Vitamin D Analogs General Statement (Monograph)

Drug class: Vitamin D
ATC class: A11CC04
VA class: VT509

Uses for Vitamin D Analogs General Statement

Vitamin D analogs are used to prevent or treat rickets or osteomalacia and to manage hypocalcemia associated with hypoparathyroidism or pseudohypoparathyroidism. Since calcitriol is more expensive than ergocalciferol, use of the former drug is generally reserved for patients with inadequate metabolism of ergocalciferol. The initial treatment of severe hypocalcemia is immediate IV administration of a calcium salt such as calcium gluconate. Vitamin D analogs are then used to maintain normocalcemia. Because of its shorter onset of action, calcitriol may be preferable to ergocalciferol in the acute treatment of hypocalcemia.

Oral calcitriol also is used in the management of secondary hyperparathyroidism and resultant metabolic bone disease in patients with moderate to severe chronic kidney disease (CKD) who do not yet require maintenance dialysis therapy (predialysis patients) and in the management of hypocalcemia and resultant metabolic bone disease in patients with CKD undergoing dialysis. IV calcitriol is used in the management of hypocalcemia in patients with chronic renal failure undergoing dialysis. IV or oral doxercalciferol is used for the treatment of secondary hyperparathyroidism in patients with CKD undergoing dialysis. Oral doxercalciferol also is used for the treatment of secondary hyperparathyroidism in patients with stage 3 or 4 CKD who do not yet require maintenance dialysis (predialysis patients). IV paricalcitol is used in the prevention and treatment of secondary hyperparathyroidism in patients with stage 5 CKD, while oral paricalcitol is used in the prevention and treatment of secondary hyperparathyroidism in patients with stage 3 or 4 CKD as well as in those with stage 5 CKD requiring hemodialysis or peritoneal dialysis. Calcifediol is used in the treatment of secondary hyperparathyroidism in patients with stage 3 or 4 CKD and vitamin D insufficiency.

Because of the risk of toxicity, therapy with vitamin D analogs should be closely monitored, and indiscriminate use of these drugs should be avoided.

Dietary Requirements

Since 1941, the Institute of Medicine's (IOM) Food and Nutrition Board of the National Academy of Sciences (NAS) has developed guidelines for adequate dietary intake of essential nutrients. Nutrient recommendations are issued through Dietary Reference Intakes (DRIs), which are a set of reference values that can be used for planning and assessing diets for healthy populations and for many other purposes. DRIs for vitamin D include the Estimated Average Requirement (EAR), Recommended Dietary Allowance (RDA), Adequate Intake (AI), and Tolerable Upper Intake Level (UL). DRIs apply to the healthy general population and consider nutrient levels needed to prevent deficiency as well as those associated with disease risk reduction. The current methods for establishing DRIs differ from those used in the past and incorporate increased understanding of both population and individual nutrient needs. The EAR is the nutrient intake value that is estimated to meet the nutrient needs of 50% of individuals in a particular life-stage and gender group. The RDA, which is derived from the EAR, currently is defined as the estimated daily dietary intake level that is sufficient to meet the nutrient requirements of 97.5% of the population's requirements. The RDA for a given nutrient, in a prescriptive sense, is the goal for dietary intake in individuals. If data are insufficient to establish an RDA for a given life-stage group, the AI may be used instead. AIs are based on observed or experimentally determined approximations of the average nutrient intake, by a defined population or subgroup, that appears to sustain a defined nutritional state (e.g., usual circulating nutrient levels, nutrient levels for normal growth).

The previous NAS report from 1997 was unable to establish EARs and RDAs for vitamin D because of inadequate data and difficulties in quantitating the amount of vitamin D required to maintain good bone health for all ages. Since then, emerging data on bone health outcomes and greater understanding of the contributions made by sun exposure and diet to vitamin D intake have allowed for estimation of EARs and RDAs for all life stage groups except for infants.

Since vitamin D intake has been found to correlate with changes in serum 25-hydroxyvitamin D concentrations, current vitamin D dietary reference intake values recommended by NAS are derived from serum 25-hydroxyvitamin D concentrations, which serve as a biomarker for intake. Recommended intakes are estimated to target specific 25-hydroxyvitamin D concentrations presumed to achieve favorable bone health outcomes for most individuals. Although there is wide variability in reported ranges of serum 25-hydroxyvitamin D concentrations, NAS states that the overall data indicate that a serum 25-hydroxyvitamin D concentration of 50 nmol/L is sufficient to meet the needs of the majority of the population and concentrations below 30 nmol/L are associated with clinical deficiency. These reference values for vitamin D were established under conditions of minimal sun exposure to reduce confounding. In addition, public health concerns about sun exposure and skin cancer preclude recommendations for an appropriate level of sun exposure to meet vitamin D requirements.

The principal goal of maintaining an adequate intake of vitamin D in the US and Canada is to support calcium metabolism and bone health, and thus prevent rickets and osteomalacia. Adequate intake of vitamin D can be accomplished through consumption of vitamin D-fortified foodstuffs, use of dietary supplements, or both. Children 1–18 years of age and most adults generally obtain some of their vitamin D requirement from sunlight exposure. Although individuals of all ages, races, and both genders can obtain all of their body’s requirement for vitamin D through exposure to an adequate amount of UVB light, the extent of sun-mediated vitamin D synthesis is affected profoundly by a variety of factors, including degree of skin pigmentation, geographic latitude, time of day, season of the year, weather conditions, and amount of body surface area protected with clothing or sunscreen. The currently available evidence indicates that vitamin D alone has very little effect on bone health outcomes and is most effective when used in conjunction with calcium.

The American Academy of Pediatrics (AAP) also has issued recommendations on intake of vitamin D for infants, children, and adolescents.

For additional information on vitamin D deficiency, see Pharmacology: Physiologic Effects of Vitamin D Deficiency and also see the subsections in Uses on Nutritional Rickets or Osteomalacia and on Mineral and Bone Disorder Secondary to Chronic Renal Disease. For specific information on currently recommended dietary reference intakes for vitamin D, see Dosage: Dietary and Replacement Requirements, in Dosage and Administration.

Nutritional Rickets or Osteomalacia

Nutritional rickets or osteomalacia is treated with ergocalciferol or cholecalciferol. Calcitriol has been used to prevent tetany in vitamin D-deficient premature infants with hypocalcemia^{† [off-label]} and, in one study, resulted in normocalcemia in more patients than did ergocalciferol. IV calcitriol has also been used in the treatment of hypocalcemic tetany in premature infants^{† [off-label]}.

Familial Hypophosphatemia

Very large doses of ergocalciferol are required to treat bone disorders in patients with familial hypophosphatemia (vitamin D-resistant rickets). These patients should also receive oral phosphate supplements (usually 1–2 g of elemental phosphorus daily) to maintain serum phosphorus concentrations of at least 3 mg/dL. Because the large doses of ergocalciferol needed in this disorder often cause toxicity and persistent hypercalcemia, dihydrotachysterol (no longer commercially available in the US) or calcitriol and phosphate supplements are preferred by some clinicians. Ergocalciferol has also been used, along with treatment of acidosis, to manage the hypophosphatemia associated with Fanconi syndrome.

Vitamin D-dependent Rickets

Large doses of ergocalciferol are required to treat vitamin D-dependent rickets; however, the metabolic defect in this disease is the failure of 1-hydroxylation of 25-hydroxyergocalciferol and 25-hydroxycholecalciferol, and patients with this disorder usually respond to calcitriol.

