DOXERCALCIFEROL- doxercalciferol injection
Hikma Pharmaceuticals USA Inc.
Doxercalciferol, the active ingredient in Doxercalciferol Injection, is a synthetic vitamin D2 analog that undergoes metabolic activation in vivo to form 1a,25-dihydroxyvitamin D2 (1a,25-(OH)2 D2 ), a naturally occurring, biologically active form of vitamin D2 . Doxercalciferol injection is available as a sterile, clear, colorless aqueous solution for intravenous injection.
Doxercalciferol single-use injection is supplied in a 2 mL amber glass ampul containing 4 mcg/2 mL or 2 mcg/mL. Each milliliter (mL) of solution contains doxercalciferol, 2 mcg; Polysorbate 20, 4 mg; sodium chloride, 1.5 mg; sodium ascorbate, 10 mg; sodium phosphate, dibasic, anhydrous 7.6 mg; sodium dihydrogen phosphate, dihydrate, 2.34 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 (1α,3β,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
Other names frequently used for doxercalciferol are 1α-hydroxyvitamin D2 , 1α-OH-D2 , and 1α-hydroxyergocalciferol.
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-α-hydroxylase to produce 1α,25-(OH)2 D2 , the primary biologically active form of vitamin D2 , and 1α,25-(OH)2 D3 (calcitriol), the biologically active form of vitamin D3.
Calcitriol (1α,25-(OH)2 D3 ) and 1α,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.
After intravenous administration, doxercalciferol is activated by CYP 27 in the liver to form 1α,25-(OH)2 D2 (major metabolite) and 1α,24-dihydroxyvitamin D2 (minor metabolite). Activation of doxercalciferol does not require the involvement of the kidneys.
Peak blood levels of 1α,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 1α,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 1α,25-(OH)2 D2 mean concentrations presumably due to volume contraction. 1α,25-(OH)2 D2 is not removed from blood during hemodialysis.
The safety and effectiveness of doxercalciferol injection were evaluated in two open-label, single-arm, multi-centered clinical studies (Study C and Study D) in a total of 70 patients with chronic kidney disease on hemodialysis (Stage 5 CKD). Patients in Study C were an average age of 54 years (range: 23 to 73), were 50% male, and were 61% African-American, 25% Caucasian, and 14% Hispanic, and had been on hemodialysis for an average of 65 months. Patients in Study D were an average age of 51 years (range: 28 to 76), were 48% male, and 100% African-American and had been on hemodialysis for an average of 61 months. This group of 70 of the 138 patients who had been treated with doxercalciferol capsules in prior clinical studies (Study A and Study B) received doxercalciferol injection in an open-label fashion for 12 weeks following an 8-week washout (control) period. Dosing of doxercalciferol injection was initiated at the rate of 4 mcg administered at the end of each dialysis session (3 times weekly) for a total of 12 mcg per week. The dosage of doxercalciferol was adjusted in an attempt to achieve iPTH levels within a targeted range of 150 to 300 pg/mL. The dosage was increased by 2 mcg per dialysis session after 8 weeks of treatment if the iPTH levels remained above 300 pg/mL and were greater than 50% of baseline levels. The maximum dosage was limited to 18 mcg per week. If at any time during the trial iPTH fell below 150 pg/mL, doxercalciferol injection was immediately suspended and restarted at a lower dosage the following week.
Fifty-two of the 70 patients who were treated with doxercalciferol injection achieved iPTH levels ≤ 300 pg/mL. Forty-one of these patients exhibited plasma iPTH levels ≤ 300 pg/mL on at least three occasions. Thirty-six patients had plasma iPTH levels < 150 pg/mL on at least one occasion during study participation.
Mean weekly doses in Study C ranged from 8.9 mcg to 12.5 mcg. In Study D, the mean weekly doses ranged from 9.1 mcg to 11.6 mcg.
Decreases in plasma iPTH from baseline values were calculated using as baseline the average of the last three values obtained during the 8-week washout period and are displayed in the table below. Plasma iPTH levels were measured weekly during the 12-week study.
|iPTH Level||Study C(n = 28)||Study D(n = 42)||Combined Protocols(n = 70)|
|Baseline (Mean of Weeks -2, -1 and 0)|
|Mean (SE)||698 (60)||762 (65)||736 (46)|
|On-treatment (Week 12*)|
|Mean (SE)||406 (63)||426 (60)||418 (43)|
|Change from Baseline †|
|Mean (SE)||-292 (55)||-336 (41)||-318 (33)|
|P-value ‡||0.004||0.001||< 0.001|
In both studies, iPTH levels increased progressively and significantly in 62.9% of patients during the 8-week washout (control) period during which no vitamin D derivatives were administered. In contrast, doxercalciferol injection treatment resulted in a clinically significant reduction (at least 30%) from baseline in mean iPTH levels during the 12-week open-label treatment period in more than 92% of the 70 treated patients.
Table 2 shows the numbers of patients who achieved iPTH levels below 300 pg/mL on one, two, or three or more non-consecutive occasions during the 12-week treatment period. Thirty-seven of 70 patients (53%) had plasma iPTH levels within the targeted range (150 to 300 pg/mL) during Weeks 10 to 12.
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.