Population pharmacokinetics of enterally administered cisapride in young infants with gastro‐oesophageal reflux disease

Abstract

Aims To investigate the pharmacokinetics of enterally administered cisapride suspension in young infants being treated for gastro-oesophageal reflux disease. Methods Plasma cisapride concentrations in 49 subjects (weight: 825-5010 g; n= 108 samples, median two per patient; concentration: 14.8-170 ng ml −1 ) were fitted to a one-compartment model with first-order absorption and elimination in the NONMEM program using a logarithmic transformation of the observed and predicted concentrations. Fitting was achieved using the first order conditional estimation (FOCE) method with interaction between the interpatient and intrapatient variabilities. The interpatient variance of clearance (CL/F) and volume of distribution (V /F) and their covariance were estimated using an exponential error model. Intrapatient (residual) variance was estimated using an additive model. Results The clearance of cisapride was shown to be linearly related to current body weight, slope: 0.538. The typical population values of CL/F, V /F and Ka (absorption rate constant) were 0.538 l h −1 kg −1 , 21.9 l, and 2.58 h −1 , respectively.The population coefficients of variation (CV%) for CL/F and V /F were 34.4% and 84.3%, respectively. The squared coefficient of correlation between random effects for CL/F and V /F was 0.45. The intrapatient variance was 0.15. V /F and Ka were not influenced significantly by any patient characteristic. Conclusions Cisapride pharmacokinetics in infants with reflux disease were satisfactorily described by a one-compartment model. Current weight should be taken into account when calculating maintenance cisapride doses in these infants.

Cisapride May Improve Feeding Tolerance of Preterm Infants: A Randomized Placebo-Controlled Trial

“…This observation is confi rmed by our data which demonstrated a signifi cant prolongation of the QTc interval in ELBW infants but not in more mature infants. In young infants, cisapride concentrations were found to be higher (up to 170 ng/ml) and to be dependent on weight [11] . Very high serum levels of cisapride, which exceeded the serum levels in adult patients (maximum 80 ng/ml) by 2-to 3-fold [17] , were found in some of our patients.…”

“…One milliliter of blood was centrifuged within 30 min. Serum was frozen and stored at -20 ° C until measurements were performed by HPLC with fl uorescence detection according to the method of Preechagoon et al [11] .…”

Age-Related Differences in the Direct Cardiac Effects of Cisapride: Narrower Safety Range in the Hearts of Young Rabbits

“…(95-98%), concentrations of free drug can still reach the low concentration range used in this experiment (15,16). At the lowest concentration (0.03 M) used in the present study, none of the electrophysiological parameters was significantly altered.…”

Population pharmacokinetics of cisapride in neonates

“…Population pharmacokinetics deals with limited data available from a wide range of patients and allows the development of a population model, including average pharmacokinetic parameters, covariates, and intra-and interindividual variability [19]. A previous population pharmacokinetic analysis of cisapride conducted in neonates and published before the end of our study showed that clearance was related to body weight, attesting to the relevance of a weight-based dosing regimen [20]. However, the authors did not find a role of postnatal age, although impaired metabolism could occur in this population and lead to drug accumulation.…”

“…The model described by Preechagoon et al [20] was first fitted to our data in order to evaluate its ability to describe concentrations in an independent group of neonates. Secondly, the data were analysed by nonlinear mixed effect modelling using NONMEM software (version V, level 1.0) and Visual-NM (RDPP, Montpellier, France) a Windows-based interface to NONMEM containing graphical and statistical tools.…”