Use of Extended-Release Calcifediol to Treat Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease

Abstract

Background/Aims: Vitamin D insufficiency and secondary hyperparathyroidism (SHPT) are associated with increased morbidity and mortality in chronic kidney disease (CKD) and are poorly addressed by current treatments. The present clinical studies evaluated extended-release (ER) calcifediol, a novel vitamin D prohormone repletion therapy designed to gradually correct low serum total 25-hydroxyvitamin D, improve SHPT control and minimize the induction of CYP24A1 and FGF23. Methods: Two identical multicenter, randomized, double-blind, placebo-controlled studies enrolled subjects from 89 US sites. A total of 429 subjects, balanced between studies, with stage 3 or 4 CKD, SHPT and vitamin D insufficiency were randomized 2:1 to receive oral ER calcifediol (30 or 60 µg) or placebo once daily at bedtime for 26 weeks. Most subjects (354 or 83%) completed dosing, and 298 (69%) entered a subsequent open-label extension study wherein ER calcifediol was administered without interruption for another 26 weeks. Results: ER calcifediol normalized serum total 25-hydroxyvitamin D concentrations (>30 ng/ml) in >95% of per-protocol subjects and reduced plasma intact parathyroid hormone (iPTH) by at least 10% in 72%. The proportion of subjects receiving ER calcifediol who achieved iPTH reductions of ≥30% increased progressively with treatment duration, reaching 22, 40 and 50% at 12, 26 and 52 weeks, respectively. iPTH lowering with ER calcifediol was independent of CKD stage and significantly greater than with placebo. ER calcifediol had inconsequential impact on serum calcium, phosphorus, FGF23 and adverse events. Conclusion: Oral ER calcifediol is safe and effective in treating SHPT and vitamin D insufficiency in CKD.

Rationale for Raising Current Clinical Practice Guideline Target for Serum 25-Hydroxyvitamin D in Chronic Kidney Disease

“…A cross-sectional study [13] concluded that PTH levels in patients with stages 1-5 CKD progressively declined as serum 25-hydroxyvitamin D increased above 30 ng/mL and that 25-hydroxyvitamin D levels well above 42-48 ng/mL would be required for iPTH normalization in the more advanced CKD. Data from 3 prospective controlled studies [12,14], including the 2 presented herein, support higher serum total 25-hydroxyvitamin D targets in patients with stage 3 or 4 CKD.…”

“…Exclusion criteria included a spot urine calcium:creatinine (Ca:Cr) ratio of > 0.2, nephrotic range proteinuria (> 3 mg/mg Cr), and a history of parathyroidectomy for SHPT or renal transplantation. Subjects were enrolled progressively from December 2012 to January 2014 at sites of many different latitudes in order to minimize seasonal variation in mean baseline serum total 25-hydroxyvitamin D. Further details regarding these studies have been previously published [14,21].…”

“…A large cross-sectional study concluded that 25-hydroxyvitamin D levels well above 42-48 ng/mL were required for normalization of elevated PTH levels in more advanced CKD [13]. Data from 2 RCTs with ERC in patients with stage 3 or 4 CKD demonstrated that serum total 25-hydroxyvitamin D levels averaging approximately 68 ng/mL were required for effective iPTH suppression [14]. No evidence of increased rates of hypercalcemia or hyperphosphatemia with higher levels of 25-hydroxyvitamin D were observed in these studies.…”

“…Herein, we report a secondary analysis of pooled data from the 2 most recent RCTs conducted with ERC in patients with stage 3 or 4 CKD [14]. This analysis focuses primarily on the observed changes in plasma iPTH, serum bone turnover markers, and widely accepted safety parameters as a function of gradual, progressive increases in mean serum total 25-hydroxyvitamin D well above 20 or 30 ng/mL and seeks to identify the minimum level of 25-hydroxyvitamin D required to halt SHPT progression.…”

Active Vitamin D in Chronic Kidney Disease: Getting Right Back Where We Started from?

“…Renewed interest in this metabolite in the recent years resulted in the FDA approval of extended release (ER) calcifediol in the US in 2016. Studies in patients with CKD stages G3–G4 showed that, unlike the immediate release calcifediol, the ER formulation induces a gradual rise in serum 25(OH)D level along with a significant suppression of PTH levels (at least 30% from baseline), in spite of lower mean calcidiol levels [68]. A slight rise in calcitriol levels (from 34.4 to 46.7 pg/mL), proportional to the rise in calcidiol, was also noted, suggesting that the renal and/or extrarenal CYP27B1 were not downregulated by the rising levels of calcitriol.…”