Original article
Plasma Levels of Antiepileptic Drugs in Children on the Ketogenic Diet

https://doi.org/10.1016/j.pediatrneurol.2005.11.001Get rights and content

Influence of the ketogenic diet on plasma concentrations of antiepileptic drugs was investigated in an open clinical study of 51 children (mean age 6.6 years) with medically refractory epilepsy. The plasma levels of concomitantly used antiepileptic drugs were determined immediately before and 3 months after initiating the ketogenic diet. To compensate for adjustments in dosing, the plasma concentration in relation to the dose per kilogram of body weight per day, i.e. the level-to-dose ratio, was used for comparison; it was calculated as the plasma concentration (μmol/L) divided by the corresponding weight-normalized dose (mg/kg body weight/day) for each drug and child. The level-to-dose ratios of each drug before and during the diet were compared. No significant changes in these ratios could be found for valproic acid, lamotrigine, topiramate, clonazepam, or phenobarbital. In 16 children, the ratio of the free unbound concentration of valproic acid to its total plasma concentration was compared before and during the diet, but it did not change significantly. Thus, the ketogenic diet did not change the plasma concentrations of commonly used antiepileptic drugs in children in any significant way. Therefore, when initiating the diet, it does not seem necessary to adjust drug doses due to pharmacokinetic interactions.

Introduction

The ketogenic diet is a high-fat, low-protein, and low-carbohydrate diet used in the treatment of medically refractory epilepsy in children [1], [2], [3]. When the diet is initiated, the patients are usually on maintenance therapy with antiepileptic drugs, involving polytherapy (≥2 antiepileptic drugs) [4], [5], [6], and most children need to continue on antiepileptic drugs.

In clinical practice during treatment with the ketogenic diet, it has been observed that the drug levels of antiepileptic drugs in blood may increase even without a change in dosage, and that blood levels of phenobarbital may increase up to 100% [2], [7], [8]. It has also been observed that phenobarbital may induce increased drowsiness [2], [8]. Because of this experience, it is common to reduce the phenobarbital dosing while beginning the ketogenic diet [2]. However, to the best of our knowledge, no previous studies evaluating the plasma concentrations of antiepileptic drugs in relation to the ketogenic diet have been conducted.

There are reasons to assume that the ketogenic diet could influence the blood levels of antiepileptic drugs through several mechanisms. Changes in the protein binding of antiepileptic drugs resulting from an altered protein intake may change the free concentration of the drug and hence its excretion. Reductions in the plasma pH may cause an increased extraction of weak acidic drugs from plasma into the central nervous system, and urinary acidifications could cause alterations in the excretion of drugs [9].

Observed adverse effects of the ketogenic diet may emanate from interactions between valproic acid and the ketogenic diet [8]. However, in a report of case studies, no relationship was found between the valproic acid dosage or the total plasma level and the development of hepatotoxicity [10]. Valproic acid has a high binding to plasma proteins, and it is eliminated by hepatic metabolism [11]. Increases in the amounts of free fatty acids in the blood [12] and changes in protein intake induced by the ketogenic diet may have a potential to change the ratio of free to protein-bound plasma concentrations of valproic acid.

The aim of this study was to examine the influence of the ketogenic diet on the plasma levels of antiepileptic drugs as well as on plasma protein binding of valproic acid.

Section snippets

Patients

The present study was conducted at the Neuropediatric Department of the Karolinska Hospital during 1998-2003. It was approved by the Ethics Committee of the Karolinska Hospital; the informed consent of the parents and, when possible, the patients was obtained. The study was part of a prospective open trial on the efficacy and safety of the ketogenic diet in children with epilepsy.

The inclusion criteria were an age of 1-18 years, medically refractory epilepsy with a prior trial of at least three

Results

The serum albumin levels and the plasma levels of antiepileptic drugs were obtained after a mean period of 2.8 (S.D. 1.4) months after onset of the diet.

The serum levels of albumin obtained at the time of the antiepileptic drug plasma level examinations were compared (n = 42). The mean albumin level before the ketogenic diet was 40.7 gm/L and during ketogenic diet it was 41.0 gm/L; the comparison yielded nonsignificant changes (P = 0.67).

At the time of the examination of the antiepileptic drug

Discussion

The results of the present study did not demonstrate any significant differences in the dose-related plasma concentrations of the studied antiepileptic drugs before and during the ketogenic diet when studied under steady-state conditions. Therefore, a possible pharmacokinetic interaction of the ketogenic diet on antiepileptic drugs was not supported by the data from this study.

The optimal design of this study would have been to keep the antiepileptic drug doses completely unchanged throughout

References (16)

There are more references available in the full text version of this article.

Cited by (0)

View full text