OBJECTIVES: We aimed to investigate the appropriate dosing regimen of burosumab in adolescent patients with XLH by applying Model-Informed Drug Development (MIDD) methodology.

METHODS: In XLH, excess circulating fibroblast growth factor 23 (FGF23) causes low serum phosphorus. Change in serum phosphorus is a primary pharmacodynamic (PD) marker related to the efficacy and on-target safety effects of burosumab in clinical trials. Population pharmacokinetic (PK) and subsequently PK/PD models were developed using timed serum burosumab and phosphate concentrations from 115 adults and 65 children (1-12 years old at enrollment) with XLH that participated in at least one burosumab clinical trial. Monte-Carlo simulations of burosumab PK and PD profiles were conducted for adolescents with XLH (13-17 years old) to evaluate an appropriate dosing regimen.

RESULTS: Among several intrinsic and extrinsic covariates evaluated, patient’s body-weight was found to be the only significant covariate to affect burosumab PK and PD. An auxiliary weight-age model was built using data from actual patients with XLH. Together, the weight-age model and population PK/PD model enabled a prospective projection of PK/PD profiles in an adolescent XLH population. The results suggest that the clinically demonstrated starting dose of 0.8 mg/kg every 2 weeks (Q2W) proposed for children with XLH will likely provide a similar PD response, and therefore efficacy and safety, in adolescents, with a predicted mean steady-state trough serum phosphate level just above the lower bound of the normal pediatric reference range. Importantly, this change in serum phosphorus is unlikely to be associated with the risk of treatment-emergent hyperphosphatemia (ie, mean predicted peak phosphate level will not exceed the approximate mid-point of the normal phosphate range).

CONCLUSIONS: Results from the model-based evaluation suggests that the clinically demonstrated starting dose of 0.8 mg/kg Q2W in children with XLH should be equally safe and efficacious in adolescents with XLH.