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Modified release active Vitamin D (calcifediol ) for those with poor Kidney function (USD 10,000 per year) – April 2015


Press Release On-line
Modified-release oral calcifediol corrects vitamin D insufficiency with minimal CYP24A1 upregulation
The Journal of Steroid Biochemistry and Molecular Biology. Volume 148, April 2015, Pages 283–289, 17th Vitamin D Workshop
Martin Petkovich, Joel Melnick, Jay White, Samir Tabash, Stephen Strugnell, Charles W. Bishop
Martin Petkovich: Cancer Research Institute, 355 Botterell Hall, Queen’s University, Kingston, ON K7L 3N6, Canada
Jay White, Samir Tabash: OPKO Health, Renal Division, Markham, ON L3R 6H3, Canada
Joel Melnick, Stephen Strugnell, Charles W. Bishop: OPKO Health, Renal Division, Miami, FL 33137, USA

VitaminDWiki comments

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Overview Kidney and vitamin D contains the following summary

 Download the PDF study VitaminDWiki

  • Abrupt calcifediol dosing triggers vitamin D catabolism, limiting iPTH lowering.
  • Rapid calcifediol administration can induce excessive FGF23 and CYP24 and lower CYP27B1.
  • Bolus administration of immediate-release calcifediol in CKD patients minimally impacts elevated iPTH.
  • Modified-release (MR) calcifediol gradually raises 25(OH)D3 and calcitriol.
  • MR calcifediol effectively lowers iPTH without raising net vitamin catabolism.

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 (≥30 ng/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 900 μg) or bolus IV (450 μg) 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.

OPKO Rayaldee™ Capsules (CTAP101 Capsules):

Rayaldee Capsules is a modified-release formulation of 25-hydroxyvitamin D3 (calcifediol) being developed as a new monotherapy to treat secondary hyperparathyroidism (SHPT) associated with vitamin D insufficiency in patients with Stage 3 through 4 chronic kidney disease (CKD). This orally administered product is designed to gradually restore serum total 25-hydroxyvitamin D concentrations to (or above) the currently accepted minimum adequate level of 30 ng/mL. It has potential application as an adjunctive therapy to vitamin D hormone replacement therapy for SHPT in patients with Stage 5 CKD. It also has potential application as adjunctive therapy to bisphosphonate, selective estrogen receptor modulator (SERM) and anti-RANK ligand (RANKL) treatment for metabolic bone diseases, including osteoporosis and metastatic bone cancer.

A randomized, double-blinded, dose-ranging placebo-controlled Phase 2b trial was completed in Q4’11. Data from this trial demonstrated that the product reliably corrected vitamin D insufficiency and effectively reduced elevated plasma intact parathyroid hormone (PTH) in the target patient population without adversely affecting serum calcium and phosphorus. These data were presented to the U.S. Food and Drug Administration (FDA) in Q1’12 during an end-of-Phase 2 meeting. At the FDA’s recommendation, a Special Protocol Assessment (SPA) was completed in Q3’12 for the planned Phase 3 trials, and the actual trials started shortly thereafter. Final data from these trials are anticipated in Q3’14. A 505(b)(2) new drug application (NDA) filing in the U.S. is targeted for H1’15. Rayaldee Capsules are protected until at least 2028 in the U.S. by method of use patents. Additional pending method of use and formulation patent applications are expected to protect the product through 2028 and beyond in all major global markets.

Modified-Release Calcifediol Controls Elevated iPTH, Corrects 25(OH)D Levels and Reduces Bone Markers in CKD Patients
2015 RBC Capital Markets’ Healthcare Conference
Opko CEO Renal Division Charles W. Bishop, PhD

This product is going to be the first with the indication of treating Secondary Hyperparathyroidism that arises from Vitamin D Insufficiency in this patient population. No other product has this indication. “We think it will be a game changer for our pre-dialysis patients.”

Rayaldee achieves Vitamin D sufficiency much more readily than any other product that is available. It lowers PTH as well as any product that is in the market. It does two things that Physician’s want to do. Rayaldee allows Physician’s to use one drug to get those two things done more effectively and safely.

Market for Rayaldee is large. Millions of patients that we target with Stage 3 & 4 CKD, one quarter are treated with active Vitamin D Hormones and one third are treated with Nutritional Vitamin D. Because neither of these options are very good about one half of the patient’s are not treated at all. We believe Rayaldee can take share from all three of these categories and in fact expand the market.

With Rayaldee’s target pricing at about $10,000 per year, you can see with every million patient’s we have under treatment we will have a major financial opportunity.

“Rayaldee will be the only product in history with this indication.” Charles W. Bishop, PhD, CEO

Attached files

ID Name Comment Uploaded Size Downloads
5327 Modified-release oral calcifediol.pdf admin 17 Apr, 2015 330.65 Kb 1179