Charles W. Bishop

Pharmacokinetics and systemic effect on calcium homeostasis of 1α,24-dihydroxyvitamin D2 in rats : Comparison with 1α,25-dihydroxyvitamin D2, calcitriol, and calcipotriol

Abstract 1α,24-Dihydroxyvitamin D 2 (1α,24(OH) 2 D 2 ) is a metabolite of 1α-hydroxyvitamin D 2 (1α-OH-D 2 ), a prodrug in development as a treatment for secondary hyperparathyroidism occurring in end stage renal disease. This prodrug has a broader therapeutic index than the corresponding vitamin D 3 analogue, possibly because hepatic metabolism of 1α-OH-D 2 shifts at higher dose levels from 1α,25-dihydroxyvitamin D 2 (1α,25(OH) 2 D 2 ) to 1α,24(OH) 2 D 2 . In this report, we present the pharmacokinetics of 1α,24(OH) 2 D 2 and its systemic effects on serum and urine calcium in rats. These properties were compared with those of 1α,25(OH) 2 D 2 , calcitriol, the active metabolite of endogenous vitamin D 3 , and calcipotriol, a vitamin D analogue noted for its rapid clearance and minimal effect on calcium homeostasis. Comparison of the blood concentration curves from time zero to infinity indicated that 1α,24(OH) 2 D 2 had about one-fifth the systemic exposure of 1α,25(OH) 2 D 2 or calcitriol, but almost 30 times that of calcipotriol. The oral bioavailabilities and circulating half-lives of 1α,24(OH) 2 D 2 and calcitriol were similar, whereas those of calcipotriol were much less. In vitamin D-deficient rats, oral doses of 1α,25(OH) 2 D 2 and calcitriol produced similar dose-dependent increases in serum calcium, whereas an oral dose 30 times greater was required for lα,24(OH) 2 D 2 to produce a similar response. Dose-response curves generated after oral and subcutaneous administration of 1α,24(OH) 2 D 2 , calcitriol, and calcipotriol to normal rats indicated that 1α,24(OH) 2 D 2 increases serum and urine calcium to a much lesser extent than calcitriol, and to a slightly greater extent than calcipotriol. These properties of 1α,24(OH) 2 D 2 suggest that production of this metabolite from 1α-OH-D 2 contributes to the lowered toxicity of 1α-OH-D 2 and indicate that 1α,24(OH) 2 D 2 itself has therapeutic potential.

Anti-proliferative activity and target cell catabolism of the vitamin D analog 1α,24(S)-(OH)2D2 in normal and immortalized human epidermal cells

Vitamin D analogs represent valuable new agents for the suppression of proliferation of a variety of cell types, including those of the skin. One such analog is the vitamin D2 metabolite, 1 alpha,24(S)-dihydroxyvitamin D2, which binds strongly to the vitamin D receptor and induces vitamin D-dependent gene expression in vitro. In the work described here, we studied the anti-proliferative activity and target cell metabolism of 1 alpha,24(S)-dihydroxyvitamin D2 in cells of human epidermal origin. We found this analog to be equally potent in its anti-proliferative effect to the hormone 1 alpha,25-dihydroxyvitamin D3. Furthermore, 1 alpha,24(S)-dihydroxyvitamin D2 was metabolized by the human keratinocyte cell line HPK1A-ras at a slower rate than either 1 alpha,25-dihydroxyvitamin D3 or calcipotriol, a drug used effectively in the treatment of psoriasis. We characterized the metabolic products of 1 alpha,24(S)-dihydroxyvitamin D2 as a mixture of side-chain truncated and hydroxylated products. The main product was identified by GC-MS and NMR techniques as 1 alpha,24(S),26-trihydroxyvitamin D2. The biological activity of this main product was determined in a vitamin D-dependent, growth-hormone reporter gene expression system to be lower than that of the parent molecule. We conclude from these data that 1 alpha,24(S)-dihydroxyvitamin D2 is a valuable new anti-proliferative agent with a slower rate of catabolism by cells of epidermal origin. Preliminary evidence suggests that the parent molecule, and not its products, is responsible for this biological activity in vitro.

