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P352 TDM of infliximab in IBD-patients: which pharmacokinetic marker to use?

S. Berends*1,2, R. Mathôt1, A. Strik2, A. De Vries3, M. Löwenberg2, G. D'Haens2

1Amsterdam UMC - location AMC, Hospital Pharmacy, Amsterdam, The Netherlands, 2Amsterdam UMC - location AMC, Gastroenterology and Hepatology, Amsterdam, The Netherlands, 3Sanquin Diagnostic Services, Biologics Lab, Bioanalysis, Amsterdam, The Netherlands

Background

According to the registered label of infliximab (IFX), patients with inflammatory bowel disease (IBD) receive 5 mg/kg IFX every 8 weeks during maintenance treatment. In clinical practice, the efficacy of IFX is often optimised by ‘therapeutic drug monitoring’ (TDM), that is, adjustment of doses and dosing intervals of IFX based on IFX serum trough levels (TL) (before an infusion). The TL is used as a pharmacokinetic (PK) surrogate reflecting the ‘total’ drug exposure or area under the concentration vs. time curve (AUC) after administration. With TDM gaining interest, we evaluated the correlation between IFX TLs and AUC in IBD patients during maintenance therapy.

Methods

We performed an analysis of a prospective cohort of 36 IBD patients treated with IFX maintenance therapy. IFX serum concentrations were measured at trough, peak (10 min after the end of infusion) and at mid-infusion (in between doses). Patients were divided into 4 groups according to their dosing interval of 4, 6, 8, or 10 weeks. TLs were measured by an enzyme-linked immunosorbent assay (ELISA) (Sanquin Laboratories, the Netherlands). AUC was calculated using Bayesian analysis (NONMEM®) and correlated to the corresponding IFX TL.

Results

Thirty-six IBD patients (Crohn’s disease: 26, ulcerative colitis: 10) were included. Median [interquartile range (IQR)] age was 30 years [43–51] and disease duration 13 years [6–26]. A total of 19 patients used a concomitant immunomodulator (thiopurine: 17, methotrexate: 2). Correlations between AUCs and IFX trough concentrations were poor for the 6- and 8-week dosing interval (Table 1). In the 8-week interval, for patients with a IFX trough concentration between 3 and 5 mg/l the AUC ranged from 1094–1953 mg/l*day (Figure 1).

4-week interval6-week interval8-week interval10-week interval
N patients35244
AUC (mg/l * day) (min–max)895–12571076–1410928–1953934–1614
Trough concentration (mg/l) (min–max)4.0 – 22.92.5–13.20.6–7.30.7–2.8
Dose IFX (mg) (min–max)350 – 400350 – 450250 – 600300 – 500
Dose IFX (mg/kg) (min–max)5.1–6.34.4–5.84.3–8.04.2–6.6
CRP (mg/l) (median [IQR])0.15 [0.3–0.6]1.2 [0.7–5.9]1.1 [0.3–3.0]9.8 [2.3–12.3]
Albumin (g/l) (median [IQR])42 [45–47]42 [45–47]41 [43–45]40 [43–48]
Correlation AUC-trough0.99 (p = 0.1)0.52 (p = 0.38)0.42 (p = 0.04)0.81 (p = 0.19)

Conclusion

Currently, IFX TLs are used as a pharmacokinetic marker for exposure in IBD patients. However, IFX TLs correlate poorly to AUCs of IFX. This raises the question if a TL is the best pharmacokinetic marker for optimising the clinical efficacy of IFX in IBD patients.