Searchable abstracts of presentations at key conferences on calcified tissues
Bone Abstracts (2014) 3 PP91 | DOI: 10.1530/boneabs.3.PP91

Bone development/growth and fracture repair

Pharmacokinetics and pharmacodynamics of a human monoclonal anti-FGF23 antibody (KRN23) after ascending single-dose administration in patients with X-linked hypophosphatemia

Xiaoping Zhang1, Thomas Carpenter2, Erik Imel3, Mary Ruppe4, Thomas Weber5, Mark Klausner1, Tetsuyoshi Kawakami1, Takahiro Ito1, Jeffrey Humphrey1, Karl Insogna2 & Munro Peacock3


1Kyowa Hakko Kirin Pharma, Inc., Princeton, New Jersey, USA; 2Yale University School of Medicine, New Haven, Connecticut, USA; 3Indiana University School of Medicine, Indianapolis, Indiana, USA; 4The Methodist Hospital at Houston, Houston, Texas, USA; 5Duke University Medical Center, Durham, North Carolina, USA.

Purpose: In X-linked hypophosphatemia (XLH), elevated serum FGF23 causes low serum phosphorus (Pi) and inappropriately normal 125-dihydroxyvitamin D (125(OH)2D) levels. We report PK and PD of KRN23 following single ascending dose administration in adults with XLH.

Methods: 38 XLH patients with baseline FGF23≥30 pg/ml were randomized to receive a single dose of KRN23 (K) or placebo (P) either i.v. (0.003–0.3 mg/kg) or s.c. (0.1–1.0 mg/kg). PK and PD samples were obtained from baseline through day 50. A validated ELISA method was used for PK and commercial assay kits were used for PD assays.

Results: 22 subjects participated in the i.v. cohort (17K, 5P), and 16 in the s.c. cohort (12K, 4P). Baseline age, sex, weight, and height of all groups were comparable in all groups. Mean KRN23 terminal half-life was shorter for i.v. (11–12 days) than for s.c. (13–19 days) administration. Absolute bioavailability was ~100% with s.c. dosing. There was a dose-proportional increase in serum KRN23 levels in both i.v. and s.c. cohorts. Following s.c. administration, peak serum KRN23 and Pi occurred at the same time. Area under the curve (AUClast) for changes from baseline in serum Pi, 125(OH)2D, and TmP/GFR were linearly correlated with AUCinf for serum KRN23. s.c. dosing exhibited a slower absorption profile (peak time: 8–11 days) and a more sustained effect than i.v. dosing as indicated by the delayed time to reach maximum mean serum Pi level (peak time: 8–15 vs 0.5–4 days) and longer time to return to baseline (50 vs 29 days).

Conclusions: KRN23 is a promising treatment for XLH patients. Complete absorption, sustained effect on serum Pi beyond 4 weeks, and a direct linear relationship between PK and PD effects supports a s.c. treatment regimen of once every 4 weeks for KRN23 in adults with XLH.

Volume 3

European Calcified Tissue Society Congress 2014

Prague, Czech Republic
17 May 2014 - 20 May 2014

European Calcified Tissue Society 

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