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

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.

Cost-Effectiveness of Therapeutic Drug Monitoring of Anti-TNF Therapy in Inflammatory Bowel Disease: A Systematic Review

“…However, Model-Informed Precision Dosing (MIPD) is a more precise alternative, based on the use of population pharmacokinetics (PopPK) models and a prospective Bayesian approach to increase the homogeneity in the drug exposure in patients and, therefore, to improve outcomes of treatments [ 61 ]. Some authors have carried out MIPD of adalimumab and infliximab in IBD patients, applying PopPk models found in the literature [ 62 , 63 ]. However, further investigations in this line are required to estimate its cost and compare it with the ones obtained from a TDM strategy.…”

Population Pharmacokinetic Model of Adalimumab Based on Prior Information Using Real World Data

“…The reference model was the one selected among all available models in the literature, according to a predictive performance evaluation published elsewhere [18,23]. Briefly, the model, developed with Monolix 4.3.2, comprises a one-compartment model with first-order absorption and linear elimination and was parameterized in terms of apparent clearance (CL/F), apparent volume of distribution (V/F) and absorption constant (ka) with a combined residual error model.…”

“…Even though a PopPK model implemented from the literature can suit a population in the clinical setting, it is convenient to adapt this PopPK model to the studied population, to re-estimate the parameters and to evaluate the inclusion of potential new covariates to obtain more accurate results in the dose optimization. In a previous study, the predictive performance of these PopPK models was externally evaluated in the clinical setting [23]. This study, conducted by our research group, concluded that the PopPK model developed by Ternant et al (reference model) was better than the others in terms of model adequacy and predictive performance [18].…”