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

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.

Modified-release oral calcifediol corrects vitamin D insufficiency with minimal CYP24A1 upregulation

Vitamin D insufficiency is prevalent in chronic kidney disease (CKD) and associated with secondary hyperparathyroidism (SHPT) and increased risk of bone and vascular disease. Unfortunately, supplementation of stage 3 or 4 CKD patients with currently recommended vitamin D2 or D3 regimens does not reliably restore serum total 25-hydroxyvitamin D to adequacy (≥30ng/mL) or effectively control SHPT. Preclinical and clinical studies were conducted to evaluate whether the effectiveness of vitamin D repletion depends, at least in part, on the rate of repletion. A modified-release (MR) oral formulation of calcifediol (25-hydroxyvitamin D3) was developed which raised serum 25-hydroxyvitamin D3 and calcitriol levels gradually. Single doses of either bolus intravenous (IV) or oral MR calcifediol were administered to vitamin D deficient rats. Bolus IV calcifediol produced rapid increases in serum 25-hydroxyvitamin D3, calcitriol and FGF23, along with significant induction of CYP24A1 in both kidney and parathyroid gland. In contrast, oral MR calcifediol produced gradual increases in serum 25-hydroxyvitamin D3 and calcitriol and achieved similar hormonal exposure, yet neither CYP24A1 nor FGF23 were induced. A 10-fold greater exposure to bolus IV than oral MR calcifediol was required to similarly lower intact parathyroid hormone (iPTH). Single doses of oral MR (450 or 900μg) or bolus IV (450μg) calcifediol were administered to patients with stage 3 or 4 CKD, SHPT and vitamin D insufficiency. Changes in serum 25-hydroxyvitamin D3 and calcitriol and in plasma iPTH were determined at multiple time-points over the following 42 days. IV calcifediol produced abrupt and pronounced increases in serum 25-hydroxyvitamin D3 and calcitriol, but little change in plasma iPTH. As in animals, these surges triggered increased vitamin D catabolism, as evidenced by elevated production of 24,25-dihydroxyvitamin D3. In contrast, MR calcifediol raised serum 25-hydroxyvitamin D3 and calcitriol gradually, and meaningfully lowered plasma iPTH levels. Taken together, these studies indicate that rapid increases in 25-hydroxyvitamin D3 trigger CYP24A1 and FGF23 induction, limiting effective exposure to calcitriol and iPTH reduction in SHPT. They also support further investigation of gradual vitamin D repletion for improved clinical effectiveness. This article is part of a Special Issue entitled 17th Vitamin D Workshop.

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

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.

Use of vitamin D4 analogs to investigate differences in hepatic and target cell metabolism of vitamins D2 and D3

In this study, we used molecules with either of the structural differences in the side chains of vitamin D(2) and vitamin D(3) to investigate which feature is responsible for the significant differences in their respective metabolism, pharmacokinetics and toxicity. We used two cell model systems-HepG2 and HPK1A-ras-to study hepatic and target cell metabolism, respectively. Studies with HepG2 revealed that the pattern of 24- and 26-hydroxylation of the side chain reported for 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)) but not for 1alpha-OH-D(3) is also observed in both 1alpha-OH-D(4) and Delta(22)-1alpha-OH-D(3) metabolism. This suggests that the structural feature responsible for targeting the enzyme to the C24 or C26 site could be either the C24 methyl group or the 22-23 double bond. In HPK1A-ras cells, the pattern of metabolism observed for the 24-methylated derivative, 1alpha,25-(OH)(2)D(4), was the same pattern of multiple hydroxylations at C24, C26 and C28 seen for vitamin D(2) compounds without evidence of side chain cleavage observed for vitamin D(3) derivatives, suggesting that the C24 methyl group plays a major role in this difference in target cell metabolism of D(2) and D(3) compounds. Novel vitamin D(4) compounds were tested and found to be active in a variety of in vitro biological assays. We conclude that vitamin D(4) analogs and their metabolites offer valuable insights into vitamin D analog design, metabolic enzymes and maybe useful clinically.

