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.
authors.affiliation: Kyowa Hakko Kirin Pharma Inc, Princeton, NJ, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Pharsight-A Certara™ Company, Montreal, Quebec, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Peyret
authors.affiliation: Pharsight-A Certara™ Company, Montreal, Quebec, Canada.
authors.forename: Nathalie H
authors.initials: NH
authors.lastname: Gosselin
authors.affiliation: Pharsight-A Certara™ Company, Montreal, Quebec, Canada.
authors.forename: J F
authors.initials: JF
authors.lastname: Marier
authors.affiliation: Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Imel
authors.affiliation: Yale Center for X-Linked Hypophosphatemia, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Carpenter
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D053098:Familial Hypophosphatemic Rickets / Q000097:blood / Q000188:drug therapy*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010710:Phosphates / Q000097:blood; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000717427:FGF23 protein, human; D010710:Phosphates; D014807:Vitamin D; D005346:Fibroblast Growth Factors; C097949:1,25-dihydroxyvitamin D; D000089703:Fibroblast Growth Factor-23; C000601956:burosumab
keywords: X-linked hypophosphatemia (XLH); human anti-FGF23 antibody (KRN23); phamacodynamics; pharmacokinetics; serum phosphorus