The aim of the study was to characterize, from the relationship between total and free serum levels of valproic acid obtained over a broad dosage range (10-50 mg/kg), the parameters defining the in-vivo kinetic behaviour of the binding of valproic acid to plasma proteins, their pharmacokinetic and clinical repercussions, and their application to therapeutic drug monitoring (TDM). The study was performed in nine healthy adults (20-35 years) who were given doses of 1000 (group A), 2000 (group B) and 3000 mg (group C) of sodium valproate according to a compensated cross-over design, simultaneously determining the total and free serum levels of valproic acid over a 24-h period. The mean free fraction increases with dose, although this increase is only significant (P < 0.05) for the highest dose (3000 mg). The variation in the free fraction of valproic acid begins to become significant (P < 0.05) at a total drug concentration above 100 mg/l. The mean values of the dissociation constant (K) and binding sites (n) were 460 mumol/l and 1.79, respectively, showing a variability of 86.6 and 38.7%, respectively, and a residual variability of 13.0%. Significant differences (P < 0.05) were found for the total plasma clearance (Cl) but not for the intrinsic plasma clearance (Clu) values, despite their tendency to decrease with the dose. If TDM is to be used for valproic acid, it is the free serum levels that should be determined, especially if high doses are administered, because the total serum levels are not a true reflection of the free ones, as is the case of other anti-epileptic drugs.

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A combination of anti-epileptic drugs gives rise to interactions that modify their disposition kinetics. To discover the clinical relevance of such interactions it is necessary to establish their direction and magnitude. Phenytoin may interact with phenobarbital either as an inducer or an inhibitor of metabolism, depending on the length of treatment with the combination of both drugs. Data obtained in six, adult, epileptic patients treated with phenobarbital alone, and later with a phenobarbital -phenytoin combination, showed that the serum levels of the barbiturate undergo an increase during the first year of treatment with the combination therapy. From this point onwards a decrease is observed in the levels of phenobarbital, to return after about 2 years to values similar to those observed with monotherapy.

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Owing to the changes occurring in the organism as a result of biological maturation, disposition kinetics of phenobarbital in newborns is significantly different to that observed in the paediatric and adult populations. Moreover, the disposition parameters change constantly during the first days of life. The data on the serum levels of phenobarbital in 17 newborns were analysed to quantify the changes in the elimination half-life of phenobarbital during the first weeks of life. The half-life of the drug was estimated to be (mean +/- SD) 114.2 +/- 43.0 h, 73.19 +/- 24.17 h and 41.23 +/- 13.95 h in patients 1-10, 11-30 and 31-70 days old, respectively. According to these values and assuming phenobarbital serum levels of 20 mg/l to be safe and effective in neonatal seizures, the initial dosing recommended is 2.9, 4.8 and 6.0 mg/kg/day in newborns 1-10, 11-30 and 31-70 days old, respectively.

A comparison was made of different methods for the prediction of the serum concentrations of phenytoin (PHT) at steady-state with a view to determining which of them had the best predictive performance. The methods employed calculated the predicted concentrations based on a dose steady-state concentration pair. Two of the methods used involved solving the Michaelis-Menten equation, determination of a single parameter in each individual and maintaining the Km (Method A) or Vmax (Method B) values at a constant. Methods C and D were Bayesian techniques that used population parameters determined in a population studied by us (Method C) and parameters drawn from the literature (Method D). Calculation of bias and precision suggests that Method C is the most suitable of those studied, with a mean prediction error (ME) of 0.56 +/- 2.16 mg/litre, a mean absolute error (MAE) of 1.76 +/- 1.31 mg/litre and a root mean squared prediction error (RMSE) of 2.17 mg/litre. Method C was also the method that showed the lowest percentage of underestimation (5.26%) and overestimation (10.53%).

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