Wannee Kantasiripitak (1), Bram Verstockt (2,3), Triana Lobatón (2,3,4), Debby Thomas (1), Ann Gils (1), Séverine Vermeire (2,3), Marc Ferrante (2,3), Erwin Dreesen (1)
(1) Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Belgium, (2) Department of Gastroenterology and Hepatology, University Hospitals Leuven, Belgium, (3) Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Belgium, (4) Department of Gastroenterology, Ghent University Hospital, Belgium.
Objectives:
Infliximab (IFX, Remicade®) is an anti-tumour necrosis factor-alpha monoclonal antibody for the treatment of patients with moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD). Standard IFX dosing involves the intravenous infusion of 5 mg/kg IFX at weeks 0, 2 and 6 during induction treatment followed by maintenance doses of 5 mg/kg every eight weeks. Twenty years after approval by the US Food and Drug Administration, data remain scarce in terms of efficacy and safety of IFX treatment in elderly patients with UC and CD [1].
Our aims were to improve our understanding of the impact of age-related factors on IFX exposure and the relationship between IFX exposure and response (endoscopic remission; ER).
Methods:
IFX concentration-time data during induction treatment (infusions at weeks [w]0, 2, and 6; trough concentration [TC] at w2, 6 and 14) of 104 patients were obtained from a retrospective case-control study [2] (n=79) and a single centre database search (n=25) at University Hospitals Leuven, Belgium. Patients ≥65 years old were defined as elderly. A population pharmacokinetic (popPK) model was developed. The M3 method was used to handle measurement results below the limit of quantification (BLQ,
Endoscopies were performed before start of IFX treatment (baseline) and after 42 to 154 days (postinduction). All patients had active disease at baseline and ER was defined as the absence of ulceration [CD] and a Mayo endoscopic sub-score ≤0 [UC] postinduction. A first-order Markov model was implemented to describe the relationship between an IFX exposure metric and ER. The patient’s age (a continuous variable) and being elderly (a dichotomised variable) were evaluated on the Markov model parameter (half-maximal effective PK metric; EX50).
Results:
The median age was 62 years (interquartile range 38-68 years). A total of 46 out of 104 patients (44%) was elderly. A total of 272 TC was available to develop the popPK model. The IFX concentration was BLQ in six serum samples (2.2%, 6/272 samples). A one-compartment model with linear elimination showed adequate descriptive and predictive ability. The estimated PK parameters (typical value [%relative standard error]) were clearance (CL: 0.346 l/day [5%]) and volume of distribution (V: 6.42 l [5%]). The residual error was best described using a combined additive and proportional error model. IFX clearance was 32% higher in the presence of antibodies to IFX (ATI; measured using a drug-tolerant immunoassay), 1.4% higher per kg fat-free mass (FFM), 4.5% lower per g/l serum albumin concentration, and 0.6% lower per year of age. Only 10% of the interindividual variability (IIV) in IFX clearance was explained by these four covariates, leaving 33% IIV unexplained. The proportion of patients with ATI was not significantly different between elderly and non-elderly (13% [6/46] versus 14% [8/58], respectively, P=1.000). FFM and serum albumin were significantly lower in elderly patients (P=0.007 and P=0.0004, respectively). Due to opposing covariate effects and the large unexplained IIV, IFX exposure metrics (observed and estimated TC and AUC) were not significantly different between elderly and non-elderly patients.
A total of 16/59 patients achieved ER (27%, available case analysis; 45/104 had no endoscopy data available). The estimated IFX TC before the w14 infusion was the best predictor of ER (lowest objective function value [OFV]). Models including the (continuous or dichotomised) age effect on EX50 did not significantly reduce the OFV. A TC of 8.8 [36%] mg/l corresponded to a 50% probability of achieving ER.
Conclusions:
Higher age is an independent predictor of lower IFX clearance and thus higher exposure. However, the effect of age did not pronounce on IFX exposure in our elderly patient cohort as a result of the opposing effects of FFM and serum albumin. The infliximab exposure-response relationship was not found to be affected by age.
References:
[1] LeBlanc JF et al. World J Gastroenterol (2019) 25, 4158-4171
[2] Lobatón T et al. Aliment Pharmacol Ther (2015) 42, 441-451
Reference: PAGE () Abstr 9461 [www.page-meeting.org/?abstract=9461]
Poster: Oral: Drug/Disease Modelling