Theophylline population pharmacokinetics from routine monitoring data in very premature infants with apnoea

Abstract

Theophylline is commonly used in neonatology for the treatment and prophylaxis of apnoea of prematurity, and during ventilator weaning. NONMEM was used to study the population pharmacokinetics of intravenous and oral theophylline from retrospective drug monitoring data in 82 premature neonates, weighing < 1500 g at birth, and 5 32 weeks gestational age.Clearance (CL), volume of distribution (V), and oral bioavailability (Fl) from liquid preparations were modelled alone, and under the influence of demographic and clinical covariates, assuming a 1-compartment model with first-order elimination.The final population models with influential co-variates were as follows: CL(1 h -I) = 0.0000123 *body weight (8) + 0.000377 *postnatal age (days); V (1) = 0.000937 *body weight (g); F=0.918. The CL was lower and V was higher than previously reported for less premature neonates, term babies, and older children. Predictive performance of the population models was evaluated by Bayesian forecasting in a similar, but independent cohort of 30 infants. There was statistically insignificant bias and imprecision between measured and predicted serum theophylline concentrations. Based on the validated population models, recommended maintenance theophylline dosages are provided for infants aged between 2 and 50 days, and weighing 700 to 2000 g.

Population Pharmacokinetics of Intravenous Amoxicillin in Very Low Birth Weight Infants

“…These results supported the fact that in parametric population modeling the fixed effects parameters are usually estimated with better precision than random effects parameters, except when there are very large numbers of subjects. 9,13 An important aspect of this study, often neglected in other population studies, was the independent assessment of the predictive performance in a subgroup of randomly selected infants who had similar characteristics to the index group but whose data were not used to develop the models. A confidence limit analysis indicated that there was a small, statistically insignificant bias of 3 mg/L among pairs of observed and model-predicted serum amoxicillin concentrations, the latter having been obtained by posthoc Bayesian forecasting in NONMEM.…”

“…9 Predictive performance was assessed in terms of bias (mean prediction error, ME) and precision (root mean square prediction error, RMSE) and the associated 95% confidence intervals. 9,14 A systematic deviation between pairs of predicted and observed measurements can be used to estimate bias by the ME statistic, whereas the RMSE estimates scatter or variability; the lower the value of the RMSE the smaller is the magnitude of the differences between pairs of measurements.…”

“…no covariates), in conjunction with a proportional error model for interpatient variability and an additive error model for intrapatient variability. 9,13 Potential covariates were added individually to the base model and the objective function (OF) and the distribution of weighted residuals were noted. Changes in the OF upon the addition or deletion of a covariate approximate the 2 distribution with 1 degree of freedom; thus, a change of >6.6 is required for significance at the R ) 0.01 level.…”

“…5 Most often, the doses have been based on those used to treat older children or even adult patients, despite the fact that drug clearances in premature infants are markedly reduced. [6][7][8][9] Amoxicillin generally is considered to have a wide therapeutic window, but it has been reported that supratherapeutic serum concentrations may cause reversible renal dysfunction. 10,11 Besides the increased cost, the use of unnecessarily high doses of antibiotics may encourage overgrowth with pathogens and the spread of nosocomial antibiotic resistance.…”

Population pharmacokinetics of cisapride in neonates

“…Because of the wellknown immaturity of this metabolic pathway in neonates, one would expect both a reduced clearance of cisapride in neonates and a progressive increase in this parameter with postnatal age [27,28,29]. Cisapride concentrations obtained in our patients were very similar to those expected in adults receiving 10 mg three times a day, i.e., 20-40 ng/mL before and 50-100 ng/mL 1-2 h after drug intake [17], suggesting that the dosage regimen currently used in neonates is safe.…”