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 Imel, Thomas O. Carpenter

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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
Volume56
Issue number4
DOIs
StatePublished - Apr 1 2016

Fingerprint

Familial Hypophosphatemic Rickets
Anti-Idiotypic Antibodies
Pharmacokinetics
Monoclonal Antibodies
Population
Serum
Phosphates
Metabolic Bone Diseases
Half-Life
Kidney

Keywords

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

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

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

In: Journal of Clinical Pharmacology, Vol. 56, No. 4, 01.04.2016, p. 429-438.

Research output: Contribution to journalArticle

@article{d5c484612c544e718cbe098d7cde157c,
title = "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",
abstract = "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.",
keywords = "human anti-FGF23 antibody (KRN23), phamacodynamics, pharmacokinetics, serum phosphorus, X-linked hypophosphatemia (XLH)",
author = "Xiaoping Zhang and Thomas Peyret and Gosselin, {Nathalie H.} and Marier, {J. F.} and Erik Imel and Carpenter, {Thomas O.}",
year = "2016",
month = "4",
day = "1",
doi = "10.1002/jcph.611",
language = "English (US)",
volume = "56",
pages = "429--438",
journal = "Journal of Clinical Pharmacology",
issn = "0091-2700",
publisher = "SAGE Publications Inc.",
number = "4",

}

TY - JOUR

T1 - 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

AU - Zhang, Xiaoping

AU - Peyret, Thomas

AU - Gosselin, Nathalie H.

AU - Marier, J. F.

AU - Imel, Erik

AU - Carpenter, Thomas O.

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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.

AB - 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.

KW - human anti-FGF23 antibody (KRN23)

KW - phamacodynamics

KW - pharmacokinetics

KW - serum phosphorus

KW - X-linked hypophosphatemia (XLH)

UR - http://www.scopus.com/inward/record.url?scp=84959873077&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959873077&partnerID=8YFLogxK

U2 - 10.1002/jcph.611

DO - 10.1002/jcph.611

M3 - Article

VL - 56

SP - 429

EP - 438

JO - Journal of Clinical Pharmacology

JF - Journal of Clinical Pharmacology

SN - 0091-2700

IS - 4

ER -