(M-084) Population Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Analysis of Burosumab in Patients with X-Linked Hypophosphatemia Aged <12 Months

Nathalie Gosselin, PhD – Vice President, Certara; Leng Hong Pheng, PhD – Associate Director, Integrated Drug Development, Certara; Nagaraju Poola, PhD – Director, Clinical Pharmacology, Kyowa Kirin Inc.; Emilia Quattrocchi, MD – Senior Director, Medical Science, Kyowa Kirin Pharmaceutical Development Ltd; Matthew Hruska, PharmD, PhD, FCP – Vice President, Global Head Clinical Pharmacology, Kyowa Kirin Inc.; Douglas Marsteller, PhD – Senior Director, Pharmacometrics, Clinical Pharmacology, Kyowa Kirin Inc.

Objectives: Burosumab is a monoclonal antibody that increases serum phosphate in patients with X-linked hypophosphatemia (XLH) by targeting fibroblast growth factor 23 (FGF23) and is approved for the treatment of XLH in adult and pediatric patients in a number of countries. The objective of this analysis was to characterize the pharmacokinetics (PK) and pharmacokinetic/pharmacodynamic (PK/PD) relationship of burosumab in patients with XLH aged < 12 months using population pharmacokinetics (PPK) and population pharmacokinetic/pharmacodynamic (PPK/PD) modeling approaches.

Methods: PPK and PPK/PD analyses were performed using data (3735 and 7786 serum samples for PK and PD [serum phosphate], respectively) from a pediatric study (NCT04188964) of patients with XLH aged < 12 months and data from 10 previously conducted clinical studies in patients with XLH aged 10 months to 12 years and 18 to 68 years. Phoenix NLME® Version 8.4 was used for nonlinear mixed effects modeling. Covariate effects were tested for significance in a stepwise manner using the likelihood ratio test. Verification of the models was performed using goodness-of-fit (GOF) plots and visual predictive checks (VPCs).

Results: Burosumab PK following subcutaneous (SC) administration in patients with XLH aged < 12 months was described using a one-compartment model with time-varying body weight (WT) on apparent clearance (CL/F) and apparent volume of distribution (V/F) with a first-order rate of absorption, maturation function [1] on CL/F, and age effect on V/F. The estimated β (fractional change in CL/F in a typical full-term neonate at birth) was 0.250 and maturation half-life for CL/F was 1.74 years, which corresponded to 8.7 years to achieve full maturation. The age effect on V/F was parameterized as a power function with estimated exponent of 0.129. The PPK/PD model of burosumab following SC administration in patients with XLH aged < 12 months was described using a sigmoid maximum effect (Emax) model with baseline age on baseline serum phosphate level (E0), time-varying WT on serum burosumab concentration to reach 50% of Emax (EC50), and time-varying age on Emax. All covariates were included in the model using a power function. The typical values of E0, EC50, and Emax for infant patients aged 0.734 years weighing 8.85 kg are 2.88 mg/dL, 1960 ng/mL, and 0.600 mg/dL, respectively. The GOF plots and VPCs for the PPK and PPK/PD models verified that both models were acceptable to be selected as a final model.

Conclusions: The PK and PD of burosumab in patients with XLH aged < 12 months were adequately characterized using these PPK and PPK/PD models. Additional parameters associated with age were included in order to capture the new data from infants and are likely associated with the rapid maturation and changes in renal physiology at this age. The PPK/PD model can be used to support the dosing of burosumab in pediatric patients with XLH aged < 12 months.

Study funded by Kyowa Kirin Inc

Citations: [1] Robbie GJ et al. Antimicrob Agents Chemother 2012;56:4927.