External validation of population pharmacokinetic models of adalimumab in adult patients with inflammatory bowel disease: towards model-informed precision dosing.

Inflammatory bowel disease (IBD) has variability in the pharmacokinetics of adalimumab, which may predispose patients to subtherapeutic concentrations, therapeutic failure, and/or drug immunogenicity. Population pharmacokinetic (popPK) models estimate individual pharmacokinetic parameters and allow to personalize therapeutic regimens through Model-Informed Precision Dosing (MIPD). This retrospective, longitudinal study evaluated the predictive performance of six popPK models of adalimumab in adult patients with IBD treated at a tertiary hospital. The adequacy and prediction of the models were externally validated using visual analysis of the goodness-of-fit (GOF) plots, prediction-corrected visual predicted checks (pcVPC), analysis of residuals, and statistical metrics such as the Akaike Information Criteria. Bias and prediction were also calculated using mean prediction error, mean absolute percentage error and root mean square error. Bootstrap resampling was applied for statistical comparisons. Pharmacokinetic parameters were estimated using Bayesian methods and compared to theoretical values. A total of 201 subjects were included, 88% with Crohn's disease, mean age 48.6 (± 16.2) years, 44.8% women. Overall, Berends and Vande Casteele models demonstrated the best predictive performance in the majority of comparative analyses: higher coverage in pcVPC and correlation between observed and predicted values, lower bias and precision values, the lowest AIC, and a homogeneous distribution of residuals. However, both models overestimated adalimumab population clearance. These findings support the application of the Berends and Vande Casteele models in clinical MIPD strategies. Therefore, pending broader evidence in different populations, driving MIPD adoption is critical to optimize adalimumab regimens and maximize sustained clinical outcomes.