Doxercalciferol (Hectorol) for patients undergoing renal dialysis
Doxercalciferol (Hectorol) for patients undergoing renal dialysis
By Andrea Alvarez, PharmD candidate
Medical University of South Carolina
Charleston, SC
Indications:
Doxercalciferol, manufactured by Bone Care International in Madison, WI, is indicated for the reduction of elevated serum intact parathyroid (iPTH) concentrations in the management of secondary hyperparathyroidism in patients undergoing chronic renal dialysis.1-3
Pharmacology:
Doxercalciferol (1-alpha-OH-D2, 1-alpha-hydroxyvitamin D2, 1-alpha-hydroxyergocalciferol) is a synthetic vitamin D analog.1-3 In the body, doxercalciferol is hydroxylated to the active metabolite, 1,25-dihydroxyvitamin D2 (1,25-dihydroxyergocalciferol), via the hepatic cytochrome P-450 isoenzyme 27.1,3 Activated metabolites and analogs of vitamin D increase the intestinal absorption of dietary calcium and increase renal tubular reabsorption, in conjunction with parathyroid hormone.
In patients who have chronic renal failure, decreased metabolic activation of vitamin D in the kidneys results in secondary hyperparathyroidism, osteodystrophy, and rickets.1,4 Because doxercalciferol, unlike vitamin D2 (ergocalciferol), does not require renal hydroxylation for activation, this analog can reduce elevated serum or plasma parathyroid concentrations in patients with chronic renal failure.1-3
Pharmacokinetics:
Doxercalciferol is absorbed from the gastrointestinal tract and activated by cytochrome P-450 isoenzyme 27 in the liver to form the active metabolite, 1-alpha,25-dihydroxyvitamin D2, and a minor metabolite, 1-alpha,24-dihydroxyvitamin D2. Activation of doxercalciferol does not require the involvement of the kidneys.1,3 The peak blood concentration of the active metabolite of doxercalciferol is reached about 12 hours after repeated oral doses of 5 to 15 mcg of doxercalciferol, and the mean elimination half-life is approximately 37 hours.
Prolonged half-lives, up to 96 hours, have been documented. The half-life in patients with end-stage renal disease on dialysis appears to be similar.1-3 Hemodialysis causes a temporary increase in mean 1-alpha,25-dihydroxyvitamin D2 concentrations, presumably due to volume contraction.1,3 However, 1-alpha,25-dihydroxyvitamin D2 is not removed from blood during hemodialysis.1-3
Selected clinical trials:
A study was conducted to evaluate the safety and efficacy of 1-alpha-hydroxyvitamin D2 in suppressing serum iPTH concentrations in patients requiring hemodialysis who had moderate-to-severe secondary hyperparathyroidism.5 Patients with serum iPTH concentrations above 400 pg/ mL were recruited from the West Los Angeles VA Medical Center, South Valley Regional Dialysis Center and BMA Culver City Dialysis Unit.
Inclusion criteria were as follows:
- a duration of hemodialysis greater than four months;
- a serum iPTH concentration above 400 pg/mL while not receiving calcitriol;
- a serum albumin concentration greater than 3.5 g/dL;
- an average serum phosphorus level between 3 and 6.9 mg/dL over the preceding two months;
- no intake of aluminum-containing phosphate binders within the preceding 12 months;
- a serum aluminum concentration below 40 mcg/mL.
Exclusion criteria were as follows:
- an underlying medical condition that might alter the absorption or metabolism of 1-alpha-hydroxyvitamin D2, such as malabsorption syndrome or severe liver disease;
- any condition that may have prohibited a patient from remaining in the study, such as alcohol/drug abuse, malignancy, or psychiatric disorder;
- parathyroid surgery within the preceding 12 months.
A total of 24 patients who required hemodialysis completed the study (18 males, six females). The patients' ages ranged from 27 to 74 (mean = 51), and patients had been receiving dialysis an average of 28 months (range four to 162 months). Eighteen patients had previously been treated with calcitriol, while six patients had not.5
After an eight-week washout period without calcitriol, patients received 1-alpha-hydroxyvitamin D2 4 mcg, administered orally each morning (n = 10), or 4 mcg administered orally three times per week at the end of dialysis (n = 14). The frequency of the initial dose depended on the serum iPTH concentration during washout and/or a history of previous treatment with high-dose calcitriol.
