ECTS2014 Poster Presentations Bone development/growth and fracture repair (55 abstracts)
Pharmacokinetics and pharmacodynamics of a human monoclonal anti-FGF23 antibody (KRN23) after ascending single-dose administration in patients with X-linked hypophosphatemia
Xiaoping Zhang 1 , Thomas Carpenter 2 , Erik Imel 3 , Mary Ruppe 4 , Thomas Weber 5 , Mark Klausner 1 , Tetsuyoshi Kawakami 1 , Takahiro Ito 1 , Jeffrey Humphrey 1 , Karl Insogna 2 & Munro Peacock 3
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.
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