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Modified-release oral calcifediol corrects vitamin D insufficiency with minimal CYP24A1 upregulation.
J Steroid Biochem Mol Biol. 2015 Apr; 148:283-9.JS

Abstract

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".

Authors+Show Affiliations

Cancer Research Institute, 355 Botterell Hall, Queen's University, Kingston, ON K7L 3N6, Canada. Electronic address: martin.petkovich@queensu.ca.OPKO Health, Renal Division, Miami, FL 33137, USA.OPKO Health, Renal Division, Markham, ON L3R 6H3, Canada.OPKO Health, Renal Division, Markham, ON L3R 6H3, Canada.OPKO Health, Renal Division, Miami, FL 33137, USA.OPKO Health, Renal Division, Miami, FL 33137, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25446887

Citation

Petkovich, Martin, et al. "Modified-release Oral Calcifediol Corrects Vitamin D Insufficiency With Minimal CYP24A1 Upregulation." The Journal of Steroid Biochemistry and Molecular Biology, vol. 148, 2015, pp. 283-9.
Petkovich M, Melnick J, White J, et al. Modified-release oral calcifediol corrects vitamin D insufficiency with minimal CYP24A1 upregulation. J Steroid Biochem Mol Biol. 2015;148:283-9.
Petkovich, M., Melnick, J., White, J., Tabash, S., Strugnell, S., & Bishop, C. W. (2015). Modified-release oral calcifediol corrects vitamin D insufficiency with minimal CYP24A1 upregulation. The Journal of Steroid Biochemistry and Molecular Biology, 148, 283-9. https://doi.org/10.1016/j.jsbmb.2014.11.022
Petkovich M, et al. Modified-release Oral Calcifediol Corrects Vitamin D Insufficiency With Minimal CYP24A1 Upregulation. J Steroid Biochem Mol Biol. 2015;148:283-9. PubMed PMID: 25446887.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modified-release oral calcifediol corrects vitamin D insufficiency with minimal CYP24A1 upregulation. AU - Petkovich,Martin, AU - Melnick,Joel, AU - White,Jay, AU - Tabash,Samir, AU - Strugnell,Stephen, AU - Bishop,Charles W, Y1 - 2014/11/22/ PY - 2014/08/29/received PY - 2014/11/19/revised PY - 2014/11/21/accepted PY - 2014/12/3/entrez PY - 2014/12/3/pubmed PY - 2015/5/23/medline KW - CYP24A1 KW - Calcifediol KW - Chronic kidney disease KW - Clinical study KW - Modified-release KW - Rat KW - Secondary hyperparathyroidism KW - Vitamin D insufficiency SP - 283 EP - 9 JF - The Journal of steroid biochemistry and molecular biology JO - J Steroid Biochem Mol Biol VL - 148 N2 - 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". SN - 1879-1220 UR - https://www.unboundmedicine.com/medline/citation/25446887/Modified_release_oral_calcifediol_corrects_vitamin_D_insufficiency_with_minimal_CYP24A1_upregulation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-0760(14)00287-8 DB - PRIME DP - Unbound Medicine ER -