:310 (2011)
[2] Brandse et al. Abstract (P500) 8th Congress of ECCO (2013)
[3] Fasanmade et al. Clin Ther. 33:946 (2011)
[4] Hanauer et al. Lancet 359:1541 (2002)