Treatment was continued for 12 weeks, and the dose of 1-alpha-hydroxyvitamin D2 was adjusted in an effort to maintain the plasma iPTH between 130 and 250 pg/mL. The treatment with 1-alpha-hydroxyvitamin D2 was stopped when serum iPTH decreased below 130 to 150 pg/mL. When that occurred, the serum iPTH was monitored weekly until it rose above 300 pg/mL, and then treatment was resumed at a reduced dose. In six of the 14 patients initially treated with 4 mcg three times per week, the dose was increased to 4 mcg/day, the maximum dose given, after six to eight weeks with less than a 25% reduction in plasma iPTH. The pretreatment plasma iPTH declined from 672 ± 70 pg/mL to 289 ± 36 pg/mL at the end of treatment (p < 0.01).
There were 13 episodes of hypercalcemia, defined as serum calcium above 10.5 mg/dL, in 10 patients during treatment with 1-alpha-hydroxyvitamin D2. For all patients, there were 4.7 episodes of hypercalcemia per 100 weeks of treatment, compared with 0.53 episodes per 100 weeks during the washout period (p < 0.02).5 These results suggest 1-alpha-hydroxyvitamin D2 may be a reasonable alternative to calcitriol in chronic renal dialysis patients with secondary hyperparathyroidism.
Treatment protocols
A second study was conducted to evaluate the efficacy and safety of a single, high-pulse oral dose of 10 mcg, administered orally three times weekly with hemodialysis.6 Ten patients who had participated in the previous study were re-treated with oral 1-alpha-hydroxyvitamin D2, using an initial dose of 10 mcg per hemodialysis treatment. Nine of the patients were male, and one was a female. Their ages ranged from 27 to 72 (median = 52) and the patients' prior duration of dialysis ranged from four to 116 months (median = 54 months). Inclusion and exclusion criteria were identical to those in the previous study.
Two treatment protocols were developed for this study, and all 10 patients completed both protocols. Patients in the first protocol received 1-alpha-hydroxyvitamin D2 orally, initially either 4 mcg each morning or 4 mcg three times a week with hemodialysis. The initial dose depended on iPTH concentration during washout and/or a history of previous treatment with high-dose 1-alpha-hydroxyvitamin D2. The dose was adjusted to achieve an iPTH concentration within the range of 130 to 250 pg/mL.
In the second protocol, all patients initially received 10 mcg of oral 1-alpha-hydroxyvitamin D2 three times a week with hemodialysis. The therapy was stopped if the iPTH concentration fell below 100 pg/mL. The iPTH was monitored weekly until it rose above 100 pg/mL, after which the patient's participation in the study
was terminated.
In both protocols, treatment was temporarily discontinued for patients who developed marked hypercalcemia, defined as a serum calcium above 11.2 mg/dL (protocol 1) or 11.4 mg/dL (protocol 2), or marked hyperphosphatemia defined as a serum phosphorus level above 8 mg/dL. Serum calcium and phosphorus were monitored before every dialysis procedure until the calcium was < 10.2 mg/dL or serum phosphorus was < 6.9 mg/dL. Treatment was then resumed at a reduced dose.6
The study demonstrated that oral 1-alpha-hydroxyvitamin D2 in a dose of 10 mcg three times a week is as efficacious and safe as 4 mcg given daily for lowering iPTH in chronic renal patients with secondary hyperparathyroidism. The iPTH concentration decreased from a baseline value of 484 ± 40 pg/mL to a nadir of 160 ± 22 pg/mL with the 4 mcg of 1-alpha-hydroxyvitamin D2 given three times per week, and from 554 ± 77 pg/mL to a nadir of 108 ± 35 pg/mL with the 10 mcg dose given three times per week (p < 0.02, p < 0.02, respectively).
The incidence of hypercalcemia and hyperphosphatemia did not differ between the two dosage regimens, which provide a similar total dose of 28 to 30 mcg per week. Additional studies evaluating larger numbers of patients are needed to compare the efficacy and safety of 1-alpha-hydroxyvitamin D2 to calcitriol.6
These data support that doxercalciferol is effective in lowering the iPTH concentrations in patients undergoing hemodialysis with moderate-to-severe secondary hyperparathyroidism; however, there is a risk for patients to develop hypercalcemia and hyperphosphatemia during therapy.
