Calcitriol

Introduction Overview

Generic Name

calcitriol

Brand Name

Rocaltrol, Calcijex

Dosage Form

oral capsule (0.25 mcg; 0.5 mcg), oral liquid (1 mcg/mL), injectable solution

Drug Class

Vitamin D analog, Vitamin

Pharmacokinetics

Absorption:
Calcitriol, the active form of vitamin D3, is well absorbed when administered orally. Absorption primarily occurs in the small intestine. Its lipophilic nature facilitates passive diffusion through the intestinal mucosa. Food intake can influence the extent of absorption, with fat-containing meals potentially enhancing bioavailability due to its fat-soluble characteristics. Unlike precursor vitamin D forms, calcitriol does not require metabolic activation in the liver or kidneys, allowing for rapid onset of effect.

Distribution:
Once absorbed, calcitriol exhibits extensive plasma protein binding, predominantly to vitamin D-binding protein (DBP), which serves as the main transport protein in circulation. This binding regulates the free, pharmacologically active fraction available to tissues. The volume of distribution reflects its distribution into tissues involved in calcium and phosphate homeostasis, such as bone, intestine, and kidney. Calcitriol crosses cellular membranes by passive diffusion and engages with intracellular vitamin D receptors (VDR) to exert its effects.

Metabolism:
Calcitriol undergoes hepatic and renal metabolism primarily through CYP24A1-mediated hydroxylation, converting it to calcitroic acid and other less active metabolites that are excreted. Metabolic clearance can be influenced by factors such as renal function, with impaired kidney function leading to altered metabolism and elimination. Enzyme inducers such as phenobarbital may increase the metabolic clearance of calcitriol, reducing its plasma concentration.

Elimination:
The metabolites of calcitriol are eliminated mainly via the bile into feces, with a smaller proportion excreted renally. The elimination half-life of calcitriol is approximately 5 to 8 hours, though this may vary based on underlying disease states such as renal impairment. Because calcitriol is the hormonally active form of vitamin D, its elimination is tightly regulated to maintain calcium homeostasis and prevent toxicity.

Clinically, the pharmacokinetic profile allows for once or twice-daily dosing in most therapeutic regimens. Close monitoring is required during treatment, especially in patients with renal impairment, to avoid hypercalcemia due to accumulation.

Dosage Forms

Available Dosage Forms:
- Oral capsules: 0.25 micrograms and 0.5 micrograms
- Oral liquid solution: 1 microgram/mL
- Injectable solution (for IV infusion) available, typically used in hospital settings

Dosages for Adults and Adolescents:
Calcitriol dosing varies based on the indication and patient condition. For hypocalcemia associated with hypoparathyroidism or chronic renal failure, initial daily doses typically range from 0.25 mcg to 0.5 mcg orally, adjusted based on serum calcium levels. Some patients may require divided doses or adjustments to a maximum of around 2 mcg daily. Injectable calcitriol may be dosed similarly but administered as intravenous infusion under medical supervision.

Specific Patient Populations:
- Renal Impairment: Since calcitriol is often administered to patients with chronic kidney disease, careful dose titration and monitoring of calcium and phosphate levels are essential to avoid hypercalcemia and hyperphosphatemia.
- Pediatric Use: Calcitriol is used cautiously in children with conditions such as hypoparathyroidism or renal osteodystrophy; doses are individualized based on growth and serum calcium. Growth monitoring is essential due to potential impacts.
- Elderly: Dose adjustments may be necessary due to altered metabolism and increased sensitivity to vitamin D toxicity.
- Pregnant and Breastfeeding Women: Safety in pregnancy has not been fully established; it should be used only if clearly needed, and breastfeeding is generally not recommended during treatment.

Mechanism Of Action

Calcitriol is the hormonally active metabolite of vitamin D3 that plays a pivotal role in calcium and phosphate homeostasis. It exerts its biological effects through binding to the intracellular vitamin D receptor (VDR), a nuclear hormone receptor expressed in target tissues including the intestines, kidneys, bone, and parathyroid glands.

