Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling

BACKGROUND AND OBJECTIVE: Phenytoin is extensively protein bound with a narrow therapeutic range. The unbound phenytoin is pharmacologically active, but total concentrations are routinely measured in clinical practice. The relationship between free and total phenytoin has been described by various binding models with inconsistent findings. Systematic comparison of these binding models in a single experimental setting is warranted to determine the optimal binding behaviors. METHODS: Non-linear mixed-effects modeling was conducted on retrospectively collected data (n = 37 adults receiving oral or intravenous phenytoin) using a stochastic approximation expectation–maximization algorithm in MonolixSuite-2019R2. The optimal base structural model was initially developed and utilized to compare four binding models: Winter–Tozer, linear binding, non-linear single-binding site, and non-linear multiple-binding site. Each binding model was subjected to error and covariate modeling. The final model was evaluated using relative standard errors (RSEs), goodness-of-fit plots, visual predictive check, and bootstrapping. RESULTS: A one-compartment, first-order absorption, Michaelis–Menten elimination, and linear protein-binding model best described the population pharmacokinetics of free phenytoin at typical clinical concentrations. The non-linear single-binding-site model also adequately described phenytoin binding but generated larger RSEs. The non-linear multiple-binding-site model performed the worst, with no identified covariates. The optimal linear binding model suggested a relatively high binding capacity using a single albumin site. Covariate modeling indicated a positive relationship between albumin concentration and the binding proportionality constant. CONCLUSIONS: The linear binding model best described the population pharmacokinetics of unbound phenytoin in adult subjects and may be used to improve the prediction of free phenytoin concentrations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40268-020-00323-2) contains supplementary material, which is available to authorized users.