Pharmacokinetics of Oral Spironolactone in Infants Up to 2 Years of Age

Purpose Spironolactone is a potassium sparing diuretic used for decades. Until now, pharmacokinetic (PK) studies of spironolactone have not been conducted in infants and therefore pediatric dosing is based on expert opinion. We aimed to describe the PK profiles of spironolactone and its main metabolites (7 alpha- thiomethylspironolactone (TMS) and canrenone (CAN)) in infants up to two years of age. Methods The PK of spironolactone and its main metabolites were evaluated following an oral administration of spironolactone (1 mg/kg/dose) to pediatric patients with chronic heart failure, ascites and/or oedema. The plasma concentration of spironolactone and metabolites (TMS and CAN) was determined using an ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Based on rich sampling PK data, the estimation of population PK parameters was performed using nonlinear mixed-effects modelling software Monolix 2018R2. Clinical trial Registration Number 2013-001189-40. Results A total of 150 spironolactone, 158 TMS and 158 CAN concentrations from 23 patients (ages: 3 days – 21 months; median weight 4.3kg (2.2–12.6) were available for PK analysis. A one-compartment model for spironolactone, TMS and CAN best fitted the data. The median (range) of individual estimated apparent clearance values were 47.7 (11.9–138.1) L/h for spironolactone, 9.7 (1.5–66.9) L/h for TMS, and 1.0 (0.2–5.9) L/h for CAN. The disposition of spironolactone and metabolites was mainly affected by size (body weight) of the patient. None of the undesirable effects of spironolactone was documented during the study period. Conclusion Based on the findings of this study, the current practice of administering oral spironolactone according to body weight appears to be justified in infants less than 24 months of age.