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.

Figure 1

a) Semi-logarithmic plot of plasma cisapride concentration vs postdose sampling time. Connected data points are from the same patient; b) Semi-logarithmic plot of pairs of (○) observed (•) population model-predicted concentration (based on WT) vs postdose sampling time. Observed and population model-predicted concentrations have been normalized to a dose of 0.2 mg kg⁻¹.

Figure 2

a) Plot of observed concentration vs population model-predicted concentration (based on WT). The line of identity (perfect agreement, slope=1) is indicated; b) Plot of weighted residual value vs concentration predicted by the final model. The zero ordinate of perfect agreement is indicated (solid line).

Figure 3

Plot of NONMEM-generated posterior Bayesian estimates of CL/F from the final population model, vs WT. Data points representing estimates within individual patients are joined.