Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children.

INTRODUCTION Desmopressin is used for treatment of nocturnal enuresis in children. In this study, we investigated the pharmacokinetics of two formulations-a tablet and a lyophilisate-in both fasted and fed children. METHODS Previously published data from two studies (one in 22 children aged 6-16 years, and the other in 25 children aged 6-13 years) were analyzed using population pharmacokinetic modeling. A one-compartment model with first-order absorption was fitted to the data. Covariates were selected using a forward selection procedure. The final model was evaluated, and sensitivity analysis was performed to improve future sampling designs. Simulations were subsequently performed to further explore the relative bioavailability of both formulations and the food effect. RESULTS The final model described the plasma desmopressin concentrations adequately. The formulation and the fed state were included as covariates on the relative bioavailability. The lyophilisate was, on average, 32.1 % more available than the tablet, and fasted children exhibited an average increase in the relative bioavailability of 101 % in comparison with fed children. Body weight was included as a covariate on distribution volume, using a power function with an exponent of 0.402. Simulations suggested that both the formulation and the food effect were clinically relevant. CONCLUSION Bioequivalence data on two formulations of the same drug in adults cannot be readily extrapolated to children. This was the first study in children suggesting that the two desmopressin formulations are not bioequivalent in children at the currently approved dose levels. Furthermore, the effect of food intake was found to be clinically relevant. Sampling times for a future study were suggested. This sampling design should result in more informative data and consequently generate a more robust model.