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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
Author(s) -
Zhang Xiaoping,
Peyret Thomas,
Gosselin Nathalie H.,
Marier J. F.,
Imel Erik A.,
Carpenter Thomas O.
Publication year - 2016
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.611
Subject(s) - pharmacokinetics , pharmacodynamics , dosing , hypophosphatemia , population , medicine , endocrinology , reabsorption , chemistry , pharmacology , kidney , environmental health
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 (E max ) and a time‐varying effective concentration to reach 50% of E max (EC 50,t ) described data adequately. Typical E max was 1.5 mg/dL. Typical EC 50,t was 1780 ng/mL and 5999 ng/mL after first and last dose, respectively.