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J Clin Pharmacol. 2016 Feb;56(2):176-85. doi: 10.1002/jcph.570. Epub 2015 Aug 11.

Pharmacokinetics and pharmacodynamics of a human monoclonal anti-FGF23 antibody (KRN23) in the first multiple ascending-dose trial treating adults with X-linked hypophosphatemia.

Author information

1
Kyowa Hakko Kirin Pharma Inc., Princeton, NJ, USA.
2
Indiana University School of Medicine, Indianapolis, IN, USA.
3
The Methodist Hospital, Houston, TX, USA.
4
Duke University Medical Center, Durham, NC, USA.
5
Shriners Hospital for Children, Montreal, Quebec, Canada.
6
University of California, San Francisco, CA, USA.
7
Yale Center for X-Linked Hypophosphatemia, Yale University School of Medicine, New Haven, CT, USA.

Abstract

In X-linked hypophosphatemia (XLH), serum fibroblast growth factor 23 (FGF23) is increased and results in reduced renal maximum threshold for phosphate reabsorption (TmP), reduced serum inorganic phosphorus (Pi), and inappropriately low normal serum 1,25 dihydroxyvitamin D (1,25[OH]2 D) concentration, with subsequent development of rickets or osteomalacia. KRN23 is a recombinant human IgG1 monoclonal antibody that binds to FGF23 and blocks its activity. Up to 4 doses of KRN23 were administered subcutaneously every 28 days to 28 adults with XLH. Mean ± standard deviation KRN23 doses administered were 0.05, 0.10 ± 0.01, 0.28 ± 0.06, and 0.48 ± 0.16 mg/kg. The mean time to reach maximum serum KRN23 levels was 7.0 to 8.5 days. The mean KRN23 half-life was 16.4 days. The mean area under the concentration-time curve (AUCn ) for each dosing interval increased proportionally with increases in KRN23 dose. The mean intersubject variability in AUCn ranged from 30% to 37%. The area under the effect concentration-time curve (AUECn ) for change from baseline in TmP per glomerular filtration rate, serum Pi, 1,25(OH)2 D, and bone markers for each dosing interval increased linearly with increases in KRN23 AUCn . Linear correlation between serum KRN23 concentrations and increase in serum Pi support KRN23 dose adjustments based on predose serum Pi concentration.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01340482.

KEYWORDS:

X-linked hypophosphatemia (XLH); fibroblast growth factor 23 (FGF23); human anti-FGF23 antibody (KRN23); pharmacokinetics; serum phosphorus

PMID:
26073451
PMCID:
PMC5042055
DOI:
10.1002/jcph.570
[Indexed for MEDLINE]
Free PMC Article

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