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Also known as: 1-hydroxycholecalciferol 1alpha-hydroxycholecalciferol 1alpha-hydroxyvitamin D3 Alphacalcidol


Mechanism of Action

Alfacalcidol is converted rapidly in the liver to 1,25-dihydroxyvitamin D. This is the metabolite of vitamin D which acts as a regulator of calcium and phosphate metabolism. Since this conversion is rapid, the clinical effects of alfacalcidol and 1,25-dihydroxyvitamin D are very similar.

Pharmacodynamic Properties

Impaired 1α-hydroxylation by the kidneys reduces endogenous 1,25-dihydroxyvitamin D production. This contributes to the disturbances in mineral metabolism found in several disorders, including renal bone disease, hypoparathyroidism, neonatal hypocalcaemia and vitamin D dependent rickets. These disorders, which require high doses of parent vitamin D for their correction, will respond to small doses of alfacalcidol.

The delay in response and high dosage required in treating these disorders with parent vitamin D makes dosage adjustment difficult. This can result in unpredictable hypercalcaemia which may take weeks or months to reverse. The major advantage of alfacalcidol is the more rapid onset of response, which allows a more accurate titration of dosage. Should inadvertent hypercalcaemia occur it can be reversed within days of stopping treatment.

Pharmacokinetic Properties

In patients with renal failure, 1-5 µg/day of 1α-hydroxyvitamin D (1α-OHD3) increased intestinal calcium and phosphorus absorption in a dose-related manner. This effect was observed within 3 days of starting the drug and conversely, it was reversed within 3 days of its discontinuation.

In patients with nutritional osteomalacia, increases in calcium absorption were noted within 6 hours of giving 1 µg 1α-OHD3 orally and usually peaked at 24 hours. 1α-OHD3 also produced increases in plasma inorganic phosphorus due to increased intestinal absorption and renal tubular re-absorption. This latter effect is a result of PTH suppression by 1α-OHD3. The effect of the drug on calcium was about double its effect on phosphorus absorption.

Patients with chronic renal failure have shown increased serum calcium levels within 5 days of receiving 1α-OHD3 in a dose of 0.5-1.0 µg/day. As serum calcium rose, PTH levels and alkaline phosphatase decreased toward normal.

In patients on regular haemodialysis administration of doses between 1-4 micrograms of intravenous 1 α-hydroxyvitamin D3 resulted in increased levels of 1,25 dihydroxyvitamin D. Formation of 1,25 dihydroxyvitamin D3 occurred within 1 hour after intravenous 1 α-hydroxyvitamin D3 and peak concentrations were reached between 2 and 5 hours. Elimination half life of the formed 1,25 dihydroxyvitamin D was between 14 and 30 hours.

Preclinical Safety Data

The non-clinical toxicity of alfacalcidol is attributed to the known vitamin D-effect of calcitriol on calcium homeostasis, which is characterised by hypercalcaemia, hypercalciuria and eventually soft tissue calcification.

Alfacalcidol is not genotoxic.

No specific effects of alfacalcidol on fertility or behaviour of the offspring were noted in rats and rabbits. In terms of embryo-fetal development, fetal toxicity (post-implantation loss, lower litter size and lower pup weight) was observed at doses high enough to cause toxicity in the dams. High doses of vitamin D are known to be teratogenic in experimental animals.

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