Fixed Dosing of Leuprolide Acetate, a GnRH Agonist, in Children with Central Precocious Puberty: A Population Pharmacokinetic Justification

Central precocious puberty is the early onset of puberty due to premature activation of the hypothalamic-pituitary-gonadal axis, which can reduce adult height. Leuprolide, a gonadotropin-releasing hormone agonist, reduces gonadotropin secretion and is the standard treatment for central precocious puberty. This study aimed to build a population model to describe the pharmacokinetics of a 3-month leuprolide acetate depot formulation in pediatric patients with central precocious puberty, evaluate covariate effects (age and weight) on leuprolide pharmacokinetics, and assess flat-dosing feasibility in pediatrics. Samples from 48 patients (aged 1–10 years) were collected over 24 weeks following the administration of 11.25 and 30 mg of a leuprolide acetate 3-month depot formulation. A population pharmacokinetic model was developed using non-linear mixed-effects modeling (NONMEM). Covariate effects were tested using a forward inclusion and backward elimination approach and exploratory data analysis. A one-compartment model with immediate and delayed first-order absorption and proportional error model best described leuprolide pharmacokinetics in children. A transit compartment model characterized the delayed absorption. Apparent clearance and volume estimates were 181 L/day and 7.11 L, respectively, which were in alignment with those estimated in adult patients with prostate cancer. The immediate and delayed absorption rate constants were 0.441 day−1 and 0.00879 day−1, respectively. The number of transit compartments and the mean transit time were 3 and 34.1 days, respectively. No covariates significantly affected leuprolide pharmacokinetics. The developed model adequately characterized leuprolide pharmacokinetics in pediatrics. No significant covariate effects were observed, supporting the use of a fixed leuprolide dose in pediatrics. NCT00635817, registered 13 March, 2008.