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P731 Impact of the rs1143634 polymorphism in the gene coding for IL1β on pharmacokinetic of infliximab in inflammatory bowel disease patients

J. Guardiola*1, L. Rodriguez-Alonso1, A. Padullés2, P. Ariadna3, H. Colom4, E. Santacana2, C. Arajol1, A. Ruiz-Cerulla1, J. Bas5, F. Morandeira5, F. Rodriguez-Moranta1, N. Padullés2

1Hospital Universitario de Bellvitge, Gastroenterology, L´Hospitalet de Llobregat, Spain, 2Hospital Universitario de Bellvitge, Pharmacy, L´Hospitalet de Llobregat, Spain, 3Hospital Universitario de Bellvitge, Laboratory of Biochemistry, L´Hospitalet de Llobregat, Spain, 4Barcelona University, Pharmacokinetics. School of Pharmacy, Barcelona, Spain, 5Hospital Universitario de Bellvitge, Immunology, L´Hospitalet de Llobregat, Spain

Background

There is a large inter-patient pharmacokinetic (PK) and pharmacodynamic (PD) variability of infliximab (IFX) in inflammatory bowel disease (IBD) that may affect the clinical outcomes. The rs1143634 polymorphism in the gene coding for IL1β has been associated with the serum concentration of this proinflamatory cytokine and with the response to Infliximab in Crohn’s disease (CD) patients. Unravelling the effect of this genetic polymorphism on IFX exposure might help to refine therapy in patients with IBD.

The objective of this study was to assess the effect of the rs1143634 single nucleotide polymorphism (SNP) of IL1β on IFX exposure and PK in IBD patients.

Methods

IBD patients receiving IFX between July 2013 and December 2014 (n = 67) were genotyped for IL1 β polymorphism (CC, CT, and TT). Associations between this SNP and predose concentrations (Cmin, mg/L), dose-adjusted Cmin (Cmin /D, mg.L-1/mg.month-1), area under the concentration-time curve (AUC, mg/h/L), and half-life (t 1/2, days) at steady-state were evaluated. Normalised by dose exposure, parameters were statistically compared after log transformation. Pharmacokinetic and statistical analyses were performed using Nonmem®7.2 and SPSSv19, respectively.

Results

In total, 67 patients were included (56.7% CC, 34.3% CT and 9.0% TT). All patients who developed antibodies towards IFX (ATI) were carriers C (15% of carriers C). Further, 60% of CC patients had Cmin < 3 mg/L vs 17% of TT patients. Univariate analysis demonstrated that median Cmin was statistically lower in CC patients than in TT patients (CC 1.38; CT 2.78; TT 6.40, p = 0.013). Cmin/D (CC 0.04; CT 0.069; TT 0.153, p = 0.019,) and AUC (CC 21771; CT 27825; TT 35875, p = 0.023) were also significantly lower in CC than in TT patients. t1/2 was significantly lower in CC patients than in CT or TT (CC 9.5 vs CT and TT 13) patients (p = 0.038). Analysis of negative ATIs patients (n = 59) showed that median Cmin (2.05 vs 6.40; p = 0.018) and Cmin/D (0.051 vs 0.135, p = 0.036) were significantly lower in CC than in TT patients. Moreover, 55% of CC had a Cmin < 3 mg/L vs 17% of TT patients when ATI was negative.

Conclusion

The rs1143634 polymorphism in the gene coding for IL1β have a major influence on PK of IFX in IBD patients. C allele was associated with lower IFX exposure. Potentially, this polymorphism could be used for IFX dose optimisation.