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

Xiaoping Zhang, Erik Imel, Mary D. Ruppe, Thomas J. Weber, Mark A. Klausner, Takahiro Ito, Maria Vergeire, Jeffrey Humphrey, Francis H. Glorieux, Anthony A. Portale, Karl Insogna, Thomas O. Carpenter, Munro Peacock

Research output: Contribution to journalArticle

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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]2D) 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)2D, 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.

Original languageEnglish (US)
Pages (from-to)176-185
Number of pages10
JournalJournal of Clinical Pharmacology
Volume56
Issue number2
DOIs
StatePublished - Feb 1 2016

Fingerprint

Familial Hypophosphatemic Rickets
Pharmacokinetics
Antibodies
Serum
Osteomalacia
Rickets
fibroblast growth factor 23
Glomerular Filtration Rate
Phosphorus
Half-Life
Immunoglobulin G
Phosphates
Monoclonal Antibodies
Kidney
Bone and Bones

Keywords

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

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Pharmacokinetics and pharmacodynamics of a human monoclonal anti-FGF23 antibody (KRN23) in the first multiple ascending-dose trial treating adults with X-linked hypophosphatemia. / Zhang, Xiaoping; Imel, Erik; Ruppe, Mary D.; Weber, Thomas J.; Klausner, Mark A.; Ito, Takahiro; Vergeire, Maria; Humphrey, Jeffrey; Glorieux, Francis H.; Portale, Anthony A.; Insogna, Karl; Carpenter, Thomas O.; Peacock, Munro.

In: Journal of Clinical Pharmacology, Vol. 56, No. 2, 01.02.2016, p. 176-185.

Research output: Contribution to journalArticle

Zhang, Xiaoping ; Imel, Erik ; Ruppe, Mary D. ; Weber, Thomas J. ; Klausner, Mark A. ; Ito, Takahiro ; Vergeire, Maria ; Humphrey, Jeffrey ; Glorieux, Francis H. ; Portale, Anthony A. ; Insogna, Karl ; Carpenter, Thomas O. ; Peacock, Munro. / Pharmacokinetics and pharmacodynamics of a human monoclonal anti-FGF23 antibody (KRN23) in the first multiple ascending-dose trial treating adults with X-linked hypophosphatemia. In: Journal of Clinical Pharmacology. 2016 ; Vol. 56, No. 2. pp. 176-185.
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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]2D) 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)2D, 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.",
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AU - Zhang, Xiaoping

AU - Imel, Erik

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AU - Weber, Thomas J.

AU - Klausner, Mark A.

AU - Ito, Takahiro

AU - Vergeire, Maria

AU - Humphrey, Jeffrey

AU - Glorieux, Francis H.

AU - Portale, Anthony A.

AU - Insogna, Karl

AU - Carpenter, Thomas O.

AU - Peacock, Munro

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N2 - 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]2D) 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)2D, 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.

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KW - pharmacokinetics

KW - serum phosphorus

KW - X-linked hypophosphatemia (XLH)

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