Desmopressin oral lyophilisate in young children: new insights in pharmacokinetics and pharmacodynamics

Abstract

Objective: To study the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of desmopressin (dDAVP) oral lyophilisate in children below the age of 8 years with special emphasis on age-related and size-related differences in bioavailability.

Design: Open label, non-randomised, interventional PK and PD trial.

Setting: Single-centre study.

Patients: Children (age: 6 months to 8 years) with nocturnal polyuria, including both children with uropathy or nephropathy (glomerular filtration rate >60 mL/min/1.73 m²) and children (age: 5-8 years) with severe monosymptomatic nocturnal enuresis, who were unresponsive to treatment with 400 µg of the dDAVP tablet for at least 1 month.

Interventions: After a water load, dDAVP was administered sublingually as a single dose of oral lyophilisate. Subsequently, blood and urine samples were collected until 7 hours post-administration.

Main outcome measures: Non-compartmental analysis of PK parameters was performed based on dDAVP concentrations in both plasma and urine. To evaluate the effect of dDAVP lyophilisate (PD parameters), the urinary concentration capacity (urine osmolality (mOsm/kg)) and antidiuretic effect (diuresis rate (mL/kg/h)) were calculated.

Results: The PK data support the need for size-dependent dosing in children. Body weight was shown to be a significant covariate for apparent clearance (CL/F) and apparent volume of distribution (V_d/F). A double absorption peak of dDAVP lyophilisate in the first 2 hours post-administration was demonstrated.

Conclusions: For the first time, a double absorption profile of dDAVP lyophilisate was found in children, questioning extrapolation of bioequivalence from adults towards children. Moreover, the need for size-adapted dosing regimens of dDAVP lyophilisate in young children is indicated.

Trial registration number: NTC02584231.

Keywords: desmopressin acetate oral disintegrating tablets; monosymptomatic nocturnal enuresis; pharmacokinetics/-dynamics; renal concentration test.