Extended-release calcifediol in stage 3-4 chronic kidney disease: a new therapy for the treatment of secondary hyperparathyroidism associated with hypovitaminosis D

Abstract

A high percentage of patients with chronic kidney disease have hypovitaminosis D, which is a driver of secondary hyperparathyroidism and an important factor in chronic kidney disease-mineral and bone disorder. Vitamin D deficiency (serum total 25-OH vitamin D levels < 30 ng/mL) occurs early in the course of chronic kidney disease and treatment guidelines recommend early intervention to restore 25-OH vitamin D levels as a first step to prevent/delay the onset/progression of secondary hyperparathyroidism. The vitamin D forms administered to replace 25-OH vitamin D include cholecalciferol, ergocalciferol, and immediate- or extended-release formulations of calcifediol. Most patients with intermediate-stage chronic kidney disease will develop secondary hyperparathyroidism before dialysis is required. Control of parathyroid hormone levels becomes a major focus of therapy in these patients. This article focuses on the position of extended-release calcifediol in the treatment of patients with stage 3-4 chronic kidney disease and secondary hyperparathyroidism with hypovitaminosis D. Several characteristics of extended-release calcifediol support its use in the intermediate stages of chronic kidney disease. The pharmacokinetics of extended-release calcifediol make it effective for replenishing 25-OH vitamin D levels, with minimal impact on vitamin D catabolism from fibroblast-growth factor-23 and CYP24A1 upregulation. Extended-release calcifediol increases circulating 25-OH vitamin D levels in a dose-dependent manner and lowers parathyroid hormone levels by a clinically relevant extent, comparable to what can be achieved by administering active vitamin D analogues, though with a lower risk of hypercalcaemia and hyperphosphataemia. Active vitamin D analogues are reserved for patients undergoing dialysis or pre-dialysis patients with severe progressive secondary hyperparathyroidism.

Keywords: Calcifediol; Chronic kidney disease; Parathyroid hormone; Secondary hyperparathyroidism; Vitamin D; Vitamin D insufficiency.

Fig. 1

Effect of bolus i.v. or oral extended-release calcifediol administration on serum levels of calcifediol and 1,25-dihydroxyvitamin D in patients with stage 3 or 4 CKD, secondary hyperparathyroidism and vitamin D insufficiency. Patients received a single bolus i.v. injection of 448 mg calcifediol (solid circles) or single doses of oral extended-release calcifediol (450 mg—solid triangles; 900 mg—solid squares). Serum samples obtained at the indicated time points were analysed for a calcifediol (25(OH)D3) and b 1,25-dihydroxyvitamin D. Data are corrected for baseline values. Asterisk denotes significant differences at all time points post-treatment between i.v. and extended-release treatment groups (p < 0.05). MR: modified release formulation providing extended-release (From Petkovich et al. [42])

Fig. 2

Mean (± SE) plasma intact parathyroid hormone versus mean serum total 25-hydroxyvitamin D (ng/mL) during the efficacy assessment period in the per protocol population (Sprague et al. [24])

Fig. 3

Mean (± SE) serum total 1,25-dihydroxyvitamin D (pg/mL) versus serum total 25-hydroxyvitamin D (ng/mL) during the efficacy assessment period in the per protocol population (Sprague et al. [24])

Fig. 4

Changes from baseline in serum 25(OH)D concentrations during the 6-week treatment period according to the extended-release calcifediol dose administered (30, 60 or 90 μg/day). EOT, end of treatment (From Sprague et al. [17])

Fig. 5

Percent changes from baseline in plasma intact parathyroid hormone at the end of the 6-week treatment period according to the administered extended-release calcifediol dose (30, 60 or 90 μg/day). *Significantly different from placebo, p < 0.05; **Significantly different from placebo, p < 0.001 (From Sprague et al. [17])

Fig. 6

Mean (SE) change over time in serum total 25(OH)D in the combined per protocol population. Data points from 0 to 26 weeks represent mean values for individual time points from placebo-controlled studies A and B. Error bars in this portion of the figure are omitted for clarity. Data points from 26 to 52 weeks represent mean ± SE values for data from the open-label extension study. SE values for 0–26 weeks were of similar magnitude to those in the open-label extension (From Sprague et al. [44])

Fig. 7

Analysis of plasma intact parathyroid hormone response rates by posttreatment 25(OH)D Quintile. The proportion of per protocol subjects achieving an intact parathyroid hormone response, defined as a mean decrease of ≥ 30% in plasma intact parathyroid hormone from pre-treatment baseline, was analysed as a function of mean posttreatment serum total 25(OH)D quintile (from Strugnell et al. [19]). ^†Significantly different from Quintile 1, p < 0.05; iPTH intact parathyroid hormone

Fig. 8

Flowchart for managing patients with nondialysis-CKD stage 3–4. ERC extended-release calcifediol, parathyroid hormone parathyroid hormone, Vit D vitamin D

Fig. 9

Current and future management of secondary hyperparathyroidism in patients with CKD and hypovitaminosis D. Vit D vitamin D IRC immediate-release calciferol, ERC extended-release calciferol, secondary hyperparathyroidism secondary hyperparathyroidism