X. Zhang,1 T. Peyret,2 N. H. Gosselin,2 J. Marier,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: In subjects with X-linked hypophosphatemia (XLH), abnormally elevated serum FGF23 results in low renal maximum threshold for phosphate reabsorption, low serum phosphorus (inorganic) (Pi), and inappropriately normal 1,25-dihydroxyvitamin D which lead to the development of rachitic deformities. KRN23 is a human anti-FGF23 antibody being developed for the treatment for XLH. The objective of this project was to construct a population pharmacokinetic (PK) model to assess sources of variability.
METHODS: KRN23 serum concentrations were measured following single subcutaneous dose (0.1 to 1.0 mg/kg, N=12) or up to 16 multiple SC doses (0.05 to 1.0 mg/kg, N=28) in adults with XLH. Initial stepwise dose escalations and subsequent dose titrations were guided by pre-dose serum Pi levels. A population PK analysis was performed to assess the effect of intrinsic covariates (age, sex, race, body weight, anti KRN23 antibodies, baseline FGF23 and bone alkaline phosphatase) on PK.
RESULTS: The PK of KRN23 was modeled with a one-compartment model with first-order absorption and elimination at doses ≥ 0.1 mg/kg. For a 70-kg subject, typical values of apparent clearance and volume of distribution of KRN23 were 0.279 L/day and 7.17 L, respectively. The typical elimination half-life was 17.8 days. Non-linear clearance was observed at the lowest dose level (0.05 mg/kg). Covariates did not affect the PK of KRN23. Simulations suggest that steady state was reached after the third dose following dosing every 28 days with a three-fold accumulation of KRN23.
CONCLUSION: The long half-life of KRN23 supports dosing every 28 days. The model can be leveraged to support the dosing rationale of KRN23 in adult and pediatric patients with XLH in future clinical studies.