D. Santos Buelga

Valproate population pharmacokinetics in children

Objective:A population analysis of the kinetics of valproic acid (VPA) in children with epilepsy was performed in order to characterize the covariates which influence VPA clearance (CL).

Plasma protein binding kinetics of valproic acid over a broad dosage range: therapeutic implications

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 add over a 24–h period.

Application of population pharmacokinetics to the optimization of theophylline therapy

The aim of this study was to determine theophylline clearance (Cl) values in adult patients using serum concentrations gathered from routine clinical care. This information was used to estimate an a priori dosing regimen that would permit steady‐state concentrations of 5–15 mg/litre, now recommended for the treatment of chronic asthma, and to evaluate the need to establish monitoring strategies when theophylline is given at these lower doses and when it can be expected that almost no adverse effects are likely.

Predictive performance of two phenytoin pharmacokinetic dosing programs from nonsteady state data

The present work evaluated the performance of two computer programs: Drugcalc, which utilizes the bayesian (method 1) approach and PKS, which can utilize both the non-bayesian (method 2) and bayesian (method 3) approaches. Both programs permit the introduction of serum level data obtained in both situations: steady-state and nonsteady-state. The prediction of phenytoin concentrations (n = 771) were made from steady-state (n = 378) and nonsteady-state (n = 175), and combined steady-state and nonsteady-state (n = 218) concentrations. The observed serum concentrations (at least two nonsteady-state and two steady-state per patient) were collected under routine clinical conditions in 15 patients receiving this drug. The main contribution to prediction errors is attributed to the difference between doses corresponding to the predicted and feedback serum concentrations, dD, in such a way that when the errors obtained for dD ≥ 100 mg/day are excluded, the predictive performance increases significantly for all methods. In this sense, increases in precision were 87, 64, and 66% for methods 1, 2, and 3, respectively. Moreover, when dD <100 mg/day, nonsteady-state feedback concentrations (≤3) only afforded clinically acceptable predictions (ME ± SD <3 mg/L) when they were combined with at least one steady-state datum value, and the bayesian approach was used. Despite this, for all the methods analyzed, nonsteady-state data are seen to be useful for detecting situations of potential toxicity in a significant proportion of cases (71.4–84.6%) and, when method 3 is used, may offer useful information for the adjustment of dosage schedules.

Dosage programming of phenobarbital in neonatal seizures.

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) 1142 + 430 h, 7319 ± 2417 h and 4123

COMPARISON OF METHODS FOR THE PREDICTION OF PHENYTOIN CONCENTRATIONS

± 1395 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/1 to be safe and effective in neonatal seizures, the initial dosing recommended is 29, 48 and 60 mg/kg/day in newborns 110, 1130 and 3170 days old, respectively.

Influence of length of treatment on the interaction between phenobarbital and phenytoin

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%).

Comparison of two methods in the estimation of the pharmacokinetic parameters of phenytoin.

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.

Study of the disposition kinetics of the N-oxide-derivative: a metabolite of picobenzide

This report compares two different methods of estimating the pharmacokinetic parameters of phenytoin (PHT) from steady‐state serum concentration data obtained in clinical practice: the standard two‐stage method (STS) and the extended least squares method (ELS). The study was carried out with the data from 27 compliant adult epileptic patients treated with PHT on a monotherapy regimen. Application of Akaike information criterion (AIC) points to a better estimation with the STS method (AIC = 26805 for ELS; AIC =11413 for STS). This was confirmed by calculating the mean prediction error (mpe) and the standard deviation of EMP, which were 0–59 ± 6–11 mg/1 and ‐0.12 ± 2‐93mg/1 for ELS, and STS methods, respectively. Despite the well‐known limitations of the STS method, a simulation study revealed that it can be successfully used when the patients to be included are selected with great care and when reliable serum concentration data are available.

Population pharmacokinetics of caffeine in premature neonates

SummaryThe disposition kinetics of the N-oxide of picobenzide were studied after administration to rabbits at a bolus dose of 30 mg/kg of picobenzide intravenously. The biotransformation process fits a first-order kinetic process, and the metabolite shows good access capacity to the peripheral compartment The N-oxide of picobenzide was determined by D.P.P. and parametric estimation was performed by the SIMPLEX method as the search algorithm.