Upon binding calcitriol, the VDR forms a heterodimer with the retinoid X receptor (RXR), which then binds to vitamin D response elements (VDREs) in the DNA. This binding modulates the transcription of various genes involved in calcium transport, promoting increased synthesis of calcium-binding proteins such as calbindin in intestinal epithelial cells. This enhances active calcium absorption from the gastrointestinal tract, crucial in maintaining serum calcium levels.

Calcitriol also modulates bone remodeling by influencing osteoblast and osteoclast differentiation and activity, facilitating bone resorption and mineralization processes as necessary to maintain extracellular calcium levels. Additionally, it suppresses parathyroid hormone synthesis via negative feedback at the parathyroid glands, helping to regulate calcium metabolism.

Clinically, calcitriol’s mechanism allows it to rapidly correct hypocalcemia, especially in patients with impaired renal function unable to produce endogenous active vitamin D. Its direct action bypasses the need for renal 1α-hydroxylase activity, a critical advantage in chronic kidney disease. Comparative to other vitamin D analogs, calcitriol has the highest potency and immediate effect, but also carries a higher risk for hypercalcemia, necessitating careful monitoring during therapy.

Pharmacological Actions

Enhances intestinal absorption of calcium and phosphate via upregulation of calcium-binding proteins.
Regulates bone mineralization by stimulating osteoclastic bone resorption and osteoblastic activity.
Suppresses parathyroid hormone synthesis through feedback inhibition mechanisms.
Facilitates renal tubular reabsorption of calcium, reducing urinary calcium excretion.
Modulates immune function by influencing T cell proliferation and cytokine production.
Promotes differentiation of various cell types through genomic effects mediated by the vitamin D receptor.
Maintains serum calcium and phosphate balance critical for neuromuscular and skeletal health.
Bypasses renal activation step, useful in patients with renal insufficiency or failure.
Influences expression of genes involved in cellular growth, differentiation, and apoptosis.

Therapeutic Or Clinical Uses

Treatment of hypocalcemia in patients with hypoparathyroidism due to surgical or congenital causes.
Management of secondary hyperparathyroidism associated with chronic kidney disease (non-dialysis and dialysis patients).
Treatment of metabolic bone diseases such as renal osteodystrophy.
Correction of vitamin D deficiency states where activation to calcitriol is impaired, notably in renal failure.
Adjunctive therapy in hypophosphatemic rickets and osteomalacia.
Prevention of bone disorders in patients undergoing long-term corticosteroid therapy.
Used off-label for certain disorders related to calcium metabolism abnormalities.
Facilitation of calcium homeostasis in patients on dialysis.
Treatment of elevated parathyroid hormone levels in renal osteodystrophy.

Side Or Adverse Effects

Hypercalcemia, presenting as nausea, vomiting, constipation, increased thirst and urination, confusion, or muscle weakness.
Symptoms of dehydration including dry mouth, excessive thirst, and decreased urine output.
Hypocalcemia symptoms such as muscle spasms, tetany, numbness, or tingling around the mouth and in extremities if dose is insufficient.
Allergic reactions including rash, hives, swelling of the face, lips, tongue, or throat with potential for breathing difficulty.
Gastrointestinal disturbances such as abdominal pain and constipation.
Fatigue, weakness, and headache possibly related to electrolyte imbalances.
Potential adverse effects on growth in pediatric patients requiring monitoring.
Elevated serum calcium can lead to kidney stones or nephrocalcinosis with long-term therapy.
Electrolyte imbalances including hyperphosphatemia in renal failure patients.
Possible cardiovascular effects related to electrolyte disturbances.
Risk of toxicity is increased if concurrent intake of other vitamin D or calcium supplements is not regulated.