Mineral and Bone Disorder Secondary to Chronic Renal Disease

Vitamin D deficiency or insufficiency in patients with stage 3a (estimated glomerular filtration rate [eGFR] 45–59 mL/minute per 1.73 m²) to stage 5 (eGFR less than 15 mL/minute per 1.73 m²) CKD may be corrected using treatment strategies recommended for the general population. As renal function declines, there is progressive disruption of mineral homeostasis with resultant bone abnormalities. Vitamin D analogs (e.g., calcitriol, calcifediol, doxercalciferol, paricalcitol) are used in the management of secondary hyperparathyroidism in patients with CKD (see introductory paragraph in Uses).

The mineral and bone disorder associated with chronic kidney disease (CKD-MBD) is associated with substantial morbidity and mortality and includes biochemical abnormalities (disruption of vitamin D metabolism, disordered calcium and phosphorus homeostasis, and elevated circulating parathyroid hormone [PTH] concentrations) as well as vascular and other soft-tissue calcification and abnormalities in bone turnover, mineralization, volume, linear growth, and strength. Secondary hyperparathyroidism results from a complex interplay of several factors, including vitamin D deficiency, hypocalcemia, hyperphosphatemia, and elevated concentrations of fibroblast growth factor 23 (FGF-23; a hormone from bone that stimulates phosphaturia and decreases 1α-hydroxylase activity in the kidney). Although vitamin D supplementation with ergocalciferol or cholecalciferol can suppress PTH, especially in stage 3 CKD, long-term studies of these agents are lacking. Vitamin D analogs (e.g., calcitriol, calcifediol, doxercalciferol, paricalcitol) are effective in lowering elevated PTH concentrations, but can increase the risk of hypercalcemia; there are limited data to date regarding effects of vitamin D analogs on clinical outcomes such as fractures rates, progression to end-stage renal disease, cardiovascular morbidity, and mortality in patients with CKD. Because of epidemiologic evidence suggesting an association between higher calcium concentrations and increased cardiovascular morbidity and mortality, hypercalcemia should be avoided.

Two randomized placebo-controlled studies of paricalcitol in patients with CKD and moderately increased intact PTH (iPTH) concentrations (PRIMO and OPERA studies) failed to demonstrate improvements in measures of left ventricular structure or function following 48–52 weeks of treatment. In the PRIMO study in 227 patients with CKD (baseline eGFR range: 24–43 mL/minute per 1.73 m²), mild to moderate left ventricular hypertrophy, preserved left ventricular ejection fraction, and baseline iPTH concentration of 50–300 pg/mL (mean baseline concentration of 100–106 pg/mL, approximately 1.5 times the upper limit of normal [ULN]), 48 weeks of treatment with paricalcitol (2 mcg daily, with reduction to 1 mcg daily if serum calcium concentration exceeded 11 mg/dL) reduced and maintained iPTH concentrations within the normal range but did not alter left ventricular mass index or improve echocardiographic measures of diastolic function relative to placebo. In the OPERA study in 60 patients with stage 3 to stage 5 CKD not requiring dialysis, left ventricular hypertrophy, and baseline iPTH concentration of 55 pg/mL or greater (median baseline concentration of 129–156 pg/mL, approximately twice the ULN), 52 weeks of treatment with paricalcitol (1 mcg daily) reduced iPTH concentrations but did not alter left ventricular mass index or echocardiographic measures of systolic or diastolic function relative to placebo. In both studies, hypercalcemia was more common in patients receiving paricalcitol.

Decisions regarding the treatment of CKD-MBD should be based on trends observed in serial assessments of serum phosphate, calcium, and iPTH concentrations, all evaluated together. In patients with stage 3a to stage 5 CKD not requiring dialysis, the optimal PTH concentration is unknown, although a modest elevation in PTH concentration may be an appropriate adaptive response to declining renal function. Experts suggest that patients with iPTH concentrations that are progressively rising or persistently elevated above the assay's ULN be evaluated for modifiable factors, including hyperphosphatemia, hypocalcemia, high phosphate intake, and vitamin D deficiency. Based on findings of randomized clinical trials (PRIMO and OPERA), the Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD guideline suggests that vitamin D analogs not be used routinely in adults with stage 3a to stage 5 CKD not requiring dialysis and that it is reasonable to reserve such use for patients with stage 4 or 5 CKD with severe and progressive hyperparathyroidism. Because of higher calcium requirements for skeletal growth, vitamin D analogs may be considered in children and adolescents to maintain serum calcium concentrations within an age-appropriate normal range. In patients with stage 5 CKD requiring dialysis, the KDIGO CKD-MBD guideline suggests maintaining iPTH concentrations in the range of approximately 2–9 times the assay's ULN. Marked changes in PTH concentrations within this range should prompt initiation or adjustment of therapy to avoid progression to concentrations outside the suggested range. Although some clinicians suggest that this range is too broad, substantial variability exists in PTH assays and there is general agreement that oversuppression of PTH should be avoided because of the potential for adynamic bone disease. Either calcimimetic agents or vitamin D analogs, or both, may be considered when PTH-lowering therapy is required in patients with stage 5 CKD requiring dialysis. Further research is needed to better define the optimal time for initiation of PTH-lowering therapy and the optimal PTH target range at each stage of CKD.

Anticonvulsant-induced Rickets and Osteomalacia

Some patients with seizure disorders receiving long-term high-dose anticonvulsant therapy (with phenobarbital and/or phenytoin) may have decreased plasma concentrations of 25-hydroxylated ergocalciferol and cholecalciferol and calcium; rarely, rickets or osteomalacia secondary to anticonvulsant therapy may occur and can be treated with ergocalciferol. (See Drug Interactions: Other Drugs.) Some clinicians recommend that patients receiving long-term anticonvulsant therapy (particularly those receiving 2 or more anticonvulsants and who have inadequate nutrition and exposure to UV light such as institutional patients) receive ergocalciferol supplements prophylactically. Providing adequate vitamin D supplementation in patients receiving anticonvulsants generally should prevent associated osteomalacia.

Hypoparathyroidism and Pseudohypoparathyroidism

Large doses of ergocalciferol are used to increase serum calcium concentrations in patients with postoperative or idiopathic hypoparathyroidism and pseudohypoparathyroidism. Because of the risk of overdosage and persistent hypercalcemia with ergocalciferol, dihydrotachysterol (no longer commercially available in the US) or calcitriol may be more useful in these patients. Oral calcium (up to 1 g of elemental calcium daily in some cases) and IM or IV parathyroid hormone may also be needed in these patients. In contrast to parathyroid hormone, vitamin D analogs are active when administered orally, exert a slower but more persistent hypercalcemic effect, and, according to one manufacturer, may be administered for long periods without requiring an increase in dosage. However, tolerance to vitamin D analogs has been reported to develop. Although dihydrotachysterol has been administered with 6 g of oral calcium lactate daily for prophylaxis of hypocalcemic tetany following thyroid surgery, most clinicians believe that dihydrotachysterol should not be used prophylactically in this condition.

Osteoporosis

Vitamin D analogs (e.g., ergocalciferol, cholecalciferol) are used in conjunction with calcium for the prevention and treatment of osteoporosis^{† [off-label]} in patients whose dietary intake of vitamin D is insufficient.

Adequate intake of calcium and vitamin D (which increases absorption of calcium) is universally recommended for all individuals to diminish age-related bone loss and prevent osteoporosis. Controlled clinical studies have demonstrated that the combination of calcium and vitamin D can reduce fracture risk. In addition to lifestyle modifications (e.g., regular weight-bearing exercise, avoidance of excessive alcohol and tobacco use), the National Osteoporosis Foundation recommends a daily intake of 800–1000 units of vitamin D for adults 50 years of age or older; however, there is some difference of opinion and other experts recommend higher amounts of vitamin D. Since there is great variability in the amount of vitamin D intake needed to correct vitamin D deficiency, serum concentrations of 25-hydroxyvitamin D should be measured in individuals at risk of deficiency. If supplementation is necessary, a sufficient amount should be given to achieve and maintain serum 25-hydroxyvitamin D concentrations within the range of approximately 30–60 ng/mL.

For information on maintaining adequate intakes of vitamin D to prevent osteoporosis, see Pharmacology: Physiologic Effects of Vitamin D Deficiency and also see Uses: Dietary Requirements.

Glucocorticoid-induced Osteoporosis

The American College of Rheumatology (ACR) recommends optimizing dietary intake of calcium (1–1.2 g daily) and vitamin D (600–800 units daily) for the prevention of glucocorticoid-induced osteoporosis^{† [off-label]} in all patients receiving long-term glucocorticoid therapy (defined as a daily dosage equivalent to 2.5 mg of prednisone or greater for at least 3 months). Although results of randomized controlled studies have demonstrated efficacy of calcium and vitamin D supplementation in glucocorticoid-treated patients, there are concerns about potential harms (e.g., adverse cardiovascular effects); therefore, ACR states that additional study is needed to determine the potential benefits versus risks of calcium and vitamin D supplementation in patients receiving glucocorticoids.

Other Uses

Although vitamin D analogs have not been proven to have any therapeutic value, the drugs have been used for the management of lupus vulgaris^{† [off-label]}, rheumatoid arthritis^†, and psoriasis^†.

Vitamin D Analogs General Statement Dosage and Administration

Administration

Vitamin D analogs are usually administered orally; however, calcitriol, doxercalciferol, and paricalcitol may be given by IV injection. Ergocalciferol may be given by IM injection; however, a suitable formulation of the drug for IM injection no longer is commercially available in the US.

Dosage

Dietary intake of ergocalciferol and cholecalciferol varies among individual patients, and dietary intake should always be considered when calculating the appropriate dosage of vitamin D analogs. During therapy with vitamin D analogs, dosage depends on the nature and severity of the patient’s hypocalcemia and must be individualized to maintain serum calcium concentrations of 9–10 mg/dL. In the management of hypoparathyroidism, pseudohypoparathyroidism, and familial hypophosphatemia, the range between therapeutic and toxic effects is narrow; however, hypercalcemia may occur at any time when therapeutic doses of vitamin D analogs are used, and careful monitoring is imperative. In the management of secondary hyperparathyroidism, dosage of vitamin D analogs should be individualized according to serum or plasma intact parathyroid hormone (iPTH) concentrations and serum calcium and phosphorus concentrations.

During therapy with vitamin D analogs, patients should receive adequate amounts of calcium through management of diet or administration of calcium supplements; however, overdosage of calcium may lead to hypercalcemia. Dosage of vitamin D analogs should be decreased when symptoms improve and before biochemical normality or complete bone healing has occurred because requirements for vitamin D analogs often decrease after bone healing occurs. In patients who become bedridden (especially children), dosage reduction may occasionally be needed to avoid hypercalcemia.

Dietary and Replacement Requirements

Children

The American Academy of Pediatrics (AAP) recommends a minimum daily intake of 400 units of vitamin D in all infants, children, and adolescents.

Because of insufficient data to establish estimated average requirements (EARs) in infants younger than 1 year of age, the National Academy of Sciences (NAS) uses adequate intake (AI) for vitamin D requirements in this age group. (See Uses: Dietary Requirements.) NAS recommends an AI of 400 units (10 mcg) daily of vitamin D in infants younger than 1 year of age. Ensuring normal healthy bone accretion is essential in establishing dietary reference values for older children and adolescents 1–18 years of age. Based on this consideration, NAS recommends an EAR of 400 units (10 mcg) daily of vitamin D in children and adolescents 1–18 years of age, and an RDA of 600 units (15 mcg) daily to cover the needs of nearly all children in this age group assuming minimal sun exposure.

For breast-fed or partially breast-fed infants, AAP recommends a supplemental dosage of 400 units of vitamin D daily starting in the first few days of life; vitamin D supplementation is continued throughout childhood until the child is weaned and consumes at least 1 L or quart of vitamin D-fortified formula or milk daily.

Infants and older children who consume less than 1 L of vitamin D-fortified formula or milk daily should receive a supplemental dosage of 400 units of vitamin D daily. Other dietary sources of vitamin D may be included in the dietary intake of the child.

Adolescents who do not consume 400 units of vitamin D daily from vitamin D-fortified milk or foods should receive a supplemental dosage of 400 units of vitamin D daily.

Children at increased risk for vitamin D deficiency (e.g., those with fat malabsorption, those receiving anticonvulsant therapy) may need higher dosages of supplemental vitamin D to achieve normal vitamin D status.

Adults

Bone maintenance is the primary concern in adults 19–50 years of age. Although data on bone health outcomes related to vitamin D generally are more limited in adults 19–50 years of age, NAS recommends an average intake of 400 units (10 mcg) daily of vitamin D and an intake of 600 units (15 mcg) daily to cover the needs of nearly all adults in this age group assuming minimal sun exposure.

Maintenance of bone mass and reduction of bone loss are essential factors in developing dietary reference intakes for vitamin D in adults 51–70 years of age. The majority of women in this life stage group will experience some degree of bone loss due to menopause, but findings generally have not supported an effect of vitamin D alone (without calcium) on bone outcomes. Because the available data do not suggest that average intake requirements increase with aging, the same dietary reference values are recommended for older adults 51–70 years of age as for younger adults (19–50 years of age). These values include an EAR of 400 units (10 mcg) daily and an RDA of 600 units (15 mcg) daily assuming minimal sun exposure.

Because risk of skeletal fractures is increased with aging, particularly for adults older than 70 years of age, reduction in fracture risk is the most important indicator in setting a reference standard for this age group. However, there are a number of unknown factors associated with the physiology of normal aging that can affect intake estimates for this population. There is compelling evidence indicating that calcium alone in this age group can modestly reduce the risk of fracture, but vitamin D alone generally does not have a substantial effect on fracture risk reduction. Therefore, based on available evidence, NAS recommends an average vitamin D intake of 400 units (10 mcg) daily in adults older than 70 years of age and an intake of 800 units (20 mcg) daily to cover the needs of nearly all adults in this age group assuming minimal sun exposure. However, these recommendations are made in light of the uncertainties that have been identified in this older age group.

Pregnant and Lactating Women

Maternal 25-hydroxyvitamin D concentrations do not appear to affect fetal calcium homeostasis or skeletal outcomes. Therefore, NAS states that intake requirements of vitamin D in pregnant women are the same as for women who are not pregnant.

During lactation, small and probably unimportant amounts of maternal circulating vitamin D and its metabolites are distributed into breast milk. Evidence from randomized controlled studies and observational data indicate that increased maternal intake of vitamin D has no effect on neonatal serum 25-hydroxyvitamin D concentrations of breastfed infants unless maternal intake is excessive. Therefore, NAS states that it is reasonable to use the same EAR values for lactating and nonlactating women.

Cautions for Vitamin D Analogs General Statement

Adverse Effects

Doses of vitamin D analogs that do not exceed the physiologic requirement are usually nontoxic. However, some infants and patients with sarcoidosis or hypoparathyroidism may have increased sensitivity to vitamin D analogs. Acute or chronic administration of excessive doses of vitamin D analogs or enhanced responsiveness to physiologic amounts of ergocalciferol or cholecalciferol may lead to hypervitaminosis D manifested by hypercalcemia. (See Chronic Toxicity.)

In patients with hyperparathyroidism secondary to chronic kidney disease (CKD), excessive use of vitamin D analogs can result in oversuppression of parathyroid hormone (PTH), hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease. Chronic hypercalcemia increases the risk of soft-tissue calcification, including vascular calcification. Hypercalcemia may be exacerbated by concomitant use of high doses of calcium-containing preparations, thiazide diuretics, or other vitamin D analogs. In addition, high intake of calcium and phosphate concomitantly with vitamin D analogs may result in hypercalciuria and hyperphosphatemia. Regular monitoring (i.e., determination of serum or plasma intact PTH, serum calcium, and serum phosphorus concentrations) and appropriate dosage adjustment of the vitamin D analog and concomitant therapy (e.g., phosphate binders) are required to manage these potential adverse effects.

In one patient with renal failure, serum AST (SGOT) concentrations increased slightly during calcitriol therapy. One normocalcemic patient receiving calcitriol developed headache, nausea, vomiting, and diarrhea which did not occur following administration of ergocalciferol. In patients with CKD who were not undergoing dialysis, decreased renal function without hypercalcemia reportedly occurred in patients receiving calcitriol; however, some clinicians question these findings. Decreased renal function without hypercalcemia has also been reported in patients with hypoparathyroidism after long-term vitamin D analog therapy. In patients with normal renal function, chronic hypercalcemia may be associated with increases in serum creatinine concentration, which generally are reversible; careful attention should be given to factors that may contribute to hypercalcemia (e.g., calcium intake), and adequate hydration should be maintained. Before therapy with vitamin D analogs is initiated, serum phosphate concentrations must be controlled. Because administration of vitamin D analogs may increase phosphate absorption, patients with renal failure may require adjustment in the dosage of phosphate binders used to decrease phosphate absorption.

Precautions and Contraindications

Vitamin D analogs should be administered with caution in patients receiving cardiac glycosides, because hypercalcemia in these patients may result in cardiac arrhythmias. Vitamin D analogs should also be used with caution in patients with increased sensitivity to these drugs. Vitamin D analogs should not be administered concurrently, and these drugs should not be administered to patients with hypercalcemia, vitamin D toxicity, or hypersensitivity to the drug or any ingredient in the formulations.

Pediatric Precautions

Safety and efficacy of IV paricalcitol have been established in children 5 years of age or older. Safety and efficacy of paricalcitol capsules have been established in children 10 years of age or older.

Safety and efficacy of calcifediol and doxercalciferol have not been established in pediatric patients.

Safety and efficacy of calcitriol in pediatric patients undergoing dialysis have not been established. Safety and efficacy of calcitriol have been established in predialysis pediatric patients based on evidence from adequate and well-controlled studies in adults with predialysis chronic renal failure and from other data from nonplacebo-controlled studies in pediatric patients. Calcitriol dosing guidelines have not been established for infants younger than 1 month of age with hypoparathyroidism nor for pediatric patients younger than 6 years of age with pseudoparathyroidism. Oral calcitriol dosages of 10–55 ng/kg daily have been shown to improve calcium homeostasis and bone disease in pediatric patients with chronic renal failure in whom hemodialysis was not yet required (predialysis). Long-term calcitriol therapy is well-tolerated in pediatric patients, with the most common safety issues being mild, transient episodes of hypercalcemia, hyperphosphatemia, and increased serum calcium times serum phosphorus product (Ca × P), which can be managed effectively by dosage adjustment or temporary discontinuance of vitamin D therapy.

Pregnancy and Lactation

Pregnancy

A characteristic physiognomy, possibly with aortic valvular stenosis, retinopathy, and mental and/or physical retardation, has occurred following prolonged hypercalcemia in infants and in neonates of mothers with hypercalcemia during pregnancy. Hypercalcemia during pregnancy may also lead to suppression of PTH concentrations in the neonate resulting in hypocalcemia, tetany, and seizures. Safe use of calcifediol, calcitriol, dihydrotachysterol (no longer commercially available in the US), paricalcitol, or ergocalciferol during pregnancy has not been established; however, the risks to the mother and fetus from untreated hypoparathyroidism or hypophosphatemia may be greater than those resulting from administration of vitamin D analogs.

Lactation

Safe use of calcifediol, calcitriol, dihydrotachysterol, doxercalciferol, paricalcitol, or ergocalciferol during lactation has not been established; however, the risks to the mother and fetus from untreated hypoparathyroidism or hypophosphatemia may be greater than those resulting from administration of vitamin D analogs. Large doses of vitamin D analogs should not be administered to nursing women.

Drug Interactions

Drugs Affecting GI Absorption of Vitamin D Analogs

Cholestyramine or colestipol hydrochloride administration may result in decreased intestinal absorption of vitamin D analogs; patients taking cholestyramine or colestipol hydrochloride should be instructed to allow as long a time interval as possible between the ingestion of vitamin D analogs and the resin.

Orlistat may result in decreased GI absorption of fat-soluble vitamins such as vitamin D analogs. At least 2 hours should elapse between (before or after) any orlistat dose and vitamin D analog administration; administering fat-soluble vitamins at bedtime may be a convenient time. Although the manufacturer of orlistat recommends that a vitamin supplement containing fat-soluble vitamins (A, D, E, and K) be used during orlistat therapy, such vitamin concentrations in clinical studies with the drug remained within the normal range for most patients despite decreases, and vitamin supplementation was only occasionally needed.

Mineral oil may interfere with intestinal absorption of vitamin D analogs. Patients taking mineral oil should be instructed to allow as long a time interval as possible between the ingestion of vitamin D analogs and mineral oil.

Drugs that Inhibit Cytochrome P-450 Enzymes

Because paricalcitol is partially metabolized by cytochrome P-450 isoenzyme 3A (CYP3A), administration of paricalcitol with a potent CYP3A inhibitor (e.g., atazanavir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, the fixed combination of lopinavir and ritonavir [lopinavir/ritonavir], nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) may result in increased plasma concentrations of paricalcitol. Administration of ketoconazole (200 mg twice daily for 5 days) with oral paricalcitol (4 mcg) has been shown to increase systemic exposure (as measured by area under the concentration-time curve [AUC]) to paricalcitol by approximately twofold.

Drugs that inhibit CYP enzymes (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may inhibit CYP27B1, which metabolizes calcifediol to its activated form (1,25-dihydroxycholecalciferol [calcitriol]), and CYP24A1, which metabolizes both calcifediol and 1,25-dihydroxycholecalciferol to inactive metabolites, thereby altering serum calcifediol concentrations. Although specific drug interaction studies between calcitriol and ketoconazole are lacking, ketoconazole may inhibit both synthetic and catabolic enzymes of the drug; reduced concentrations of the endogenous vitamin (1,25-dihydroxycholecalciferol) have been observed in healthy individuals receiving ketoconazole. CYP inhibitors also may inhibit 25-hydroxylation of doxercalciferol, resulting in decreased formation of the activated moiety.

The manufacturers of calcifediol and paricalcitol recommend close monitoring (e.g., serum concentrations of intact parathyroid hormone [iPTH], calcium, and 25-hydroxyvitamin D) when concomitant therapy with a potent CYP3A4 inhibitor is initiated or discontinued, since dosage adjustment of the vitamin D analog may be required.

Drugs that Induce Hepatic Microsomal Enzymes

Administration of anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin) and other drugs that induce hepatic microsomal hydroxylation may decrease plasma concentrations of 25-hydroxylated ergocalciferol and 25-hydroxylated cholecalciferol (calcifediol) and increase metabolism of the vitamins to inactive metabolites. (See Uses: Anticonvulsant-Induced Rickets and Osteomalacia.) Dosage adjustment of vitamin D analogs may be required. The manufacturer states that serum concentrations of total 25-hydroxyvitamin D, iPTH, and calcium should be monitored in patients receiving calcifediol when concomitant therapy with anticonvulsants or other drugs that stimulate microsomal hydroxylation is initiated or discontinued.

Thiazide Diuretics

Concurrent administration of thiazide diuretics and pharmacologic doses of vitamin D analogs in patients with hypoparathyroidism may result in hypercalcemia which may be transient and self-limited or may require discontinuance of vitamin D analogs. Thiazide-induced hypercalcemia in hypoparathyroid patients is probably caused by increased release of calcium from bone.

Thiazide diuretics also can induce hypercalcemia by decreasing renal calcium excretion. More frequent monitoring of serum calcium concentrations may be required in patients with secondary hyperparathyroidism and chronic kidney disease receiving such concomitant therapy.

Other Drugs

Corticosteroids counteract the effects of vitamin D analogs.

Concurrent use of vitamin D analogs and cardiac glycosides may result in cardiac arrhythmias. (See Cautions: Precautions and Contraindications.)

Chronic Toxicity

Pathogenesis

The difference between therapeutic dosage and that causing hypercalcemia is very small, and dosage must be carefully titrated. The dosage of a vitamin D analog required to produce hypervitaminosis varies considerably among individual patients; chronic ingestion of 1.25–2.5 mg of ergocalciferol daily in adults or 25 mcg daily in infants or children may result in hypervitaminosis D. Because of the shorter duration of action of calcitriol and dihydrotachysterol (no longer commercially available in the US), the potential hazards of hypercalcemia and/or tissue accumulation of these drugs during therapy are less than may occur during administration of ergocalciferol.

Manifestations

Patients should be informed of the dangers and symptoms of vitamin D intoxication. Early symptoms of hypercalcemia may include weakness, fatigue, somnolence, headache, anorexia, dry mouth, metallic taste, nausea, vomiting, abdominal cramps, constipation, diarrhea, vertigo, tinnitus, ataxia, exanthema, hypotonia (in infants), muscle pain, bone pain, and irritability. Later and sometimes more serious consequences of hypercalcemia may include rhinorrhea, pruritus, decreased libido, nephrocalcinosis, impairment of renal function (resulting in polyuria, nocturia, polydipsia, hyposthenuria, and proteinuria), osteoporosis in adults, decreased growth in children, weight loss, anemia, calcific conjunctivitis, photophobia, metastatic calcification, pancreatitis, generalized vascular calcification, and seizures. Rarely, patients may develop hypertension or overt psychosis. Urinary calcium, phosphate, and albumin; BUN; and serum cholesterol, AST (SGOT), and ALT (SGPT) concentrations may increase. Serum alkaline phosphatase concentrations may decrease. Serum electrolyte imbalances along with mild acidosis may result in cardiac arrhythmias.

Treatment

Since hypercalcemia may be more dangerous than hypocalcemia, overtreatment of hypocalcemia should be avoided. Frequent determinations of serum calcium concentrations should be performed, and serum calcium concentrations should be maintained at 9–10 mg/dL (4.5–5 mEq/L). Serum calcium concentrations usually should not be allowed to exceed 11 mg/dL. Although determinations of urine calcium concentrations have been advised, qualitative tests are generally unreliable as a guide to therapy (particularly the Sulkowitch test) and quantitative tests should be used. Hypercalciuria can occur in the presence of hypocalcemia. Some clinicians recommend administration of large amounts of fluids to produce increased urine volume and thus prevent the formation of renal stones in patients with hypercalciuria. Serum calcium, phosphate, magnesium, BUN, and alkaline phosphatase, and 24-hour urinary calcium and phosphate concentrations should be determined periodically during therapy with vitamin D analogs. A decrease in serum alkaline phosphatase concentrations usually precedes hypercalcemia in patients with osteomalacia or renal osteodystrophy.

Treatment of vitamin D analog intoxication consists of withdrawal of both the drug and calcium supplements, maintenance of a low-calcium diet, administration of oral or IV fluids and, if needed, corticosteroids or other drugs, particularly calciuric diuretics (e.g., furosemide and ethacrynic acid) to decrease serum calcium concentrations. Hemodialysis or peritoneal dialysis against a calcium-free dialysate may also be used. If ingestion is recent, gastric lavage or emesis may prevent further absorption. If the drug has passed through the stomach, administration of mineral oil may promote fecal elimination. Because the 25-hydroxylated metabolites of ergocalciferol and cholecalciferol are stored in the body, hypercalcemia can last for 2 or more months following chronic administration of excessive doses of these drugs. Hypercalcemia following long-term administration of dihydrotachysterol or calcifediol persists for about 2 weeks or 2–4 weeks, respectively, after withdrawal of the drug; serum calcium concentration returns to normal within 2–7 days after discontinuing long-term calcitriol therapy. Signs and symptoms of hypercalcemia are usually reversible; however, metastatic calcification may result in severe renal or cardiac failure and death. After normocalcemia is achieved, therapy with vitamin D analogs may be reinstituted, if needed, at a lower dosage. Some patients with hypoparathyroidism who became hypercalcemic during treatment with ergocalciferol were more responsive to the drug after correction of hypercalcemia. Resistance to the hypercalcemic effects of vitamin D analogs may occur in patients with hypomagnesemia.

Pharmacology

Ergocalciferol and doxercalciferol (1-hydroxyergocalciferol); cholecalciferol and calcifediol (25-hydroxycholecalciferol); and dihydrotachysterol (no longer commercially available in the US) in their activated forms (1,25-dihydroxyergocalciferol; 1,25-dihydroxycholecalciferol [calcitriol]; and 25-hydroxydihydrotachysterol; respectively), along with parathyroid hormone (PTH) and calcitonin, regulate serum calcium concentrations; in addition to conversion to the active 1,25-dihydroxycholecalciferol, calcifediol also has intrinsic activity.

The principal biologic function of vitamin D is to maintain serum calcium and phosphorus concentrations within the normal range by enhancing the efficiency of the small intestine to absorb these minerals from the diet. Calcitriol (activated vitamin D) enhances the efficiency of intestinal calcium absorption along the entire small intestine, but principally in the duodenum and jejunum. Calcitriol also enhances phosphorus absorption along the entire small intestine, but principally in the jejunum and ileum. The activated forms of ergocalciferol, doxercalciferol, and cholecalciferol may have a negative feedback effect on PTH production. Vitamin D analogs have been shown to reduce serum or plasma PTH concentrations.

Endogenous Vitamin D Synthesis

Humans can synthesize cholecalciferol; however, if exposure to UV light is inadequate or if metabolism of cholecalciferol is abnormal, an exogenous source of ergocalciferol, cholecalciferol, dihydrotachysterol, calcifediol, or calcitriol is required. The principal source of vitamin D in populations throughout the world is exposure of the skin to sunlight.

