Population pharmacokinetics of mycophenolic acid in paediatric patients.

Mycophenolic acid (MPA) is widely used in paediatric kidney transplant patients and sometimes prescribed for additional indications. Population pharmacokinetic or pharmacodynamic modelling has been frequently used to characterize the fixed, random and covariate effects of MPA in adult patients. However, MPA population pharmacokinetic data in the paediatric population have not been systematically summarized. The objective of this narrative review was to provide an up-to-date critique of currently available paediatric MPA population pharmacokinetic models, with emphases on modelling techniques, pharmacological findings and clinical relevance. PubMed and EMBASE were searched from inception of database to May 2020, where a total of 11 studies have been identified representing kidney transplant (n = 4), liver transplant (n = 1), haematopoietic stem cell transplant (n = 1), idiopathic nephrotic syndrome (n = 2), systemic lupus erythematosus (n = 2), and a combined population consisted of kidney, liver and haematopoietic stem cell transplant patients (n = 1). Critical analyses were provided in the context of MPA absorption, distribution, metabolism, excretion and bioavailability in this paediatric database. Comparisons to adult patients were also provided. With respect to clinical utility, Bayesian estimation models (n = 6) with acceptable accuracy and precision for MPA exposure determination have also been identified and systematically evaluated. Overall, our analyses have identified unique features of MPA clinical pharmacology in the paediatric population, while recognizing several gaps that still warrant further investigations. This review can be used by pharmacologists and clinicians for improving MPA pharmacokinetic-pharmacodynamic modelling and patient care.

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.