A comparison of the pharmacokinetics of two dosing regimens of cisapride and their effects on corrected QT interval in premature infants

Objective: To compare the pharmacokinetics of two dosing regimens of cisapride and their effects on QT(c) interval. Design: Thirty-one pre-term infants were enrolled in two neonatal intensive care units. In 16 infants, cisapride was started at 0.2 mg/kg orally every 6 h (group A) and in 15 infants at 0.1 mg/kg orally every 3 h (group B). Electrocardiograms were performed before and after 72 h of treatment to calculate the QT(c) interval according to the Bazett formula. After 72 h of treatment, cisapride and norcisapride trough concentrations, and concentrations I h after the next cisapride administration were quantified in serum. A linear regression analysis was performed to analyse the effect of postnatal and post-conception age. Results: At the start of cisapride treatment, mean postnatal age was 22.9 +/- 13.9 days (mean +/-SD) for group A and 23.3 +/- 15.0 days for group B, and mean postconception age was 34.0 +/- 1.8 weeks for group A and 33.3 +/- 0.8 weeks for group B. The QT(c) interval increased equally in both groups (group A: + 37 +/- 20 ms, and group B: + 38 +/- 25 ms; P = 0.9). Mean concentration of cisapride I h after administration was, as expected from the dosing regimen, significantly higher in group A than in group B (123.7 +/- 43.2 ng/ml versus 86.7 +/- 27.8 ng/ml; P = 0.03). The difference in trough concentration was not significant (107.4 +/- 44.3 ng/ml versus 78.2 +/- 35.4 ng/ml; P = 0.09). There was a positive correlation between QT(c) prolongation and cisapride serum concentration (peak: R-2 = 0.20, P = 0.015; trough: R-2 = 0.24, P=0.008) and an inverse correlation between postnatal age and concentration I h after administration concentration of cisapride (R-2 = 0.19, P = 0.02). No correlation was found for postconception age. Conclusion: Postnatal age has an inverse relationship with cisapride serum concentration in premature infants, whereas postconception age is not correlated. The maturation process of the biotransformation system of cisapride during the first weeks of life, triggered by birth, but independent of gestational age at birth can explain this observation. The effect of cisapride on cardiac repolarisation is positively related with the cisapride serum concentration. Administering cisapride every 3 h instead of every 6 h could be advantageous, as it is associated with lower peak cisapride serum concentrations. Further investigations are required to confirm this and its potential clinical benefit on QT(c) and arrhythmia risk.