Adverse reactions:
Common adverse effects occurring in more than 2% of patients and more frequently than with placebo include edema, headache, malaise, nausea/vomiting, dizziness, dyspnea, pruritus, bradycardia, anorexia, dyspepsia, weight increase, arthralgia, constipation, abscess, and sleep disorder.1-3
Potential adverse effects of doxercalciferol generally are similar to those of excessive vitamin D intake, with early manifestations of such toxicity (in association with hypercalcemia) including weakness, headache, somnolence, nausea, dry mouth, constipation, muscle or bone pain, and metallic taste.
Late manifestations of excessive vitamin D intake include polyuria, polydipsia, anorexia, weight loss, nocturia, calcific conjunctivitis, pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated serum AST and ALT, ectopic calcifications, hypertension, cardiac arrhythmias, and rarely overt psychosis.1,3
Pregnancy/lactation:
Doxercalciferol is considered pregnancy category B, meaning that animal-reproduction studies have not demonstrated a fetal risk but there are no adequate and well-controlled studies in pregnant women. Reproduction studies in rats and rabbits, at doses of doxercalciferol up to 20 mcg/kg/day and 0.1 mcg/kg/day (approximately 25 times less than the maximum recommended human oral dose of 60 mcg/week based on the mcg/m2 body surface area, respectively) have revealed no teratogenic effects. Because animal reproduction studies are not always predictive of human response, doxercalciferol should be used during pregnancy only if clearly needed.1,3
It is not known whether doxercalciferol is excreted in human milk. Because other vitamin D derivatives are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from doxercalciferol, a decision should be made whether to discontinue nursing or to discontinue the drug.1,3
Contraindications:
Doxercalciferol should not be given to patients with a tendency toward hypercalcemia or hyperphosphatemia or those with evidence of vitamin D toxicity. It also should be avoided in patients with known hypersensitivity to doxercalciferol or any ingredients in the formulation.1-3
Warnings:
Overdose of any form of vitamin D, including doxercalciferol, is dangerous. Hypercalcemia may occur due to overdosage of vitamin D and its metabolites and may be so severe that it requires emergency attention. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures, as well as having synergistic inotropic and toxic effects in the presence of cardiac glycosides.
Chronic hypercalcemia increases the risk of soft-tissue calcification, including in the vasculature. The serum calcium phosphorus product (Ca X P) should not exceed 70. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of calcification.1,3,4 Vitamin D and its analogs should not be used during doxercalciferol therapy because of possible additive effects.1,3
Oral calcium-based or other nonaluminum containing phosphate binders and a low phosphate diet should be used to control serum phosphate concentrations in patients undergoing dialysis. Uncontrolled serum phosphate exacerbates secondary hyperparathyroidism and can lessen the effectiveness of doxercalciferol in reducing blood parathyroid concentrations. After initiating doxercalciferol therapy, the dose of phosphate binders should be decreased to correct persistent mild hypercalcemia (10.6 to 11.2 mg/dL for three consecutive determinations) or increased to correct persistent mild hyperphosphatemia (7 to 8 mg/dL for three consecutive determinations).1,3
Magnesium-containing antacids and doxercalciferol should not be used concomitantly in patients on chronic renal dialysis because such use may lead to the development of hypermagnesemia.1,3
Because patients with hepatic insufficiency may not metabolize doxercalciferol appropriately, the drug should be used with caution in patients with impaired hepatic function. More frequent monitoring of iPTH, calcium, and phosphorus concentrations should be done in these patients.1,3
Safety and efficacy of doxercalciferol in pediatric patients have not been established.1-3
Dosage and administration:
The recommended initial dose of doxercalciferol is 10 mcg administered orally, three times weekly at dialysis, or approximately every other day. The initial dose should be adjusted, as needed, in order to lower blood iPTH concentrations in the range of 150 to 300 pg/mL. The dose may be increased at eight-week intervals by 2.5 mcg if iPTH is not lowered by 50% and fails to reach the target range. The maximum recommended dose of doxercalciferol is 20 mcg administered orally, three times a week at dialysis for a total of 60 mcg per week.
Drug administration should be suspended if iPTH falls below 100 pg/mL and restarted one week later at a dose that is at least 2.5 mcg lower than the last administered dose. In the early phase of doxercalciferol treatment, iPTH, serum calcium, and serum phosphorus concentrations should be obtained prior to initiation of treatment and weekly thereafter.
