Population pharmacokinetics of cisapride in neonates

We conducted a population pharmacokinetic analysis of cisapride in neonates to study whether metabolic immaturity in this population may lead to increased concentrations. Cisapride was administered orally in 91 neonates at the dose of 0.2 mg/kg four times a day. Plasma concentrations were measured using a validated HPLC method. A one-compartment model with first-order absorption was fitted to the data using NONMEM software. One to seven plasma samples were obtained from neonates aged 7-123 days. Cisapride concentrations ranged from 5.5 ng/mL to 172 ng/mL and were not higher than those reported in adults. The absorption constant rate was fixed to 2.5 h-1. Clearance (CL/F) and volume of distribution (V/F) both significantly correlated to weight (WT), but addition of this covariate in V/F did not improve the objective function after it was added in the CL/F covariate model. Prematurity, postnatal age, or coadministered drugs did not affect cisapride clearance. Final population pharmacokinetic parameters (interindividual variability) were: V/F=17,200 mL (90.4%) and CL/F=3.91 x WT(3/4) mL/h (36.3%). Our finding that cisapride clearance is primarily influenced by weight is in agreement with current recommendations of weight-adjusted doses. This study indicates that no clinically relevant maturational changes in cisapride clearance have to be considered during the first quadrimester of life.