Population Pharmacokinetics and Pharmacodynamics of Burosumab in Adult and Pediatric Patients With X-linked Hypophosphatemia

Abstract

Burosumab is a fully human monoclonal antibody against fibroblast growth factor 23, which has been approved to treat X-linked hypophosphatemia (XLH) in adult and pediatric patients. The present work describes the pharmacokinetics (PK) of burosumab and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between burosumab and serum phosphorus in adult and pediatric patients with XLH. A total of 2844 measurable serum concentrations of burosumab and 6047 measurable serum concentrations of phosphorus in 277 subjects from 9 clinical studies were included in the population PK and PK-PD modeling. The serum concentration of burosumab following a subcutaneous administration was well described by a population PK model comprising a first-order absorption, 1-compartmental distribution, and a linear elimination. The relationship between serum burosumab and serum phosphorus was adequately described by a sigmoid maximal efficacy model. Body weight was the only covariate associated with PK and PK-PD parameters. No other intrinsic factors affected PK or PK-PD relationship in adult and pediatric patients with XLH. Further simulations helped to guide the dosing regimen of burosumab in adult and pediatric patients with XLH including age groups with no clinical data.

Keywords: X-linked hypophosphatemia; burosumab; pharmacodynamics; pharmacokinetics; serum phosphorus.

Figure 1

Diagnostic plots of the final Population PK model of burosumab in subjects with XLH. Light gray crosses = infants with XLH; gray triangles = children with XLH; black circles = adults with XLH. Observed concentrations versus individual and population predicted concentrations are presented on log scales in the upper left and upper central plots, and in linear scales in the lower left and lower central plots. Age categories are infants (1‐2 years), children (2‐12 years), and adults (>17 years). IDENT, line of identity; LOESS, locally weighted scatter plot smoothing; PK, pharmacokinetic; XLH, X‐linked hypophosphatemia.

Figure 2

Prediction‐corrected visual predictive check plots of the final population PK model of burosumab in subjects with XLH. Uncertainty on observations was determined by resampling the observations within each bin (N = 1000) and model predictions were based on 1000 replicates of the data set. Gray dashed lines represent percentiles of observed burosumab concentrations within each bin; gray shaded area represents 95th percentile interval of percentiles of predicted concentrations, and black shaded area represents 95th percentile interval of percentiles of observed concentrations. Obs, observations; P10, 10th percentile; P50, 50th percentile; P90, 90th percentile; PI, prediction interval; PK, pharmacokinetic; XLH, X‐linked hypophosphatemia.

Figure 3

Diagnostic plots of the final population PK/PD model of serum phosphorus‐burosumab relationship in subjects with XLH. Light gray crosses = infants with XLH; gray triangles = children with XLH; black circles = adults with XLH. Observed concentrations vs individual and population predicted concentrations are presented on log scales in the upper left and upper central plots, and in linear scales in the lower left and lower central plots. Age categories are infants (1‐2 years), children (2‐12 years), and adults (>17 years). IDENT, line of identity; LOESS, locally weighted scatter plot smoothing; PK, pharmacokinetic; XLH, X‐linked hypophosphatemia.

Figure 4

Prediction‐corrected visual predictive check plots of the final population PK/PD model of serum phosphorus‐burosumab relationship in subjects with XLH. Uncertainty on observations was determined by resampling the observations within each bin (N = 1000) and model predictions were based on 1000 replicates of the data set. Gray dashed lines represent percentiles of observed serum phosphorus levels within each bin; gray shaded area represents 95th percentile interval of percentiles of predicted levels, and black shaded area represents 95th percentile interval of percentiles of observed levels. Obs, observations; P10, 10th percentile; P50, 50th percentile; P90, 90th percentile; PD, pharmacodynamic; PK, pharmacokinetic; PI, prediction interval; XLH, X‐linked hypophosphatemia.