If hypercalcemia, hyperphosphatemia, or a serum calcium phosphorus product greater than 70 is noted, the drug should be suspended immediately until those parameters are appropriately lowered. The drug should be restarted at a dose at least 2.5 mcg lower than the previous dose.1,3
The optimal dose of doxercalciferol must be carefully determined for each patient. Dosing must be individualized and based on iPTH levels with monitoring of serum calcium and serum phosphorus concentrations.
Drug interactions:
Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; therefore, it may impair intestinal absorption of doxercalciferol.1-3 Magnesium-containing antacids and doxercalciferol should not be used concomitantly because such use may lead to the development of hypermagnesemia.
The use of mineral oil or other substances that may affect absorption of fat may influence the absorption and availability of doxercalciferol. Although not examined specifically, metabolic enzyme inducers or inhibitors (e.g., phenobarbital, phenytoin) may need dosage adjustment when used concomitantly with doxercalciferol.1,3
Drug-food interactions:
To date, there are no drug-food interactions reported for doxercalciferol.
Dosage forms available:
Doxercalciferol (Hectorol) is available as a 2.5 mcg soft gelatin, sunshine yellow, oval capsule imprinted with BCI in bottles of 50.1 The FDA approved an injectable form of doxercalciferol in April 2000, but the product is not yet commercially available. The injection will be supplied in 1 mL and 2 mL amber glass ampules containing 2 mcg and 4 mcg of drug, respectively.7
Samples status:
Samples should not be available because doxercalciferol is only intended for use in patients undergoing chronic renal dialysis.
Potential for medication errors:
There may be a potential for confusion with ergocalciferol (Calciferol, Drisdol), cholecalciferol (Delta-D, Vitamin D3), and doxercalciferol (Hectorol). These are three different vitamin D analogs with different indications.
Discussion:
Hyperparathyroidism is a common problem among patients on chronic renal dialysis. The reductions in blood calcitriol concentration that occur with advanced renal insufficiency decrease calcium absorption by the intestine, thereby lowering the plasma calcium concentration, which indirectly stimulates secretion of parathyroid hormone.4-6 Calcitriol has been playing an important role in the treatment of patients requiring dialysis who have secondary hyperparathyroidism for more than 15 years.
Conventional therapy with daily oral calcitriol has been limited by the occurrence of hypercalcemia and hyperphosphatemia. This has prompted the use of intravenous pulse dose calcitriol given with each dialysis treatment, approximately three times per week. However, the pulse dose regimen has not decreased the occurrence hypercalcemia or hyperphosphatemia compared with regular dosing.6
More study needed
There has been a search for other vitamin D analogs that can suppress parathyroid hormone secretion without causing hypercalcemia and hyperphosphatemia. To date, two clinical trials demonstrate that doxercalciferol, when given at the dosage regimens studied, is efficacious and safe in the treatment of patients on chronic renal dialysis with moderate to severe secondary hyperparathyroidism.5,6 Although the efficacy and safety profiles of doxercalciferol look promising in these short-term trials, additional long-term comparative trials with calcitriol will be necessary to conclude that this agent is superior to calcitriol.
References
- Hectorol (Doxercalciferol) package insert. Madison, WI: Bone Care International, Inc.; 1999.
- Gelman CR, Rumack BH, Hutchison TA, eds. Drugdex System. Englewood, CO: Micromedex Inc.; August 2000.
- Mosby's GenRx. 2000. MD Consult. Cited 7 July 2000. Available from http://home.mdconsult.com/das/drug/
body/0/1/3471.html.
- Dipiro JT, ed. Pharmacotherapy: A Pathophysiologic Approach. 4th ed. Stamford, CT: McGraw-Hill Professional Publishing; 1998.
- Tan AU, Levine BS, Mazess RB, et al. Effective suppression of parathyroid hormone by 1-alpha-hydroxyvitamin D2 in hemodialysis patients with moderate to severe secondary hyperparathyroidism. Kidney International 1997; 51:317-323.
- Frazao JM, Levine BS, Tan AU, et al. Efficacy and safety of intermittent oral 1-alpha-hydroxyvitamin D2 in suppressing secondary hyperparathyroidism in hemodialysis patients. Dialysis and Transplantation 1997; 26:583-595.
- Hectorol (Doxercalciferol) Injection package insert (draft). Madison, WI: Bone Care International Inc.; 2000.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.