Robin Michelet (1), Pauline De Bruyne (2), Lien Dossche (2), Johan Vande Walle (3), Jan Van Bocxlaer (1), An Vermeulen (1)
(1): Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Belgium, (2): Department of Pediatrics and Medical Genetics, Faculty of Medicine and Health Sciences, Ghent University, Belgium, (3): Department of Pediatric Nephrology, Ghent University Hospital, Belgium
Introduction: Off-label use of drugs in the pediatric population is widespread: 50-90% of drugs are not tested in children [1]. The project SAFE-PEDRUG aims to provide new medical and ethical guidelines for conducting clinical trials in children, based on a rational combination of bottom-up and top-down investigations. Desmopressin (DDAVP), one of the drugs under study, is a synthetic vasopressin analogue used in nocturnal enuresis treatment. Two formulations, a tablet (TAB) and a lyophilisate (MELT), exist of which the bio-equivalence has been established in adults but not in children. This pilot study investigates how the drug product influences the pharmacokinetics and provides suggestions for subsequent studies.
Methods: Earlier published data on 22 children (mean age 12.7 y and mean weight 50.1 kg) were included in the study. Blood samples were taken 1h, 2h and 6h after both TAB and MELT dosing at 200 and 120 µg, respectively. Dosing events were 2 weeks apart and patients received a standardized meal before administration [2]. In addition, an available part of historical data (28 patients, 1-3 samples per patient) from Osterberg et al. [3] were also included in the analysis.
A 1-compartment model with first order absorption was fitted to the data using NONMEM (v. 7.3, [4]). Covariates were selected through one-by-one screening to construct a full model, followed by backward deletion. The final model goodness-of-fit (GOF) was evaluated by means of diagnostic tools and a sensitivity analysis (SA) was performed to evaluate the sampling design.
Results: The popPK model was able to describe DDAVP plasma concentrations adequately as is shown by the different diagnostics. The NPDE distribution did not significantly differ from the normal distribution and the basis GOF plots only showed a slight bias at low concentrations. In this model, formulation and fasted/fed state were included as significant covariates on F1 and body weight on distribution volume. MELT was found to be 1.321 times more available as TAB, while being fasted increased the bioavailability 2.01 times. SA showed optimal sampling times to be between 0.5 and 1.5, and at 5 hours.
Conclusions: For the first time in children, the difference in relative bioavailability between the two DDAVP drug products has been proven to be significant. Furthermore, sampling times for a further study were suggested which should result in more informative data and consequently generate a more reliable model.
References:
[1] Francesca R., Paolo T., The development of medicines for children: Part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni, Pharmacological Research, Volume 64, Issue 3, September 2011, Pages 169-175, ISSN 1043-6618.
[2] De Bruyne, P., De Guchtenaere, A., Van Herzeele, C., Raes, A., Dehoorne, J., Hoebeke, P., Van Laecke, E., et al. (2014). Pharmacokinetics of desmopressin administered as tablet and oral lyophilisate formulation in children with monosymptomatic nocturnal enuresis. European Journal of Pediatrics, 173(2), 223–228.
[3] Osterberg O., Savic R., Karlsson M., Simonsson U., Norgaard J., Vande Walle J., Agerso H. (2006) Pharmacokinetics of desmopressin administrated as an oral lyophilisate dosage form in children with primary nocturnal enuresis and healthy adults. Journal of Clinical Pharmacology 46(10):1204-121.
[4] Beal S., Sheiner L., Boeckmann J. NONMEM user’s guides. Icon Development Solutions, Ellicott City, MD. 1989-2006.
Reference: PAGE 24 (2015) Abstr 3535 [www.page-meeting.org/?abstract=3535]
Poster: Drug/Disease modeling - Paediatrics