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

Xiaoping Zhang, Thomas Peyret, Nathalie H. Gosselin, J. F. Marier, Erik A. Imel, Thomas O. Carpenter

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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 (0.05-0.6 mg/kg) and a subsequent 12-month titration period (0.1-1.0 mg/kg) in XLH adults. The PK of KRN23 was described by a 1-compartmental model with first-order absorption and elimination at doses ≥0.1 mg/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 (Emax) and a time-varying effective concentration to reach 50% of Emax (EC50,t) described data adequately. Typical Emax was 1.5 mg/dL. Typical EC50,t was 1780 ng/mL and 5999 ng/mL after first and last dose, respectively.

Original languageEnglish (US)
Pages (from-to)429-438
Number of pages10
JournalJournal of clinical pharmacology
Issue number4
StatePublished - Apr 1 2016



  • X-linked hypophosphatemia (XLH)
  • human anti-FGF23 antibody (KRN23)
  • phamacodynamics
  • pharmacokinetics
  • serum phosphorus

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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