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P302. Utility of “trough levels” determination and anti-infliximab antibodies in patients with inflammatory bowel disease. Estimation of individual pharmacokinetic parameters (PK) through population pharmacokinetic model

G. Juan1,2, A. Alvariño3,4, L. Oltra4, N. Maroto4, N. Cano2, I. Ferrer2, J. Hinojosa2,4, 1Hospital de Manises, Farmacia Hospitalaria, Valencia, Spain, 2Hospital de Manises, Digestivo, Manises, Spain, 3Hospital de Manises, LABCO, Valencia, Spain, 4Hospital de Manises, Gastroenterology, Valencia, Spain

Background

Anti-TNF agents are effective in inducing and maintaining remission in patients with Inflammatory Bowel Disease (IBD). However, 10–15% are primary non-responders and even 40% lose the response in the follow-up, in connection with the formation of anti-drug antibodies (ADA) and their effect on the trough levels of infliximab (TLI). Recently, the importance of the plasma clearance of the drug has been pointed out in the individualization of treatment.

Aim: To analyze TLI and ADA in a cohort of patients with IBD. Estimating individual pharmacokinetic (PK) parameters through population pharmacokinetic model and bayesian adjustment.

Methods

Retrospective, descriptive study of 27 patients with IBD and with IFX therapy with loss of response (LR), maintained remission (MR) and response to IFX induction (IR). Blood samples for TLI and ADA analyses were obtained prior to IFX infusion. Samples were analyzed by ELISA (Promonitor). ADA presence is considered positive (level apart) and levels >2.5 mcg/ml therapeutics to IFX. Individual PK parameters were estimated using NONMEN VI program and different dosing regimens were simulated.

Results

27 patients (21 CD, 6 UC); 12 M, 15 W; mean age 39 y (15–74). Azathioprine 16 patients. LR:13; MR:8; IR:6 patients, respectively. TLI: undetectable 7%; <3 mcg/ml, 30%; 3–7 mcg/ml, 23%; >7 mcg/ml, 40%. All the patients with undetectable TLI had ADA (>1 mcg/ml). In LR shorten interval +10 mg/kg IFX obtains higher TLI just for shortening interval (13.2 vs 8.8 mcg/ml, respectively). In group IR (TLI 2.74 mcg/ml; 0.01–9.53) 3 patients had low levels and 2 showing ADA. PK study: A biological half life was estimated t1/2: 9.5 days and in ADA presence 5.8 days; plasma clearance of 0.35 L/d (rank: 0.2–0.6 L/d), central distribution volume of 3.55 L (rank: 2.5–4.9 L) and peripheral distribution volume of 1.27 L (rank: 0.95–1.55 L). TLI availability with the simulation strategy of dosing regimens using Bayesian methodology would have changed the therapeutic post-intensify behavior in 10 (77%) patients with LR (8 to reduce dose; 1 to increase dose; 1 biological treatment switch).

Conclusion

Determining TL-IFX and ADA along with the estimation of individual PK parameters appears promising for optimizing treatment in patients with IBD.

1. Clin Ther. 2011; 33: 946–964.