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Hectorol

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Hectorol

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 the 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-l-α-hydroxylase to produce l&alpha,25-(OH)2D2, the primary biologically active form of vitamin D2, and l&alpha,25-(OH)2D3 (calcitriol), the biologically active form of vitamin D3.

Mechanism of Action

Calcitriol (lα,25-(OH)2D3) and lα,25-(OH)2D2 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 patients with chronic kidney disease (CKD), 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.

Pharmacokinetics and Metabolism

Doxercalciferol is absorbed from the gastrointestinal tract and activated by CYP 27 in the liver to form lα,25-(OH)2D2 (major metabolite) and lα,24-dihydroxyvitamin D2 (minor metabolite). Activation of doxercalciferol does not require the involvement of the kidneys.

In healthy volunteers, peak blood levels of lα,25-(OH)2D2, the major metabolite of doxercalciferol, are attained at 11-12 hours after repeated oral doses of 5 to 15 mcg of Hectorol (doxercalciferol liquid filled capsule) and the mean elimination half-life of lα,25-(OH)2D2 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) on dialysis appears to be similar. Hemodialysis causes a temporary increase in lα,25-(OH)2D2 mean concentrations, presumably due to volume contraction. 1α,25-(OH)2D2 is not removed from blood during hemodialysis.

Clinical Studies

Dialysis

The safety and effectiveness of Hectorol (doxercalciferol liquid filled capsule) were evaluated in two double-blind, placebo-controlled, multicentered clinical studies (Study A and Study B) in a total of 138 patients with chronic kidney disease on hemodialysis (Stage 5 CKD). Patients in Study A were an average age of 52 years (range: 22-75), were 55% male, and were 58% African-American, 31% Caucasian, and 11% Hispanic, and had been on hemodialysis for an average of 53 months. Patients in Study B were an average of 52 years (range: 27-75), were 45% male, and 99% African-American, and 1% Caucasian, and had been on hemodialysis for an average of 56 months. After randomization to two groups, eligible patients underwent an 8-week washout period during which no vitamin D derivatives were administered to either group. Subsequently, all patients received Hectorol (doxercalciferol liquid filled capsule) in an open-label fashion for 16 weeks followed by a double-blind period of 8 weeks during which patients received either Hectorol (doxercalciferol liquid filled capsule) or placebo. The initial dose of Hectorol (doxercalciferol liquid filled capsule) during the open-label phase was 10 micrograms after each dialysis session (3 times weekly) for a total of 30 mcg per week. The dosage of Hectorol (doxercalciferol liquid filled capsule) was adjusted as necessary by the investigator in an attempt to achieve intact parathyroid hormone (iPTH) levels within a targeted range of 150 to 300 pg/mL. The maximum dosage was limited to 20 mcg after each dialysis session (60 mcg/week). If at any time during the trial iPTH fell below 150 pg/mL, Hectorol (doxercalciferol liquid filled capsule) was immediately suspended and restarted at a lower dosage the following week.

Results

One hundred and six of the 138 patients who were treated with Hectorol (doxercalciferol liquid filled capsule) during the 16-week open-label phase achieved iPTH levels ≤ 300 pg/mL. Ninety-four of these patients exhibited plasma iPTH levels ≤ 300 pg/mL on at least 3 occasions. Eighty-seven patients had plasma iPTH levels < 150 pg/mL on at least one occasion during the open-label phase of study participation.

Mean weekly doses during the 16-week open-label period in Study A ranged from 14.8 mcg to 28.7 mcg. In Study B, the mean weekly doses during the 16-week open-label period ranged from 19.2 mcg to 28 mcg.

Decreases in plasma iPTH from baseline values were calculated using as baseline the average of the last 3 values obtained during the 8-week washout phase and are displayed in Table 1 below.

Table 1: iPTH Summary Data for Dialysis Patients Receiving Hectorol® (doxercalciferol liquid filled capsule)

  iPTH (pg/mL)
means ± s.d.(n*)
p Value v. Baseline
p Value v. Placebo
Hectorol® Placebo
Study A Baseline 797.2 ± 443.8 (30)
n.a. 0.97
847.1 ± 765.5(32)
Week 16
(open-label)
384.3 ± 397.8 (24)
< 0.001 0.72
526.5 ± 872.2 (29)
< 0.001
Week 24
(double-blind)
404.4 ± 262.9(21)
< 0.001 0.008
672.6 ± 356.9 (24) 0.70
Study B Baseline 973.9 ± 567.0 (41) n.a. 0.81 990.4 ± 488.3 (35)
Week 16 (open-label) 476.1 ± 444.5(37)
< 0.001 0.91
485.9 ± 443.4(32) < 0.001
Week 24 (double-blind) 459.8 ± 443.0 (35)
< 0.001 < 0.001
871.9 ± 623.6(30) < 0.065
* all subjects; last value carried to discontinuation

