Age-dependent changes in sirolimus metabolite formation in patients with neurofibromatosis type 1.

Abstract

Sirolimus is an inhibitor of mammalian target of rapamycin, which exhibits large interindividual pharmacokinetic variability. We report sirolimus pharmacokinetic data collected as part of a concentration-controlled multicenter phase II clinical trial in pediatric patients with neurofibromatosis type 1. The purpose of this study was to explore the effect of growth on age-dependent changes in sirolimus clearance with a focus on cytochrome P450 3A (CYP3A) subfamily mediated metabolism. Predose blood samples were obtained at steady state from 18 patients with neurofibromatosis type 1. Sirolimus and its 5 CYP3A-dependent primary metabolites were quantified by HPLC-UV/MS. Concentration ratios of metabolites to sirolimus (metabolic ratio) were calculated as an index of metabolite formation. Metabolic ratios of the main metabolites, 16-O-demethylsirolimus (16-O-DM) and 24-hydroxysirolimus (24OH), were significantly correlated with sirolimus clearance, whereas this was not the case for the other 3 metabolites (25-hydroxysirolimus, 46-hydroxysirolimus, and 39-O-demethylsirolimus). The ratios for the 16-O-DM and 24OH metabolites were lower in children than adults. No significant difference in allometrically scaled metabolic ratios of 16-O-DM and 24OH was observed between children and adults. This study suggests that the age-dependent changes in sirolimus clearance can be explained by size-related increases in CYP3A metabolic capacity, most likely due to liver and intestinal growth. These findings will help facilitate the development of age-appropriate dosing algorithms for sirolimus in infants and children.