Evaluation of the Predictive Performance of Population Pharmacokinetic Models of Adalimumab in Patients with Inflammatory Bowel Disease.

Silvia Marquez-Megias,Patricio Más-Serrano,Amelia Ramon-Lopez,Maria Remedios Candela-Boix,Ricardo Nalda-Molina,Marcos Diaz-Gonzalez

doi:10.3390/pharmaceutics13081244

Abstract

Adalimumab is a monoclonal antibody used for inflammatory bowel disease. Due to its considerably variable pharmacokinetics, the loss of response and the development of anti-antibodies, it is highly recommended to use a model-informed precision dosing approach. The aim of this study is to evaluate the predictive performance of different population-pharmacokinetic models of adalimumab for inflammatory bowel disease to determine the pharmacokinetic model(s) that best suit our population to use in the clinical routine. A retrospective observational study with 134 patients was conducted at the General University Hospital of Alicante between 2014 and 2019. Model adequacy of each model was evaluated by the distribution of the individual pharmacokinetic parameters and the NPDE plots whereas predictive performance was assessed by calculating bias and precision. Moreover, stochastic simulations were performed to optimize the maintenance doses in the clinical protocols, to reach the target of 8 mg/L in at least 75% of the population. Two population-pharmacokinetic models were selected out of the six found in the literature which performed better in terms of adequacy and predictive performance. The stochastic simulations suggested the benefits of increasing the maintenance dose in protocol to reach the 8 mg/L target.

Highlights

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) characterized by the intermittent destructive inflammation of the intestinal tract associated with significant morbidity, high burden of hospitalization and a severe impact on the quality of life of patients
An important aspect to validate is the predictive performance of the models, in similar conditions to the clinical routine
Many validations published in the literature do not really validate the predictive performance, but rather evaluate the model adequacy to the data

Summary

Introduction

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) characterized by the intermittent destructive inflammation of the intestinal tract associated with significant morbidity, high burden of hospitalization and a severe impact on the quality of life of patients. There are several pharmacological alternatives available, including corticosteroids, immunosuppressive agents (methotrexate or azathioprine) and monoclonal antibodies that have shown clinical response in the treatment of these diseases [1,2,3]. Adalimumab is effective for induction and maintenance of remission in patients with moderate-to-severe IBD older than 6 years who fail with corticosteroids, immunosuppressive agents or other biologic therapy [4,5,6]. Several studies have shown that some patients can experience a loss of response to adalimumab or can develop antibodies against adalimumab (AAA) after long periods of subtherapeutic drug levels [7,8,9,10,11,12,13,14]. Most of the time, the serum concentration guide dosing was done through algorithms [15,16]

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