Background: In X-linked hypophosphatemia (XLH), abnormally elevated serum fibroblast growth factor 23 (FGF23) results in low renal maximum threshold for phosphate reabsorption (TmP/GFR), low serum phosphorus (Pi), inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2D) and development of rachitic deformities.
Methods: Up to four s.c. KRN23 doses were given every 28 days to 28 adults with XLH according to a dose-escalation algorithm (0.050.10.30.6 mg/kg). Blood and urine samples were collected pre-dose and on days 3, 7, 12, 18, and 26 after each dose.
Results: Mean KRN23 dose increased from 0.05 to 0.48 mg/kg. Mean times to maximum serum KRN23 level were similar across four dosing intervals (7.08.5 days). The mean KRN23 maximum, minimum, and area under the concentrationtime curve (AUCn) for the nth dosing interval increased proportionally with increases in mean dose. Mean KRN23 half-life was 16.4±5.8 days. Serum Pi and TmP/GFR increased from baseline at all subsequent samplings except the first-dose trough (P<0.05). Serum 1,25(OH)2D increased from baseline except for first and second-dose troughs (P<0.05). Bone markers increased significantly for BALP and CTx after three doses, osteocalcin after two doses, and P1NP after one dose (P<0.05). Serum KRN23 and Pi concentrations changed in parallel throughout the dosing interval, supporting a direct pharmacokinetics (PK)pharmacodynamics (PD) relationship. The AUCn for change from baseline in TmP/GFR, serum Pi, and 1,25(OH)2D at each dosing interval increased linearly with increase in KRN23 AUCn. No meaningful PKPD correlations were observed for serum calcium, parathyroid hormone, 25-hydroxyvitamin D, 2-h urine calcium/creatinine ratio, or 24-h urine calcium.
Conclusion: The effects of KRN23 on serum Pi, TmP/GFR, and serum 1,25(OH)2D levels were sustained after each dose. PK dose proportionality and the linear PKPD relationship between serum KRN23 concentrations and serum Pi concentrations support adjusting the dose based on serum Pi levels.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology