Vitamin D Metabolome (VDM) Profiles After Single and Repeated Doses of Extended-Release Calcifediol (ERC) in Patients on Hemodialysis (HD)

Background: Circulating 1,25-dihydroxyvitamin D (1,25D) levels are low in HD patients and presumed unresponsive to 25-hydroxyvitamin D (25D) repletion due to loss of renal CYP27B1 (cytochrome P450 25D-1α-hydroxylase). Serum 1,25D normalization has been demonstrated with regular dosing of oral ERC during HD, raising serum 25D sufficiently high (≥50 ng/mL) to drive hormone production by extra-renal CYP27B1. However, potential changes in the VDM profile have not been examined after single and repeated ERC doses. Methods: VDM profiles were studied in adults requiring thrice-weekly HD during 24-hour periods after the first and last ERC doses in a 6-month phase 2 trial. Participants were randomized 3:1 to ERC (n=19) or placebo (n=7). Dosing began with 900 µg on Day 1 and continued with 300 µg/HD from Day 8 to 184. Serum obtained at -12, -3, 0, 4, 8, 12, 16, 20 and 24 hours post-dose was assayed for calcifediol (25D3), total and free 25D, 1,25D, 24,25-dihydroxyvitamin D3 (24,25D3), vitamin D binding protein (DBP), corrected calcium (Ca) and phosphorus (P). Data were analyzed using mixed-effects models with repeated measures to estimate geometric mean time-courses, changes from baseline (BL), and metabolite:calcifediol ratios at each time point. Results: Participants (60±13 yrs and BMI of 34±10 kg/m2) were 44% female, 78% black, 22% white and 17% Hispanic. Mean (SD) 25D, Ca and P at BL were 25±10 ng/mL and 9.0±0.5 and 4.4±1.0 mg/dL. On Day 1, mean (95% CI) calcifediol rose maximally after the initial 900 µg dose by 24.7 (8.7-51.8) ng/mL or 27.4 pg/mL/µg at 12 hours, and increased with repeated 300 µg doses to steady-state at 101.2 (94.3-108.6) ng/mL. On Day 184, mean calcifediol rose maximally after the last 300 µg dose by 9.0 (1.8-16.8) ng/mL or 30.0 pg/mL/µg at 12 hours. Free 25D and 1,25D increased in constant ratios (relative to calcifediol) of 0.02 and 0.04, respectively, after both single and repeated doses; 24,25D3 also increased but with ratios decreasing from 2.3 to 1.3. DBP, Ca and P remained unchanged versus placebo. Conclusion: ERC therapy produced dose-proportional increases in circulating concentrations of total and free calcifediol and 1,25D, decreases in 24,25D3 ratios and no changes in DBP, Ca or P. Increases in 1,25D likely resulted from substrate-driven production by extra-renal CYP27B1. Funding: Commercial Support - OPKO Health, Inc. and CSL-Vifor Pharma