Population kinetics of tobramycin in neonates.

The population kinetics of tobramycin were studied in 140 neonates (100/40 patients for the index/validation groups, respectively) of 30 to 42 weeks' gestational age and 0.8 to 4.25 kg current body weight in their first 2 weeks of life, undergoing routine therapeutic drug monitoring of their tobramycin serum levels. The 365 tobramycin concentration measurements obtained were analyzed by use of NONMEM according to a one-compartment open model with zero-order absorption and first-order elimination. The effect of a variety of demographic, developmental, and clinical factors (gender, height, birth weight, current weight, gestational age, postnatal age, postconceptional age, and serum creatinine concentration) on clearance and volume of distribution was investigated. Forward selection and backward elimination regression identified significant covariates. The final pharmacostatistical model with influential covariates was as follows (full population): clearance (L/h) = 0.0508 x current weight (kg), multiplied by 0.843 if birth weight was 2.5 kg or less (low-birthweight infants), and volume of distribution (L) = 0.533 x current weight (kg). Using the proportional error model for the random-effects parameters, interindividual variability for clearance and for volume of distribution was determined to be 25.8% and 21.9%, respectively, and the residual variability was 19.2%. In this study, the use of the NONMEM gave significant and consistent information on the pharmacokinetics and the determinants of the pharmacokinetic variability of tobramycin in neonates when compared with available bibliographic information. Moreover, the final population pharmacokinetic model may be used to design a priori recommendations for tobramycin and to improve the dosing readjustments through Bayesian estimation.

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). METHODS: A total of 770 steady-state serum concentration samples was analysed. These were collected during VPA therapy from 255 children, aged 0.1-14 years and weighting 4-74 kg. Age, total body weight (TBW), VPA daily dose, sex and comedication with carbamazepine (CBZ) were considered as covariates. Population analysis was made with NONMEM program, assuming a one-compartment model, fixing the VPA absorption rate, bioavailability and distribution volume at values found in the literature. The results of the population pharmacokinetics analysis were validated in a group of 45 epileptic patients. RESULTS: The final regression model for VPA clearance, that included TBW (kg), daily dose (mg/kg) and CBZ comedication as covariates with a significant influence on this parameter, was as follows: CL (L/h) = 0.012 TBW0.715 DOSE0.306(1.359 CBZ). The coefficient of variation for interpatient variability in CL was 21.4% and the residual variability estimated was 23.9% for a concentration of 65 mg/l. In order to estimate the predictive performance of the selected final model, predictions of the VPA serum concentrations were calculated and compared with VPA measured concentrations in the validation group. This assessment revealed an important improvement in the predictive performance of VPA concentrations in comparison with the basic model that did not include any covariates (root squared mean error: 19.50 vs. 39.73 mg/l). CONCLUSION: A population pharmacokinetic model is proposed to estimate the individual CL for paediatric patients receiving VPA in terms of patient's dose, weight and concomitant CBZ, in order to establish a priori dosage regimens.

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. Retrospective data from 204 asthmatic and COPD patients, with a total of 517 serum concentrations, were studied. Population pharmacokinetic analysis was performed with the MULTI(ELS) computer program according to a one-compartment model. The influence of the following factors on theophylline Cl were investigated: body weight (TBW, IBW and LBM) and age as continuous variables, and gender, smoking habit and the presence of congestive heart failure (CHF) as indicator variables. To validate the results of the population pharmacokinetic analysis, a second independent group of 63 patients was studied prospectively. Hypothesis testing to evaluate potentially significant factors produced a final model in which Cl was based on IBW (kg) and age (years), and was reduced by 25% in patients with moderate CHF and increased by 28% in patients who smoked (Cl (litres/h) = (0.037 IBW-0.006 age) x 1.284 smoke x 0.751 CHF). The variability in Cl, expressed as the coefficient of variation, was 36%. In adult non-smoker and non-CHF patients, application of a maintenance dosing regimen calculated from IBW and age using the final model for Cl would theoretically afford only 1.5% of patients with potentially toxic concentrations. Thus, measurement of serum theophylline concentrations (STC) would only be required when other conditions known to alter theophylline metabolism exist, such as smoking or disease factors. These appreciations could have important clinical implications at a time when the potential immunomodulatory activity of theophylline is being emphasized and health resources should be allocated properly.