Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children

Abstract

Introduction: Desmopressin is used for nocturnal enuresis treatment 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 (22 children aged 6 to 16 yr and 25 children aged 6 to 13 yr) were analyzed using population pharmacokinetic modeling. A 1-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 desmopressin plasma concentrations adequately.Formulation and 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 relative bioavailability of 101%, compared to fed children. Body weight was included as a covariate on distribution volume, using a power function with exponent 0.402.Simulations suggest both the formulation and the food effect are clinically relevant. Conclusions:Bioequivalence data of two formulations of the same drug in adults, cannot be readily extrapolated to children. This is the first study in children suggesting that the two desmopressin formulations in children are not bioequivalent 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. Key points Population pharmacokinetic modeling was applied to pediatric desmopressin PK data and used to extract more information out of existing pediatric drug data, generate new information and improve the collection of future information. In this study it was found that the established bioequivalence of desmopressin in adults might be different in the pediatric population. A profound food effect was also quantified. In order to make solid conclusions regarding desmopressin efficacy in children, PK and PD data should be gathered simultaneously in a well-designed study, for which some design suggestions are presented in this paper. Abbreviations

PP-7 The safe-pedrug initiative: an opportunity for academia to close the gap

“…The SAFE-PEDRUG project explored the value of the porcine juvenile animal model3 and PK modelling4 (population pharmacokinetics and physiological-ly based pharmacokinetic modelling) in providing prior paediatric PK/PD knowledge, before the actual adult trials have been completed. For the evaluation of this approach, three case compounds were selected: des-mopressin, lisinopril, and fluoroquinolones.…”

Population Pharmacokinetic Modeling of a Desmopressin Oral Lyophilisate in Growing Piglets as a Model for the Pediatric Population

“…Most articles describing the PK parameters of desmopressin administered to adults (Fjellestad-Paulsen et al, 1993 ; Agersø et al, 2004 ; Fransén et al, 2009 ) applied a two- or three-compartmental model to fit the data. Michelet et al ( 2016 ) combined the data collected in children by Osterberg et al ( 2006 ) and De Bruyne et al ( 2014 ) and concluded that a one-compartmental model with first-order absorption best described the data. In the current study, a two-compartmental model was chosen based on a smaller OFV (ΔOFV = 87.42) in comparison with a one-compartmental model, despite the high values of RSE and shrinkage for V 2 /F (31.4 and 61.8%, respectively).…”

“…Plasma concentrations below the LOQ were excluded from the analysis (4 pg/mL; n = 8%) and a logarithmic transformation of the remaining plasma concentrations was performed. A one-compartmental model with first-order absorption was chosen as the pop-PK base model, analogous to the human pop-PK model development (Michelet et al, 2016 ). Subsequently, based on a visual exploration of the plasma concentration-time profiles obtained in the growing piglets, a two-compartmental disposition model and a dual-input were evaluated to describe the absorption of the sublingual desmopressin lyophilisate.…”

“…Blood was sampled at 1, 2, and 6 h post administration. The full PK profiles were obtained through pop-PK simulation (Michelet et al, 2016 ), but likely do not capture all characteristics of desmopressin's PK, since the original studies applied a sparse sampling protocol. It is in this respect, that trials using pediatric animal models, such as the conventional piglet, might provide supplementary information to complement the information gap since full PK studies can be performed.…”

Food effects in paediatric medicines development for products Co-administered with food

“…Physiologically based pharmacokinetic (PBPK) modelling is used to predict food effects although it is acknowledged that these models are much more predictive of adult populations compared to children [8]. Preclinical development efforts for drug development are likely to include in vitro screening of transporter substrate activity and metabolic profiling to identify potential food effects as part of the standard development pathway.…”