The Quantitative Effect of Serum Albumin, Serum Urea, and Valproic Acid on Unbound Phenytoin Concentrations in Children

Abstract

Dosing of phenytoin is difficult in children because of its variable pharmacokinetics and protein binding. Possible covariates for this protein binding have mostly been univariately investigated in small, and often adult, adult populations. We conducted a study to identify and quantify these covariates in children. We extracted data on serum phenytoin concentrations, albumin, triglycerides, urea, total bilirubin and creatinine concentrations and data on coadministration of valproic acid or carbamazepine in 186 children. Using nonlinear mixed effects modeling the effects of covariates on the unbound phenytoin fraction were investigated. Serum albumin, serum urea concentrations, and concomitant valproic acid use significantly influenced the unbound phenytoin fraction. For clinical practice, we recommend that unbound phenytoin concentrations are measured routinely. However, if this is impossible, we suggest to use our model to calculate the unbound concentration. In selected children, close treatment monitoring and dose reductions should be considered to prevent toxicity.

Population pharmacokinetics of phenytoin in critically ill children

“…The model presented here showed a linear relationship between the partition coefficient and albumin concentration, which translates to a nonlinear relationship between f u and albumin concentration (since, f u = 1/(1 + P UB )). Compared to our results, others reported greater increases in f u in hypoalbuminemia . We suspect that a power model may provide a better prediction of f u in severe hypoalbuminemia, but unfortunately our data set contained only a few patients having serum albumin concentrations less than 25 g/L.…”

“…Compared to our results, others reported greater increases in f u in hypoalbuminemia. 12,30 We suspect that a power model may provide a better prediction of f u in severe hypoalbuminemia, but unfortunately our data set contained only a few patients having serum albumin concentrations less than 25 g/L. Therefore, until more data from patients having very low albumin concentrations are collected, the final reported (linear) model should be restricted to the range of albumin concentrations presently used.…”

Dried blood spot assay for the quantification of phenytoin using Liquid Chromatography-Mass Spectrometry

“…Therapeutic drug monitoring (TDM) in pediatric samples is necessary because of the very different responses in terms of drug availability [8,9].…”

The significance of a new parameter – plasma protein binding – in therapeutic drug monitoring and its application to carbamazepine in epileptic patients

“…In fact, with protein-bound compounds, the primary cause of the variability of C f in pharmacology is the change in plasma protein binding (PPB). 7 The binding of a drug to plasma proteins could be in a steady-state equilibrium under stable disease conditions and constant during a relatively long time, which can reect the whole process of drug disposition. However, the co-administration of other drugs, pathological conditions and gender of patients can markedly change PPB and directly result in a variation in C f , further inuencing the efficacy and toxicity of the drug.…”