Population pharmacokinetic and pharmacodynamic analyses from a 4-month intradose escalation and its subsequent 12-month dose titration studies for a human monoclonal anti-FGF23 antibody (KRN23) in adults with X-linked hypophosphatemia

摘要

X-linked hypophosphatemia (XLH) is an inherited metabolic bone disease with abnormally elevated serum FGF23 resulting in low renal maximum threshold for phosphate reabsorption, low serum phosphate (Pi) and 1,25-dihydroxyvitamin D levels with subsequent development of short stature and skeletal deformities. KRN23 is a novel human anti-FGF23 antibody for the treatment of XLH. The pharmacokinetics (PK) and pharmacodynamics (PD) models of KRN23 were assessed following subcutaneous dosing every 28 days over an initial 4-month dose escalation (0.05-0.6mg/kg) and a subsequent 12-month titration period (0.1-1.0mg/kg) in XLH adults. The PK of KRN23 was described by a 1-compartmental model with first-order absorption and elimination at doses 0.1mg/kg. The elimination half-life was 17.8 days. Covariates did not affect KRN23 PK. Mean peak serum Pi was attained 7-10 days after dosing and progressively increased following each of the initial 4 doses with comparable peak values attained following the sixth through tenth doses with a slight decrease thereafter. A PK-PD model with a maximum effect (E-max) and a time-varying effective concentration to reach 50% of E-max (EC50,t) described data adequately. Typical E-max was 1.5mg/dL. Typical EC50,t was 1780ng/mL and 5999ng/mL after first and last dose, respectively.