Modified-Release Calcifediol Effectively Controls Secondary Hyperparathyroidism Associated with Vitamin D Insufficiency in Chronic Kidney Disease

Abstract

Background/Aims: Vitamin D insufficiency drives secondary hyperparathyroidism (SHPT) and is associated with increased cardiovascular mortality in patients with chronic kidney disease (CKD). SHPT is poorly addressed by current vitamin D repletion options. The present study evaluated a novel investigational vitamin D repletion therapy: a modified-release (MR) formulation of calcifediol designed to raise serum 25-hydroxyvitamin D in a gradual manner to minimize the induction of CYP24 and, thereby, improve the SHPT control. Methods: This randomized, double-blind, placebo-controlled trial evaluated MR calcifediol in CKD subjects (n = 78) with plasma intact parathyroid hormone (iPTH) >70 pg/ml and serum total 25-hydroxyvitamin D <30 ng/ml. Subjects received daily treatment for six weeks with oral MR calcifediol (30, 60 or 90 µg) or a placebo. Results: More than 90% of subjects treated with MR calcifediol achieved serum 25-hydroxyvitamin D levels ≥30 ng/ml versus 3% of subjects treated with placebo (p < 0.0001). Mean plasma iPTH decreased from baseline (140.3 pg/ml) by 20.9 ± 6.2% (SE), 32.8 ± 5.7 and 39.3 ± 4.3% in the 30, 60 and 90 µg dose groups, respectively, and increased 17.2 ± 7.8% in the pooled placebo group (p < 0.005). No clinically significant safety concerns arose during MR calcifediol treatment. Conclusion: Oral MR calcifediol appears safe and highly effective in treating SHPT associated with vitamin D insufficiency in CKD.

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

“…Data from the 3 trials presented herein, and from one previous controlled study [10] , have all demonstrated that ER calcifediol is well tolerated at higher 25-hydroxyvitamin D levels within the normal range and that subjects' compliance with the prescribed doses is excellent. The incidences of TEAEs in studies A and B were similar between subjects treated with ER calcifediol and placebo, and there was a low rate of discontinuations due to TEAEs (5.3% for ER calcifediol compared with 4.2% for placebo).…”

“…A single-dose comparative clinical study showed that ER calcifediol was more effective than IR calcifediol in lowering elevated plasma iPTH in CKD patients with vitamin D insufficiency [14] . A 6-week randomized, double-blind placebo-controlled study in CKD patients demonstrated that daily bedtime doses of 30, 60 or 90 μg of ER calcifediol increased serum 25-hydroxyvitamin D levels to ≥ 30 ng/ml in more than 90% of treated subjects and dosages of ≥ 60 μg/day reduced plasma iPTH by ≥ 30% from pretreatment baseline in more than 60% of subjects without meaningful impact on serum Ca, P or FGF23 [10] .…”

“…It is defined in clinical practice guidelines applicable to CKD as serum total 25-hydroxyvitamin D <30 ng/ml [7,8] and it arises from nutritional inadequacy, decreased sunlight exposure, proteinuric loss and decreased hepatic synthesis of 25-hydroxyvitamin D and increased expression of CYP24A1, the cytochrome P450 enzyme that specifically catabolizes 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D and more polar catabolites [9,10] . There is general agreement amongst nephrologists and endocrinologists that vitamin D insufficiency should be corrected [7,8,11] .…”

“…In contrast, extended-release (ER) calcifediol has been shown in a 6-week randomized, double-blind, placebo-controlled trial to reliably correct vitamin D insufficiency and to effectively suppress elevated plasma intact PTH (iPTH) in CKD patients while maintaining normal serum total 25-hydroxyvitamin D concentrations [10]. We report herein additional studies that examine the safety and efficacy of ER calcifediol administered for periods of up to 52 weeks in patients with stage 3 or 4 CKD.…”

Treatment Failure of Active Vitamin D Therapy in Chronic Kidney Disease: Predictive Factors

“…Unfortunately, there are limited reports of well-designed, randomized, controlled studies of these agents, or for comparisons of the efficacy of active vitamin D or analogs, conducted in patients with CKD [10] . In one recently published (2014) trial in patients with CKD who were not undergoing dialysis, calcifediol for 6 weeks has been shown to significantly increase serum 25-hydroxyvitamin D and decrease plasma iPTH ( ≥ 30% in >60% patients treated with 60 or 90 μg/day) levels compared with placebo [22] . In pre-dialysis patients with CKD stage 3 or 4, treatment with cholecalciferol for 12 weeks has been shown to significantly increase serum vitamin D compared with placebo; however, effects on plasma PTH levels were not statistically significant (-31 vs. -7% for placebo) [23] .…”