M. J. Garcia

Monitoring of Serum Levels of Imipramine and Desipramine and Individualization of Dose in Enuretic Children

The serum levels of imipramine (IMI) and its active metabolite desipramine (DMI) were monitored in 90 children with primary nocturnal enuresis. Ages ranged between 5 and 14 years. Serum concentrations were determined in 21 children at 24 h after administration of a dose of 75 mg and once when steady state had been reached, 12 h after the last dose; a good correlation was seen between the total levels (IMI ± DMI) on those two occasions (r = 0.81; p < 0.01). This serves as a basis to predict the steady-state levels of IMI ± DMI reached in an individual patient. In the remaining patients the serum levels of IMI ± DMI were determined at steady state. Dosage regimens were adjusted individually to obtain a favorable response with regard to the frequency of enuresis and to the possible occurrence of side effects. Good correlation was established between the serum concentrations of IMI ± DMI at steady state and the frequency of enuresis, with a favorable response being obtained for levels greater than 80 ng/ml. Monitoring of serum levels leads to better compliance with the regimen throughout treatment.

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.

COMPARISON OF METHODS OF CARBAMAZEPINE DOSAGE, INDIVIDUALIZATION IN EPILEPTIC PATIENTS

The aim of the present work was to analyse the predictive capacity of different optimization methods for carbamazepine dosage regimens according to population pharmacokinetic parameters and/or serum levels data.

Population pharmacokinetics of imipramine in children.

SummaryThe population pharmacokinetics of imipramine (IMI) and its active metabolite desipramine (DMI) have been evaluated using 177 IMI and DMI serum levels from 49 enuretic children (6–13 y) on IMI treatment. Standard two stage (STS) and maximum likelihood (ML) methods were used to estimate fixed and random effect parameters of IMI. Simultaneous estimation of the drug and metabolite parameters was carried out by the STS method.The mean value of the elimination constant of the drug and metabolite were 0.0425 h−1 and 0.0359, h−1 respectively. Significantly higher variability was found in the pharmacokinetic parameters of the metabolite. According to these estimated pharmacokinetic parameters, the recommended dose for enuretic children should be 1.7 mg · kg−1 · day−. The population pharmacokinetic parameters obtained in the study permit dosage individualisation using a bayesian algorithm.

Prediction of Imipramine Serum Levels in Enuretic Children by a Bayesian Method: Comparison with Two Other Conventional Dosing Methods

The aim of the present study was to characterize the kinetic behavior of imipramine (IMI) and desipramine in enuretic children and to evaluate the performance of different methods for dosage prediction based on individual and/or population data. The study was carried out in 135 enuretic children (93 boys) ranging in age between 5 and 13 years undergoing treatment with IMI in variable single doses (25–75 mg/day) administered at night. Sampling time was one-half the dosage interval at steady state. The number of data available for each patient varied (1–4) and was essentially limited by clinical criteria. Pharmacokinetic calculations were performed using a simple proportional relationship (method 1) and a multiple nonlinear regression program (MULTI 2 BAYES) with two different options: using the ordinary least-squares method (method 2) and the least-squares method based on the Bayesian algorithm (method 3). The results obtained point to a coefficient of variation for the level/dose ratio of the drug (58%) that is significantly lower than that of the metabolite (101.4%). The forecasting capacity of method 1 is deficient both regarding accuracy [mean prediction error (MPE) = −5.48 \Pm 69.15] and precision (root mean squared error = 46.42 \Pm 51.39). The standard deviation of the MPE (69) makes the method unacceptable from the clinical point of view. The more information that is available concerning the serum levels, the greater are the accuracy and precision of methods (2 and 3). With the Bayesian method, less information on drug serum levels is needed to achieve clinically acceptable predictions.

Disposition of Cefoxitin in Patients with Ascites

SummaryThe pharmacokinetics of Cefoxitin was studied in 8 cirrhotic patients with ascites after i.v. administration of a single 30 mg/kg dose. Concentrations of cefoxitin in serum and in ascitic fluid were determined simultaneously by a microbiologic plate diffusion method. The antibiotic followed a two-compartment open kinetic model. In ascitic fluid, Cefoxitin reached its maximum concentration of 32.80±13,78 µg/ml 2 h after administration. The mean elimination constant from ascitic fluid was 0.201±0.008 h−1, significantly lower (p<0.05) than the slow disposition phase constant (β=0.556±0.17 h−1). At the dose studied and with a dosage interval of 8 h, the level of antibiotic in the ascitic fluid would be maintained at a value greater than the MIC of most cefoxitin-sensitive organisms.

Dosage optimization methods applied to imipramine and desipramine in enuresis treatment.

Three methods for estimating maintenance dosage requirements of imipramine were compared retrospectively in 146 enuretic patients. The dosing methods evaluated included individual (serum levels data) and/or population (average pharmacokinetic parameter) information. The use of imipramine and desipramine serum concentrations, as opposed to average population parameters only, improved forecast precision and accuracy for dosage individualization. The clinical acceptability of this was achieved through knowledge of a single serum concentration. No significant differences were seen between non‐linear regression and the Bayesian method, this is in agreement with the high contribution of the patients data to the Bayesian fitting (FF = 0.8). When one or two serum level data were available, a better performance was obtained by estimating pharmacokinetic parameters than level:dose ratios.

Pharmacokinetics of cefoxitin administered by i.v. infusion to patients with a pleural effusion.

SummaryThe pharmacokinetics of cefoxitin was studied in 6 healthy volunteers and in 5 patients with a pleural effusion after administration of a single dose of 30 mg/kg i.v. infusion. The serum and pleural fluid concentrations of cefoxitin were determined microbiologically. The elimination half-life of the antibiotic from pleural fluid in all cases was 2–3fold longer than from serum, which shows a difference between the kinetic elimination processes of the antibiotic from the two fluids. The slow elimination of cefoxitin from pleural fluid facilitates its accumulation in this compartment during a multiple dosage regimen.

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

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.

TDM of theophylline--compliance evaluation.

Non‐compliance to dosage regimes is an important clinical problem with severe repercussions for the management of chronic illnesses requiring continued treatment. In the present study, we evaluated the degree of noncompliance in a group of 100 patients with chronic asthma undergoing continued treatment with theophylline, and the effect of the application of a monitoring programme on their degree of compliance. The evaluation was carried out by anamnesis and from the level/dose ratio. In the control group studied (n= 50) the degree of non‐compliance was 44% and in the previously monitored group (n= 50) it was 18%. Serum theophylline levels in the former were: 7·6 ± 5·8 μg/ml, significantly lower (P < 0.005) than that observed in the latter: 10·1 ± 4·0 μg/ml. The use of monitoring programmes can improve the degree of compliance.