Burosumab is approved for the treatment of hypophosphatemia in persistent tumor-induced osteomalacia. This work exemplifies a model-informed drug development approach that evaluated burosumab pharmacokinetics and pharmacokinetic/pharmacodynamics in the ultrarare tumor-induced osteomalacia population to support adult and pediatric dosing. Data from tumor-induced osteomalacia participants were combined with data from X-linked hypophosphatemia to understand pharmacokinetic and pharmacokinetic/pharmacodynamic characteristics and covariates specific to tumor-induced osteomalacia. Pharmacokinetic and pharmacokinetic/pharmacodynamic simulations were performed using final models to support dosing recommendations for adults and extrapolation to pediatric patients. Burosumab pharmacokinetics were described using a one-compartment model with first-order absorption and body weight as a significant covariate. Pharmacokinetic/pharmacodynamic relationships were described using a sigmoidal Emax model with significant covariates of baseline fibroblast growth factor 23 on baseline fasting serum phosphate and potency of burosumab response and tumor-induced osteomalacia disease state resulting in a steep slope of response; however, the covariates are not clinically meaningful. Simulations demonstrated that, in pediatric patients, starting doses of burosumab 0.3 and 0.4 mg/kg every 2 weeks at steady state would achieve normal serum phosphate levels in ≥ 30% of patients with relatively low risk of hyperphosphatemia (< 3%). In adults, burosumab 0.3 and 0.5 mg/kg every 4 weeks achieves similar percentages of responders and a relative low risk of hyperphosphatemia (< 7%). Serum phosphate titration-based burosumab dosing increased the probability of achieving normal serum phosphate levels. The models supported a model-informed drug development approach for global approvals of titration-based burosumab dosing, guided by monitoring fasting serum phosphate levels.
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