Precautions

Monitor serum calcium, phosphate, and creatinine levels regularly to prevent hypercalcemia and renal complications.
Avoid use in patients with existing hypercalcemia or vitamin D toxicity.
Use cautiously in patients with impaired renal function; dose adjustments and frequent monitoring necessary.
Ensure adequate hydration to reduce risk of nephrolithiasis and renal impairment.
Patients should avoid concurrent use of other vitamin D or calcium supplements unless prescribed.
Inform clinicians about all medical conditions, particularly kidney disease, sarcoidosis, or other granulomatous diseases.
Pregnancy use only if clearly needed; animal studies insufficient to confirm safety.
Breastfeeding is generally not recommended during treatment due to potential risks.
Children on therapy require growth monitoring and clinical assessment to detect adverse effects.
In case of vomiting or diarrhea, contact healthcare provider promptly to avoid dehydration and altered medication effect.
Adjust dosage during periods of immobility or major surgery as calcium metabolism may be altered.
Careful handling and storage; do not use if solution changes color or contains particles.

Warnings

Contraindicated in patients with hypercalcemia or hypervitaminosis D.
Do not use in patients with known hypersensitivity to calcitriol or other forms of vitamin D.
Risk of severe hypercalcemia with overdose or incorrect dosing.
Use with caution in patients receiving thiazide diuretics due to increased risk of hypercalcemia.
Potential teratogenic effects; use only if benefits outweigh risks during pregnancy.
Not recommended during breastfeeding due to potential for adverse effects on infant calcium metabolism.
Risk of serious electrolyte imbalances, particularly in renal impairment.
Increased sensitivity to the effects of calcitriol in elderly patients may necessitate dose adjustments.
Avoid abrupt discontinuation in patients dependent on calcitriol to maintain calcium homeostasis.
Signs of overdose include gastrointestinal, neurologic, and cardiovascular symptoms and require urgent medical attention.

Contraindication

Known hypersensitivity to calcitriol or any component of the formulation.
Hypercalcemia or evidence of vitamin D toxicity prior to initiation.
Conditions associated with increased calcium absorption leading to hypercalcemia, such as certain lymphomas or sarcoidosis.
Patients with persistent hyperphosphatemia without adequate control.
Inability to monitor serum calcium and phosphate adequately during treatment.
Use in infants without specialist supervision.
Simultaneous use of other active vitamin D analogs without proper medical guidance.
Severe renal impairment without appropriate clinical monitoring.

Drug Interactions

Concurrent use with thiazide diuretics (e.g., hydrochlorothiazide) can potentiate hypercalcemia.
Interaction with cholestyramine may reduce calcitriol absorption by binding bile acids necessary for solubilization.
Caution with digitalis glycosides (e.g., digoxin) because hypercalcemia increases the risk of digitalis toxicity.
Anticonvulsants such as phenobarbital and phenytoin increase calcitriol metabolism, reducing its efficacy.
Ketoconazole may inhibit metabolism of calcitriol, potentially increasing plasma levels and toxicity risk.
Glucocorticoids like prednisone and dexamethasone can antagonize vitamin D effects, requiring dose adjustments.
Magnesium-containing antacids or laxatives may increase serum magnesium leading to cardiac effects when combined with calcitriol.
Concurrent use with other vitamin D supplements can potentiate hypercalcemia risk.
Drugs altering calcium metabolism, such as bisphosphonates, require close monitoring when administered concurrently.
Effectiveness can be decreased by drugs accelerating hepatic metabolism through CYP enzymes.
Caution when combined with digoxin due to increased risk of arrhythmias secondary to hypercalcemia.

Preparations Of The Drug

Oral capsules available in 0.25 microgram and 0.5 microgram strengths for precise dosing adjustments.
Oral liquid formulation at 1 microgram/mL concentration allows flexibility in pediatric and difficult-to-dose patients.
Intravenous injectable solution utilized in hospital settings for situations requiring rapid correction or when oral administration is not feasible.
All formulations require protection from moisture, heat, and light to maintain stability.
Packaging includes dosing syringes or measuring devices for oral liquid to ensure accurate administration.
Injectable forms are supplied in sterile vials intended for infusion, requiring preparation immediately before use to avoid degradation.
Oral dosage forms are designed for ease of administration and improved bioavailability.
Calcium and vitamin D supplements are often co-administered with calcitriol for enhanced therapeutic outcomes.
Parenteral preparations serve patients with malabsorption or those unable to tolerate oral forms.
Each preparation is accompanied by a package insert detailing handling instructions, storage, and administration precautions.