During sun exposure, UVB light with energies between 290–315 nm is absorbed by cutaneous 7-dehydrocholesterol to form the split (seco) sterol previtamin D₃ and subsequently cholecalciferol (vitamin D₃). Latitude, time of day, and season of the year affect cutaneous synthesis of vitamin D substantially. Above or below latitudes 40° N or S, respectively, cutaneous cholecalciferol synthesis is absent during most of the 3–4 months of winter, with such synthesis being absent for up to 6 months each year for the far northern and southern latitudes. However, vitamin D that is synthesized during the summer and fall months can be stored in fat for use during the winter. Relatively high skin melanin pigmentation, topical use of sunscreens that absorb UVB light, and increased use of clothing that protects the skin from sun exposure also can substantially reduce cutaneous vitamin D synthesis as can skin changes associated with aging. By contrast, excessive exposure to sunlight causes photodegradation of previtamin D₃ and cholecalciferol, thus limiting the possibility of vitamin D intoxication from such exposure.

Exogenous Sources of Vitamin D

Very few foods naturally contain vitamin D. Sources that contain the vitamin include fatty fish, the liver and fat of aquatic mammals (e.g., seals, polar bears), and eggs from chickens fed vitamin D-fortified feed. Therefore, dietary sources of vitamin D from unfortified foods other than fish generally are minimal. As a result, the US, Canada, and many other countries instituted policies to fortify certain foods with vitamin D in an effort to ensure adequate dietary intake of the vitamin and thus prevent rickets, particularly to compensate for potentially low exposures of skin to sunlight (the usual principal source of the vitamin) in certain individuals.

In the US and Canada, milk was chosen as the principal dietary source to be fortified with vitamin D (i.e., ergocalciferol or cholecalciferol), containing 10 mcg (400 units) per 32 ounces (quart) or 9.6 mcg per L regardless of the fat content of the milk; such fortification is necessary since milk, like most other dietary sources, does not have naturally high concentrations of the vitamin. Despite such policies, however, about 70% of US and Canadian fortified milk did not contain amounts of vitamin D within the prescribed range (8–12 mcg/quart) in several sampling surveys during the 1980s and 1990s, and 62% contained less than 8 mcg/quart and 14% of skim milk contained no detectable vitamin D.

Commercially available infant formulas also must be fortified with vitamin D at a concentration of 10 mcg/L, but these products also have been found to contain widely variable amounts of vitamin D. Other common fortified food sources of vitamin D include certain commercially available orange juices and cereals. In some countries, breads and margarine also may be fortified with vitamin D.

Physiologic Effects of Vitamin D Deficiency

Vitamin D deficiency results in inadequate mineralization of bone or compensatory skeletal demineralization. In children, vitamin D deficiency leads to rickets as a result of inadequate mineralization of bone and is characterized by widening of the end of long bones, rachitic rosary, skeletal deformations (e.g., frontal bossing), and outward and inward deformities of the lower limbs resulting in bowed legs and knocked knees, respectively. In adults, vitamin D deficiency leads to a mineralization defect resulting in osteomalacia.

Vitamin D deficiency causes decreased ionized calcium concentrations in blood and a resultant increase in the production and secretion of PTH. PTH stimulates the mobilization of skeletal calcium, inhibits renal excretion of calcium, and stimulates renal excretion of phosphorus resulting in normal fasting serum calcium concentrations and low or near-normal serum phosphorus. The enhanced mobilization of skeletal calcium induced by this secondary hyperparathyroidism results in porotic bone.

Any alteration in cutaneous production of cholecalciferol, GI vitamin D absorption, or metabolism of the vitamin to its active form (i.e., calcitriol) can result in deficiency. Alterations in receptor recognition of calcitriol also can result in vitamin D deficiency, metabolic bone disease, and accompanying biochemical abnormalities. If permanent deformities have not already occurred, administration of ergocalciferol or cholecalciferol completely reverses the signs of nutritional rickets or osteomalacia in patients who can adequately absorb and activate these forms of vitamin D. Calcitriol and dihydrotachysterol reverse the signs of rickets or osteomalacia in patients who cannot activate and utilize ergocalciferol or cholecalciferol.

In patients with chronic renal failure, decreased metabolic activation of vitamin D in the kidneys results in secondary hyperparathyroidism and metabolic bone disease. Administration of calcitriol or dihydrotachysterol increases GI absorption of calcium, decreases elevated blood concentrations of PTH and serum alkaline phosphatase, and corrects renal osteodystrophy, muscle weakness, and bone pain in such patients; calcifediol increases GI absorption and serum concentration of calcium, may decrease serum alkaline phosphatase and blood PTH concentrations, and may decrease subperiosteal bone resorption and histologic signs of hyperparathyroid bone disease and mineralization defects in these patients. Calcifediol and calcitriol may improve osteitis fibrosa cystica more than osteomalacia in adults with renal osteodystrophy. Because doxercalciferol, unlike ergocalciferol, does not require renal hydroxylation for activation, this analog can reduce serum or plasma PTH concentrations in patients with chronic renal failure; which contributes to metabolic bone disease in these patients. In addition, paricalcitol reduces serum or plasma PTH concentrations in patients with chronic renal failure. Paricalcitol appears to be as effective as calcitriol in suppressing PTH secretion.

The exact physiologic function of vitamin D in brain, heart, pancreas, mononuclear cells, activated lymphocytes, and skin remains unknown, and although the vitamin exhibits potent antiproliferative and prodifferentiation effects, there currently is little evidence that vitamin D deficiency results in major disorders in these organs and cellular systems. The possibility that vitamin D deficiency may be associated with an increased risk of colon, breast, and prostate cancer has been suggested by epidemiologic evidence from individuals living in higher latitudes, but current evidence is too limited to indicate categorically a cancer risk associated with deficiency.

Physiologic Activity of Vitamin D Analogs

In humans, activated ergocalciferol and activated cholecalciferol (calcitriol) have equal biologic activity and function to increase serum calcium and phosphate concentrations, principally by increasing intestinal absorption of calcium and phosphate. 25-Hydroxycholecalciferol (calcifediol) and 25-hydroxyergocalciferol are considered intermediary metabolites of cholecalciferol and ergocalciferol, respectively. Although these intermediate metabolites exhibit 2–5 times more activity than unactivated vitamin D (i.e., cholecalciferol or ergocalciferol) in curing rickets and inducing calcium absorption and mobilization (from bone) in animals, this increased activity still is insufficient to affect these functions at physiologic concentrations. In very high concentrations, these metabolites may increase serum calcium concentrations.

Activated ergocalciferol and cholecalciferol stimulate resorption of bone and are required for normal mineralization of bone. Dihydrotachysterol has only weak antirachitic activity compared with ergocalciferol or cholecalciferol. Dihydrotachysterol, in its activated form, increases intestinal absorption of calcium to a lesser extent than does ergocalciferol; however, in large doses, dihydrotachysterol may be more effective than ergocalciferol or cholecalciferol in mobilizing calcium from bone. Physiologic doses of ergocalciferol or cholecalciferol also promote calcium reabsorption by the kidneys; however, the importance of this effect is not known. In pharmacologic doses, ergocalciferol and calcitriol may cause hypercalciuria and hyperphosphaturia. Dihydrotachysterol probably causes phosphaturia indirectly by increasing serum calcium concentrations. Although 24,25-dihydroxycholecalciferol was previously considered a metabolically inactive metabolite of cholecalciferol or calcifediol, there is some evidence that it affects bone mineralization in uremic patients and animals; however, the precise effects of 24,25-dihydroxycholecalciferol remain to be established. The principal effect of calcifediol, doxercalciferol, and paricalcitol established to date has been in suppressing elevated serum or plasma PTH concentrations in patients with hyperparathyroidism secondary to chronic kidney disease (CKD).

