Quantitative Systems Pharmacology Modeling of X-linked Hypophosphatemia Disease Pathway Normalization to Predict the Impact of Burosumab Treatment on Serum Biomarkers in Adult and Pediatric Patients
Authors: Takaichi Daisuke , Gewitz Andy , Okada Hiroki , Mehta Krina , Hosogi Jun , Nagata Yoshinori , Utsey Kiersten , Riggs Matthew 
Published: February 2025

Objectives: X-linked hypophosphatemia (XLH) is a rare disease characterized by hypophosphatemia caused by elevated levels and activity of fibroblast growth factor 23 (FGF23). Burosumab, a monoclonal antibody targeting FGF23, has been approved for XLH treatment in adult and pediatric patients in various countries. Burosumab effectively increases serum phosphate (sPi) levels, addressing XLH pathology. The objectives of this study were to extend a published bone QSP model by incorporating XLH disease mechanism and burosumab impact on sPi and other biomarkers in both pediatric and adult XLH patients.Methods: Serum concentrations of burosumab- and XLH-associated biomarkers, including FGF23, sPi, calcium, vitamin D, parathyroid hormone, and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were obtained from 28, 22, and 15 patients with XLH in studies KRN23-INT-001, KRN23-INT-002, and KRN23-003 (NCT01340482, NCT01571596, NCT03233126), respectively. A QSP model for XLH patients was developed by extending a published bone QSP model to incorporate the FGF23 pathway [1, 2]. The model was estimated using a maximum posterior (MAP) Bayesian method with fixed and random effects derived from a one-compartment population PK model. This PK model was linked to both a target-mediated drug disposition (TMDD) structure (to capture individual serum burosumab concentrations and FGF23 dynamics in XLH patients) and a transit compartment (TC) model (to describe changes in TmP/GFR with burosumab dosing). Model calibration and evaluation were conducted by comparing summary plots to obtained data. Model simulations were conducted on a virtual XLH population selected based on parameter distribution boundaries and clinical inclusion criteria.Results: The bone QSP model for XLH was successfully optimized to account for new information. FGF23 production rate was updated to be greater in patients with XLH than healthy subjects and to set FGF23 production and degradation rates to equate to steady state in patients with XLH. FGF23 production rate was estimated and set based on individual baseline FGF23 levels and the FGF23 degradation rate constant derived from the literature [3]. The full TMDD model was incorporated by optimizing the parameters for FGF23-burosumab binding interaction (KD, Kint, Kon). The TC model showed that TmP/GFR doubled within a burosumab dosing interval when predicted unbound FGF23 decreased to 35% and 45% of baseline for XLH in adult and pediatric patients, respectively. The final QSP model described patient-level data well for changes in PK and PD biomarkers; simulations reproduced results from other burosumab studies.Conclusion: The QSP model reproduced clinically observed changes in PD markers in both adult and pediatric patients with XLH. It also successfully replicated sPi normalization with burosumab treatment. This model facilitates a better understanding of burosumab dosing in patients with XLH going forward.Citations: [1] Peterson MC & Riggs MM. Bone 2010;46:49–63.[2] Riggs MM et al. Poster presented at ACoP 2020. https://metrumrg.com/wp-content/uploads/2020/11/RiggsMM_ACOP2020_BoneModelExtensionHyperphosphatemia.pdf. [3] Khosravi A et al. J Clin Endocrinol Metab 2007;92:2374–7.