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

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]2 D) 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)2 D, 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.

Trial registration: ClinicalTrials.gov NCT01340482.

Keywords: X-linked hypophosphatemia (XLH); fibroblast growth factor 23 (FGF23); human anti-FGF23 antibody (KRN23); pharmacokinetics; serum phosphorus.

© 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Mean serum KRN23 concentration over time (A) and dose proportionality between mean log KRN23 AUCn and mean log dose during the 4 dosing intervals (B). Error bars represent standard deviation (SD). The mean ± SD dose was 0.05 ± 0.0, 0.10 ± 0.01, 0.28 ± 0.06, and 0.48 ± 0.16 mg/kg for dosing intervals 1, 2, 3, and 4, respectively. N = 27 for dosing intervals 1 to 3 and n = 26 for dosing interval 4.

Figure 2

Pharmacodynamic (PD) profiles over 4 dosing intervals (left) and relationship of pharmacokinetic (PK) and PD parameters (right). (A and B) Serum Pi; (C and D) TmP/GFR; (E and F) 1,25(OH)2D. AUCn, area under the KRN23 serum concentration–time curve; AUECn, area under the effect concentration–time curve for PD change from baseline during interval n (n = 1, 2, 3, or 4); R, Pearson correlation coefficient.

Figure 3

Relationship of pharmacokinetic and bone marker change from baseline. (A) BALP; (B) P1NP; (C) Osteocalcin; (D) CTx; (E) NTx/creatinine. AUCn, area under the KRN23 serum concentration–time curve; AUECn, area under the effect concentration–time curve for bone marker change from baseline during interval n (n = 1, 2, 3, or 4); R, Pearson correlation coefficient.

Figure 4

Pharmacodynamic (PD) profiles over 4 dosing intervals (left) and relationship of PK and PD parameters (right). (A and B) Serum calcium; (C and D) serum PTH; (E and F) 2‐hour urine calcium/creatinine ratio; (G and H) 24‐hour urine calcium. AUCn: area under the KRN23 serum concentration–time curve; AUECn, area under the effect concentration–time curve for PD change from baseline during interval n (n = 1, 2, 3, or 4); R, Pearson correlation coefficient.