In both studies, iPTH levels increased progressively and significantly in 65.9% of the patients during the 8-week washout (control) period during which no vitamin D derivatives were administered. In contrast, Hectorol (doxercalciferol liquid filled capsule) treatment resulted in a statistically significant reduction from baseline in mean iPTH levels during the 16-week open-label treatment period in more than 93.5% of the 138 treated patients. During the double-blind period (weeks 17 to 24), the reduction in mean iPTH levels was maintained in the Hectorol (doxercalciferol liquid filled capsule) treatment group compared to a return to near baseline in the placebo group.

In the clinical trials, the values for iPTH varied widely from patient to patient and from week to week for individual patients. Table 2 shows the numbers of patients within each group who achieved and maintained iPTH levels below 300 pg/mL during the open-label and double-blind phases. Seventy-four of 138 patients (53.6%) had plasma iPTH levels within the target range (150-300 pg/mL) during Weeks 14-16.

Table 2: Number of Times iPTH < 300 pg/mL

  1 2 ≥ 3
Hectorol® Placebo Hectorol® Placebo Hectorol® Placebo
Study A Weeks 1-16
(open-label)
2/30 2/32 0/30 0/32 22/30 23/32
Weeks 17-24
(double-blind)
0/24 9/29 3/24 1/29 17/24 5/29
Study B Weeks 1-16
(open-label)
2/41 4/35 1/41 0/35 29/41 21/35
Weeks 17-24
(double-blind)
2/37 6/32 1/37 4/32 26/37 4/32

During the 8-week double-blind phase, more patients achieved and maintained the target range of values for iPTH with Hectorol (doxercalciferol liquid filled capsule) than with placebo.

Pre-dialysis

The safety and effectiveness of Hectorol (doxercalciferol liquid filled capsule) were evaluated in two clinical studies in 55 patients with Stage 3 or Stage 4 chronic kidney disease. Eighty-two percent of the patients were male, the average age was 64.6 years, 51% were Caucasian, 40% African-American, and the average serum iPTH level at baseline was 194.6 pg/mL. While levels of 25-(OH) vitamin D were not evaluated at baseline, retrospective assessments of stored serum revealed that the mean + SD serum 25-(OH) vitamin D was 18.5 + 8.1 ng/mL (range: < 5 to 54 ng/mL) in the study population.

After randomization to two groups, eligible patients underwent an 8-week washout period during which no vitamin D derivatives were administered to either group. Subsequently, one group received Hectorol (doxercalciferol liquid filled capsule) and the other placebo during a double-blind period of 24 weeks. The initial dose of Hectorol (doxercalciferol liquid filled capsule) was 1 mcg per day. The dosage of Hectorol (doxercalciferol liquid filled capsule) was adjusted as necessary by the investigator in order to reduce intact parathyroid hormone (iPTH) levels to a target of ≥ 30% below post-washout baseline. The maximum dosage was limited to 3.5 mcg per day. If at any time during the trial iPTH fell below 15 pg/mL, Hectorol (doxercalciferol liquid filled capsule) was immediately suspended and restarted at a lower dosage the following week.

Results

Decreases in the mean plasma iPTH from baseline values were calculated using as baseline the average of the last 2 values obtained during the 8-week washout phase. In analyses of pooled data from the two studies, iPTH levels decreased from baseline by an average of 101.4 pg/mL in the Hectorol (doxercalciferol liquid filled capsule) group and by 4.4 pg/mL in the placebo group (p < 0.001). Greater reductions of iPTH with Hectorol (doxercalciferol liquid filled capsule) compared to placebo were observed in each study. Twenty (74%) of 27 subjects in the Hectorol (doxercalciferol liquid filled capsule) group achieved mean plasma iPTH suppression of ≥ 30% from baseline for the last four weeks of treatment, whereas two (7%) of the 28 subjects treated with placebo achieved this level of iPTH suppression. In the Hectorol (doxercalciferol liquid filled capsule) -treated patients, the reductions in plasma iPTH were associated with a reduction in serum bone-specific alkaline phosphatase.

Last reviewed on RxList: 4/12/2011
This monograph has been modified to include the generic and brand name in many instances.

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