Vitamin D Analogs General Statement Pharmacokinetics

Absorption

Many vitamin D analogs are readily absorbed from the GI tract following oral administration if fat absorption is normal. The presence of bile is required for absorption of ergocalciferol and the extent of GI absorption may be decreased in patients with hepatic, biliary, or GI disease (e.g., Crohn’s disease, Whipple’s disease, sprue). Because vitamin D is fat soluble, it is incorporated into chylomicrons and absorbed via the lymphatic system; approximately 80% of ingested vitamin D appears to be absorbed systemically through this mechanism, principally in the small intestine. Although some evidence suggested that intestinal absorption of vitamin D may be decreased in geriatric adults, other evidence did not show clinically important age-related alterations in GI absorption of the vitamin in therapeutic doses. It currently is not known whether aging alters the GI absorption of physiologic amounts of vitamin D. Calcifediol and calcitriol are absorbed from the intestine.

Normal combined (i.e., 25-hydroxyvitamin D) plasma concentrations of 25-hydroxycholecalciferol (calcifediol) and 25-hydroxyergocalciferol, which are the major circulating metabolites of cholecalciferol and ergocalciferol, have been reported to range from 8–80 ng/mL, depending on the assay used, and vary with exposure to UV light. A commonly reported range for the lower limit of normal is 8–15 ng/mL, depending on geographic location (e.g., Southern California would be higher than Massachusetts). Concentrations less than 11 ng/mL are considered consistent with vitamin D deficiency in neonates, infants, and young children. Although the concentration essential for maintaining normal calcium metabolism and peak bone mass in older children and middle-aged adults remains to be elucidated, geriatric individuals appear to have increased requirements for vitamin D intake in order to maintain normal calcium metabolism and maximize bone health. Circulating concentrations of the 25-hydroxy metabolites generally increase with increasing intake of ergocalciferol or cholecalciferol. Serum concentrations of nonhydroxylated vitamin D are not indicative of vitamin D status. Serum concentrations of dihydroxylated vitamin D (i.e., calcitriol) also are not a good indicator of vitamin D status since circulating concentrations are regulated tightly by a variety of factors including serum calcium, phosphorus, parathyroid hormone (PTH), and other hormone concentrations.

After oral or IM administration of ergocalciferol, the onset of hypercalcemic action is 10–24 hours; maximal hypercalcemic effects occur about 4 weeks after daily administration of a fixed dose, and the duration of action of the drug can be 2 months or more. After oral administration of calcitriol, there is about a 2-hour lag-time before calcium absorption in the GI tract increases. Maximal hypercalcemic effect occurs in about 10 hours, and the duration of action of calcitriol is 3–5 days. After oral administration of dihydrotachysterol (no longer commercially available in the US), an increase in serum calcium occurs in several hours and is maximal about 2 weeks after daily administration of a fixed dose and about 1 week after administration of a loading dosage followed by a daily maintenance dosage. The duration of action of dihydrotachysterol is about 2 weeks.

Following oral (absorbed from the GI tract) and IV administration, doxercalciferol is activated in the liver to form 1,25-dihydroxyergocalciferol (1,25-dihydroxyvitamin D₂), the major metabolite, via the hepatic cytochrome P-450 (CYP) isoenzyme 27. Activation of doxercalciferol does not require the involvement of the kidneys. In healthy individuals, peak blood concentrations of 1,25-dihydroxyergocalciferol are attained within 11–12 hours after repeated oral doses of 5–15 mcg of doxercalciferol. Following IV administration of a single 5-mcg dose of doxercalciferol, peak blood concentrations of 1,25-dihydroxyergocalciferol are achieved in about 8 hours.

Absolute bioavailability of orally administered paricalcitol is 72–86%. Food delays the time to peak plasma concentrations (by about 2 hours) but does not affect bioavailability of orally administered paricalcitol. Studies in healthy individuals indicate that area under the plasma concentration-time curve (AUC) increases proportionally over a dose range of 0.06–0.48 mcg/kg. Following direct IV administration of paricalcitol 0.24 mcg/kg in patients with stage 5 chronic kidney disease (CKD) undergoing hemodialysis or peritoneal dialysis, mean peak plasma paricalcitol concentrations were about 1680 or 1832 pg/mL, respectively. Hemodialysis does not appear to affect plasma concentrations of paricalcitol.

Following oral administration of calcitriol, peak serum concentrations of the drug are attained within 3–6 hours. In patients with nephrotic syndrome and those undergoing hemodialysis, peak concentrations are attained in 4 or 8–12 hours, respectively; peak and trough serum concentrations in these patient populations appear to be lower than those observed in healthy individuals.

Following repeated oral administration of calcifediol extended-release capsules, increased serum concentrations of total 25-hydroxyvitamin D are associated with corresponding increases in 1,25-dihydroxyvitamin D concentrations. In patients with stage 3 or 4 CKD, steady-state concentrations of 25-hydroxyvitamin D are attained after approximately 3 months. Administration of a supratherapeutic dose of calcifediol with a high-fat, high-calorie meal increased peak plasma concentrations and systemic exposure to the drug by approximately fivefold and 3.5-fold, respectively, compared with administration in the fasted state.

Distribution

After absorption, ergocalciferol and cholecalciferol enter the blood via chylomicrons of lymph and then associate mainly with a specific α-globulin (vitamin D-binding protein). The hydroxylated metabolites of ergocalciferol and cholecalciferol also circulate associated with the same α-globulin. 25-Hydroxylated ergocalciferol and cholecalciferol are stored in fat and muscles for prolonged periods. Once vitamin D enters systemic circulation from lymph via the thoracic duct or from skin, it accumulates in the liver within a few hours. Calcitriol is distributed into human milk in low concentrations. 25-Hydroxyergocalciferol may be distributed into milk after large doses of ergocalciferol; it is not known if calcifediol, doxercalciferol, or paricalcitol is distributed into human milk. Paricalcitol is distributed into milk in rats.

Elimination

In the liver, ergocalciferol and cholecalciferol are converted in the mitochondria to their 25-hydroxy derivatives by the enzyme vitamin D 25-hydroxylase. Vitamin D 25-hydroxylase activity is regulated in the liver by concentrations of vitamin D and its metabolites; therefore, increases in the systemic circulation of the 25-hydroxy metabolites following exposure to sunlight or ingestion of vitamin D are relatively modest compared with cumulative production or intake of the vitamin. Serum concentrations of nonhydroxylated vitamin D are short-lived as a result of storage in fat or metabolism in the liver. In the kidneys, these metabolites are further hydroxylated at the 1 position by the enzyme vitamin D 1α-hydroxylase (also known as cytochrome P-450 [CYP] isoenzyme 27B1 ) to their active forms, 1,25-dihydroxycholecalciferol (calcitriol) and 1,25-dihydroxyergocalciferol. The circulating half-life of the 25-hydroxy metabolites is about 10 days to 3 weeks and that of the 1,25-hydroxy metabolites is about 4–6 hours. Activity of the vitamin D 1-hydroxylase enzyme requires molecular oxygen, magnesium ion, and malate and is regulated principally by PTH in response to serum concentrations of calcium and phosphate, and perhaps by circulating concentrations of 1,25-dihydroxyergocalciferol and 1,25-dihydroxycholecalciferol. Other hormones (i.e., cortisol, estrogens, prolactin, and growth hormone) also may influence the metabolism of cholecalciferol and ergocalciferol.

