HECTOROL- doxercalciferol injection, solution
Genzyme Corporation
DESCRIPTION
Doxercalciferol, the active ingredient in Hectorol� , is a synthetic vitamin D2 analog that undergoes metabolic activation in vivo to form 1?,25-dihydroxyvitamin D2 (1?,25-(OH)2 D2 ), a naturally occurring, biologically active form of vitamin D2 . Hectorol is available as a sterile, clear, colorless aqueous solution for intravenous injection.
Hectorol single-use injection is supplied in a stoppered 2 mL amber glass vial containing either 4 mcg/2 mL or 2 mcg/mL. Each vial includes an aluminum seal and yellow (4 mcg/2 mL) or green (2 mcg/mL) flip-off cap. Each milliliter (mL) of solution contains doxercalciferol, 2 mcg; ethanol, 100%, 0.05 mL; Polysorbate 20, 10 mg; sodium chloride, 1.5 mg; butylated hydroxytoluene, 0.02 mg; sodium phosphate dibasic, heptahydrate, 14.4 mg; sodium phosphate monobasic, monohydrate, 1.8 mg; and disodium edetate, 1.1 mg.
Hectorol is also supplied as a multi-dose injection contained within a stoppered 2 mL amber glass vial containing 4 mcg/2 mL. Each vial includes an aluminum seal and an orange plastic flip-off cap. Each milliliter (mL) of solution contains doxercalciferol, 2 mcg; ethanol, 100%, 0.075 mL; Polysorbate 20, 10 mg; sodium chloride, 1.5 mg; butylated hydroxytoluene, 0.02 mg; sodium phosphate dibasic, heptahydrate, 14.4 mg; sodium phosphate monobasic, monohydrate, 1.8 mg; and disodium edetate, 1.1 mg.
Doxercalciferol is a colorless crystalline compound with a calculated molecular weight of 412.66 and a molecular formula of C28 H44 O2 . It is soluble in oils and organic solvents, but is relatively insoluble in water. Chemically, doxercalciferol is (1?,3?,5Z,7E,22E)-9,10-secoergosta-5,7,10(19),22-tetraene-1,3-diol and has the structural formula presented in Figure 1.
Figure 1: Chemical Structure of Doxercalciferol
Figure 1
(click image for full-size original)
Other names frequently used for doxercalciferol are 1?-hydroxyvitamin D2 , 1?-OH-D2 , and 1?-hydroxyergocalciferol.
CLINICAL PHARMACOLOGY
Vitamin D levels in humans depend on two sources: (1) exposure to the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol in the skin to vitamin D3 (cholecalciferol) and (2) dietary intake of either vitamin D2 (ergocalciferol) or vitamin D3 . Vitamin D2 and vitamin D3 must be metabolically activated in the liver and kidney before becoming fully active on target tissues. The initial step in the activation process is the introduction of a hydroxyl group in the side chain at C-25 by the hepatic enzyme, CYP 27 (a vitamin D-25-hydroxylase). The products of this reaction are 25-(OH)D2 and 25-(OH)D3 , respectively. Further hydroxylation of these metabolites occurs in the mitochondria of kidney tissue, catalyzed by renal 25-hydroxyvitamin D-1-?-hydroxylase to produce 1?,25-(OH)2 D2 , the primary biologically active form of vitamin D2 , and 1?,25-(OH)2 D3 (calcitriol), the biologically active form of vitamin D3 .
Mechanism of Action
Calcitriol (1?,25-(OH)2 D3 ) and 1?,25-(OH)2 D2 regulate blood calcium at levels required for essential body functions. Specifically, the biologically active vitamin D metabolites control the intestinal absorption of dietary calcium, the tubular reabsorption of calcium by the kidney and, in conjunction with parathyroid hormone (PTH), the mobilization of calcium from the skeleton. They act directly on bone cells (osteoblasts) to stimulate skeletal growth, and on the parathyroid glands to suppress PTH synthesis and secretion. These functions are mediated by the interaction of these biologically active metabolites with specific receptor proteins in the various target tissues. In uremic patients, deficient production of biologically active vitamin D metabolites (due to lack of or insufficient 25-hydroxyvitamin D-1-alpha-hydroxylase activity) leads to secondary hyperparathyroidism, which contributes to the development of metabolic bone disease in patients with renal failure.
Pharmacokinetics and Metabolism
After intravenous administration, doxercalciferol is activated by CYP 27 in the liver to form 1?,25-(OH)2 D2 (major metabolite) and 1?,24-dihydroxyvitamin D2 (minor metabolite). Activation of doxercalciferol does not require the involvement of the kidneys.
Peak blood levels of 1?,25-(OH)2 D2 are reached at 8 +/- 5.9 hours (mean +/- SD) after a single intravenous dose of 5 mcg of doxercalciferol. The mean elimination half-life of 1?,25-(OH)2 D2 after an oral dose is approximately 32 to 37 hours with a range of up to 96 hours. The mean elimination half-life in patients with end stage renal disease (ESRD) and in healthy volunteers appears to be similar following an oral dose. Hemodialysis causes a temporary increase in 1?,25-(OH)2 D2 mean concentrations presumably due to volume contraction. 1?,25-(OH)2 D2 is not removed from blood during hemodialysis.
