PK/PD studies in pigs leading to optimization of treatment dose in MNE?

INTRODUCTION AND AIM OF THE STUDY : Desmopressin is used to treat primary nocturnal enuresis in children. Over the years, various formulations of desmopressin were commercialized of which the sublingual melt tablet is preferred in the pediatric population, despite the lack of full PK studies in this population. MATERIALS AND METHODS : A full PK study was performed in growing conventional piglets to evaluate if this juvenile animal model can provide supplementary information to complement the information gap in the pediatric population. A desmopressin sublingual melt tablet (120 μg) was administered to 32 male piglets aged 8 days, 4 weeks, 7 weeks, and 6 months (each group n = 8). Population PK (pop-PK) analysis was performed to derive the PK parameters, the between- and within-subject variabilities and the effects of covariates. RESULTS : Desmopressin demonstrated two-compartmental PK, with a dual, sequential absorption process, and linear elimination. Body weight was the only significant covariate on clearance and on apparent volume of distribution of the central compartment. INTERPRETATION OF RESULTS : In human pediatric trials, a one-compartmental model with first-order absorption was fitted to the data and no double peaks were observed in the curves, likely due to the sparse sampling strategy applied in those studies. CONCLUSIONS : Therefore, it is recommended that additional studies in children, based on the sampling protocol in the current study, are performed to determine the PK parameters in children based on a full documentation of the plasma concentration-time profil