X. Zhang,1 N. H. Gosselin,2 J. Marier,2 T. Peyret,2 T. Ito,1 E. Imel,3 T. O. Carpenter4; 1Kyowa Hakko Kirin Pharma Inc., Princeton, NJ, 2Pharsight-A Certara Company, Montreal, QC, Canada, 3Indiana University School of Medicine, Indianapolis, IN, 4Yale University School of Medicine, New Haven, CT

BACKGROUND: X-linked hypophosphatemia (XLH) is an inherited metabolic bone disease caused by mutations of PHEX, with abnormally elevated serum FGF23 resulting in low renal maximum threshold for phosphate reabsorption, low serum phosphorus (inorganic, Pi), and inappropriately normal 1,25 dihydroxyvitamin D levels with subsequent development of short stature and skeletal deformities. KRN23 is an anti-FGF23 antibody being developed for the treatment of XLH. The objective was to assess the pharmacokinetic/pharmacodynamic (PK/PD) relationship between KRN23 concentrations and change from baseline serum phosphorus (ΔPi) levels in adults with XLH.
METHODS: Serum Pi concentrations were collected during escalating dosing subcutaneous regimen of KRN23 every 28 days over an initial 4-month period (0.05 to 0.6 mg/kg, N=28) and a subsequent 12-month titrated dosing period (0.1 to 1.0 mg/kg, N=22). KRN23 concentrations were derived from a KRN23 pharmacokinetic model to pair with the observed serum Pi data. Multiple PK/PD models and quality of fit were evaluated using graphical and statistical estimators.
RESULTS: Mean ΔPi increased and reached a plateau of effect between the 6th and 10th doses of KRN23, and slightly decreased thereafter. A PK/PD model with maximum effect (Emax) and a time-varying concentration to reach 50% of maximal effect (EC50) described the data adequately. Typical Emax and EC50 at the start of treatment were 1.5 mg/dL and 1780 ng/mL, respectively. Typical EC50 values at week 32 and 72 increased to 4102.4 and 5998.7 ng/mL, respectively
CONCLUSION: An Emax model with time-varying EC50 accurately described the time-course of ΔPi after every 28 days dosing of KRN23 up to 16 doses. The PK/PD model can be used to perform trial simulations of KRN23 in adults with XLH.