Position Statement from ADA/AACE/EASD/TES in Response to a Recently Published Letter to the Editor in The Lancet and an Editorial Addressing the Israeli-Palestinian Fighting in Gaza

Derek LeRoith, MD, PhD, Editor in Chief, Endocrine Practice R. Mack Harrell , MD, President, American Association of Clinical Endocrinologists George Grunberger, MD, President Elect, American Association of Clinical Endocrinologists Leonard Wartofsky, MD, Editor in Chief, The Journal of Clinical Endocrinology and Metabolism Andrea C. Gore, PhD, Editor in Chief, Endocrinology Margaret Wierman, MD, Acting Editor in Chief, Endocrine Reviews Stephen R. Hammes, MD, PhD, Editor in Chief, Molecular Endocrinology Carol A. Lange, PhD, Editor in Chief, Hormones and Cancer Richard J. Santen, MD, President, Endocrine Society George L. Bakris, MD, Editor in Chief, American Journal of Nephrology

Extended-Release Calcifediol in Renal Disease

Abstract Vitamin D supplementation in chronic kidney disease (CKD) is recommended by current clinical practice guidelines, but is unreliable in correcting vitamin D insufficiency and ineffective for treating secondary hyperparathyroidism (SHPT). Vitamin D receptor agonist therapy can lower elevated parathyroid hormone, but leaves serum total 25-hydroxyvitamin D (25(OH)D) uncorrected, depriving tissues of adequate substrate for local 1,25-dihydroxyvitamin D (1,25(OH)2D) production. Such therapy also causes unwanted elevation of Fibroblast Growth Factor 23 and CYP24A1-mediated vitamin D catabolism, both of which are associated with resistance to vitamin D therapy, and increases calcium and phosphorus “burden.” This drives vascular and renal calcification, leading to morbidity, mortality, and increased costs of associated medical care. Recently, an extended-release calcifediol formulation has been demonstrated in randomized controlled clinical trials to be a safe and effective treatment for SHPT associated with vitamin D insufficiency in patients with stage 3 or 4 CKD, overcoming challenges associated with prior and current therapies.

Extended-release calcifediol for secondary hyperparathyroidism in stage 3-4 chronic kidney disease

ABSTRACT Introduction: Extended-release calcifediol (ERC) 30 µg capsules were recently approved as Rayaldee® by the United States Food and Drug Administration (FDA) for the treatment of secondary hyperparathyroidism (SHPT) in adults with stage 3–4 (not 5) chronic kidney disease (CKD) and vitamin D insufficiency (serum total 25-hydroxyvitamin D < 30 ng/mL). Calcifediol is 25-hydroxyvitamin D3, a prohormone of calcitriol (1,25-dihydroxyvitamin D3), the endogenous active vitamin D hormone. ERC capsules have a lipophilic fill which gradually releases calcifediol, corrects vitamin D insufficiency and increases serum calcitriol and thereby suppresses production of parathyroid hormone (PTH) in CKD patients without perturbing normal vitamin D and mineral metabolism. Areas covered: This review focuses on the chemical, pharmacokinetic, pharmacodynamic and clinical profiles of ERC and describes the product’s utility relative to other current treatment options for SHPT. Expert commentary: Randomized clinical trials (RCTs) have demonstrated that nutritional vitamin D is ineffective for treating SHPT whereas vitamin D receptor activators can correct elevated PTH but with increased risk of hypercalcemia and hyperphosphatemia. ERC offers healthcare professionals a new treatment option that has been demonstrated in RCTs to be safe and effective for controlling SHPT without meaningfully increasing serum concentrations of calcium or phosphorus.