Optimización de la terapia con infliximab en pacientes con enfermedad inflamatoria intestinal según parámetros PK/PDestrategia, modelo y validación de resultados

Abstract

Introduction Infliximab is a monoclonal antibody, highly effective in inflammatory bowel disease (IBD), however it has great interindividual pharmacokinetic variability. A 30% of patients show a primary non-renpose to biological therapy, and over time, around 50% of patients show a loss of secondary response or develop adverse effects. Proactive pharmacokinetic monitoring during the induction and maintenance period plays a key role in these patients and can improve the response of treatment. In the same way, the individualized estimation of the pharmacokinetic parameters by bayesian methods, could improve the precision in the selection of the most optimal dosage regimen for each patient. Objective For this reason, the first objective of our study was to compare the drug survival of infliximab versus adalimumab as first and second line anti-TNF treatments in patients with IBD and factors associated with achieving greater therapeutic survival. The second objective was to compare two methods of dose adjustment strategy using pharmacokinetic monitoring based: (1) on algorithms and (2) on bayesian prediction, to achieve an optimal infliximab trough concentration in these patients. As well as, evaluate the predictive performance of a population pharmacokinetic model of infliximab in patients with IBD. Finally, the pharmacokinetic variability of infliximab was evaluated and the factors associated with achieving an optimal infliximab trough level during the induction period were determined. Patients and Methods A retrospective observational study was performed in patients with IBD in treatment with biological therapy and drug levels. It was carried out in a Murcia hospital that cares for a population of around 200,892 inhabitants. Drug survival analysis was performed in the first and second line of treatment. To carry out the second objective, the external validation of a previously published population pharmacokinetic model was performed using NONMEM¿ software, and two methods of dose adjustment strategy using therapeutic drug monitoring were compared. Finally, the percentage of patients who achieving optimal infliximab trough level at week 6 was determined, and remission and clinical response were evaluated, as well as biochemical remission, at week 26. Results In our study, infliximab and adalimumab showed similar drug survival as first- and second-line anti-tumour necrosis factor treatments, where therapeutic drug monitoring was associated with a greater survival of the drug in both treatment lines (p = 0.001 and p = 0.004, respectively). Regarding the second objective, it was observed that a dose adjustment strategy based on Bayesian estimates, was associated with higher infliximab trough level, compared to the strategy based on clinical algorithms (OR: 8.94 [95% CI: 2.24 - 35.6], p = 0.001). Finally, it was determined that only the 43.3% of the patients had target infliximab levels during the induction period, with the need to optimize therapy. Conclusions Therapeutic drug monitoring is an effective tool to optimize treatment in patients with IBD, both in induction and maintenance, in addition our study suggests that it may increase the survival of the drug. The incorporation of the Bayesian methodology for dose adjustment of infliximab is an important advance in the individualized optimization of therapy. Keywords: therapeutic drug monitoring, infliximab, inflammatory bowel disease , drug survival, population pharmacokinetics, induction.