When circulating concentrations of the 1,25-dihydroxy metabolites of ergocalciferol and cholecalciferol are adequate, 25-hydroxyergocalciferol and 25-hydroxycholecalciferol are hydroxylated in the kidneys and other target tissues at the 24 position by CYP24A1; these 24,25-dihydroxy metabolites apparently have minimal biologic activity. 1,25-Dihydroxycholecalciferol (calcitriol) and 1,25-dihydroxyergocalciferol appear to be metabolized to their respective trihydroxy metabolites (i.e., 1,24,25-trihydroxycholecalciferol, 1,24,25-trihydroxyergocalciferol) and to other compounds. The principal metabolite excreted in urine is calcitroic acid, which is more water soluble. Although all the metabolites of cholecalciferol and ergocalciferol have not been identified, hepatic microsomal enzymes may be involved in degrading metabolites of ergocalciferol and cholecalciferol.

Activated macrophages, certain lymphoma cells, and skin and bone cells also have been shown to produce 1,25-dihydroxylated vitamin D, but the physiologic importance of such locally produced activated vitamin D is not well understood. Excessive unregulated production of 1,25-dihydroxylated vitamin D by activated macrophages and lymphoma cells is responsible for the hypercalciuria associated with chronic granulomatous disorders and the hypercalcemia associated with lymphoma.

Dihydrotachysterol is activated in the liver by hydroxylation to 25-hydroxydihydrotachysterol; further renal activation is not necessary. In the body, doxercalciferol is hydroxylated to the active moiety, 1,25-dihydroxyergocalciferol (1,25-dihydroxyvitamin D₂), via hepatic CYP27. Because doxercalciferol, unlike ergocalciferol, does not require renal hydroxylation for activation, this analog can reduce serum or plasma PTH concentrations in patients with chronic renal failure. Following oral administration of doxercalciferol, the mean elimination half-life of 1,25-dihydroxyergocalciferol is approximately 32–37 hours (range: up to 96 hours); the elimination half-life in patients with end-stage renal disease (ESRD) receiving dialysis appears to be similar. Hemodialysis causes a temporary increase in mean 1,25-dihydroxyergocalciferol concentrations in patients receiving doxercalciferol, presumably secondary to volume contraction; 1,25-dihydroxyergocalciferol is not removed from blood during hemodialysis. Doxercalciferol also undergoes metabolism in the liver to 1,24-dihydroxyergocalciferol (1,24-dihydroxyvitamin D₂), which is a minor metabolite.

Calcifediol is activated mainly in the kidney by CYP27B1 to form 1,25-dihydroxycholecalciferol (calcitriol); calcifediol also is metabolized by CYP24A1 in vitamin D-responsive tissues to form inactive metabolites. The mean elimination half-life of the drug is approximately 11 days after administration of a single dose in healthy individuals and approximately 25 days following repeated daily administration in patients with stage 3 or 4 CKD. The major route of elimination of calcifediol is excretion into the feces via the bile.

The elimination half-life of calcitriol is approximately 5–8 hours in healthy individuals, 16 hours in patients with nephrotic syndrome, and 22 hours in patients undergoing hemodialysis.

Following IV or oral administration of paricalcitol, the drug undergoes extensive metabolism. In vitro data suggest that paricalcitol is metabolized by multiple hepatic and nonhepatic enzymes, including CYP24, CYP3A4, and uridine diphosphate-glucuronosyltransferase (UGT) 1A4. The elimination half-life of paricalcitol in healthy individuals is approximately 4–7 hours. Following oral administration of paricalcitol in patients with CKD, including those undergoing hemodialysis or peritoneal dialysis, the mean half-life reportedly is 14–20 hours. Following IV administration of paricalcitol doses ranging from 0.04–0.24 mcg/kg, concentrations of the drug decline rapidly during the first 2 hours, followed by log-linear elimination; the mean half-life in patients undergoing hemodialysis or peritoneal dialysis is about 14–15 hours. The major route of elimination of paricalcitol appears to be excretion into the feces via the bile. Paricalcitol is not removed by hemodialysis.

The metabolites of vitamin D analogs are excreted principally in bile and feces. Although some vitamin D that is excreted in bile is reabsorbed in the small intestine, enterohepatic circulation does not appear to be an important mechanism for conservation of the vitamin. Following oral or IV administration of a single dose of radiolabeled calcitriol, 19–41% of radioactivity is recovered in urine within 6–10 days. Following oral or IV administration of a radiolabeled dose of paricalcitol, approximately 18–19% of radioactivity is recovered in urine.

For information on the metabolism and activation of vitamin D precursors in the skin secondary to UVB light exposure, see Pharmacology: Endogenous Vitamin D Synthesis and also see Physiologic Activity of Vitamin D Analogs. Aging decreases substantially the capacity of skin to produce cholecalciferol, with geriatric adults older than 65 years of age having a fourfold decrease in this capacity relative to adults 20–30 years of age.

Chemistry

Vitamin D analogs are split (seco) sterols with antirachitic and hypercalcemic activity; these fat-soluble vitamins occur in nature and/or are prepared synthetically. Because they are activated in the body and have regulatory effects, vitamin D analogs are sometimes considered hormones. Commercially available vitamin D analogs include calcifediol, calcitriol, cholecalciferol (vitamin D₃), doxercalciferol, paricalcitol, and ergocalciferol (vitamin D₂). Cholecalciferol is commercially available only in combination products.

Ergocalciferol is formed by ultraviolet (UV) irradiation of ergosterol, a provitamin D sterol that occurs in fungi and yeast. Cholecalciferol is formed from 7-dehydrocholesterol in the skin after exposure to UV light. Cholecalciferol is also present in fish liver oils and in the livers of animals that eat fish. Cod liver oil contains about 2 mcg of cholecalciferol and 780 units of vitamin A per mL. Butter and eggs contain cholecalciferol or ergocalciferol; milk is a poor source of these vitamins unless it is fortified by addition of ergocalciferol or by irradiation with UV light. In the body, cholecalciferol is hydroxylated to calcifediol (25-hydroxyvitamin D, 25-hydroxycholecalciferol) and then to calcitriol (1,25-dihydroxyvitamin D, 1,25-hydroxycholicalciferol). Dihydrotachysterol (no longer commercially available in the US), a synthetic analog of ergocalciferol, differs structurally from ergocalciferol by the presence of a methyl group instead of a methylene group at C 10 and stereochemically in that the A ring is rotated 180°. Doxercalciferol (1-α-hydroxyvitamin D₂, 1-hydroxyvitamin D₂), a synthetic analog, is the 1-hydroxylated form of ergocalciferol; in the body, doxercalciferol is hydroxylated to the active moiety, 1,25-dihydroxyergocalciferol (1,25-dihydroxyvitamin D₂), via the hepatic cytochrome P-450 (CYP) isoenzyme 27. Paricalcitol (19-nor-1α-25-dihydroxyvitamin D₂), a synthetic analog of calcitriol, differs structurally from calcitriol by the absence of an exocyclic carbon at position 19 and by the presence of a vitamin D₂ side chain instead of a vitamin D₃ side chain.

Activity of ergocalciferol and cholecalciferol is sometimes expressed in terms of USP or International Units (IU, units) which are equivalent. One unit of vitamin D equals the biologic activity of 25 ng of ergocalciferol or cholecalciferol.

Related Monographs

For further information on the chemistry, stability, and dosage and administration of vitamin D analogs, see the individual monographs in 88:16.

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