Rocaltrol Mechanism of Action

Therapeutic/Pharmacologic Class of Drug: Biologically active form of vitamin D₃. ATC Code: A11CC04.
Pharmacology: Pharmacodynamics: Mechanism of Action: Calcitriol is the most active known form of vitamin D₃ in stimulating intestinal calcium transport.
The biological effects of calcitriol are mediated by the vitamin D receptor, a nuclear hormone receptor expressed in most cell types and functioning as a ligand-activated transcription factor that binds to specific DNA sites to modify the expression of target genes.
The two known sites of action of calcitriol are intestine and bone.
A calcitriol receptor-binding protein appears to exist in the mucosa of human intestine. Additional evidence suggests that calcitriol may also act on the kidney and the parathyroid glands. In acutely uremic rats calcitriol has been shown to stimulate intestinal calcium absorption.
The kidneys of uremic patients cannot adequately synthesize calcitriol, the active hormone formed from precursor vitamin D. Resultant hypocalcemia and secondary hyperparathyroidism are a major cause of the metabolic bone disease of renal failure. However, other bone-toxic substances which accumulate in uremia (e.g., aluminium) may also contribute.
The beneficial effect of Calcitriol (Rocaltrol) in renal osteodystrophy appears to result from correction of hypocalcemia and secondary hyperparathyroidism. It is uncertain whether Calcitriol (Rocaltrol) produces other independent beneficial effects.
Clinical/Efficacy Studies: Calcitriol is one of the most important active metabolites of vitamin D₃. It is normally formed in the kidney from its precursor, 25-hydroxycholecalciferol (25-HCC). Physiological daily production is normally 0.5-1.0 mcg and is somewhat higher during periods of increased bone synthesis (e.g. growth or pregnancy). Calcitriol promotes intestinal absorption of calcium and regulates bone mineralization. The pharmacological effect of a single dose of calcitriol lasts about 3-5 days.
The key role of calcitriol in the regulation of calcium homeostasis, which includes stimulating effects on osteoblastic activity in the skeleton, provides a sound pharmacological basis for its therapeutic effects in osteoporosis.
In patients with marked renal impairment, synthesis of endogenous calcitriol is correspondingly limited or may even cease altogether. This deficiency plays a key role in the development of renal osteodystrophy.
In patients with renal osteodystrophy, oral administration of Calcitriol (Rocaltrol) normalizes reduced intestinal absorption of calcium, hypocalcemia, increased serum alkaline phosphatase and serum parathyroid hormone concentration. It alleviates bone and muscle pain and corrects the histological alterations that occur in osteitis fibrosa and other mineralisation defects.
In patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism, hypocalcemia and its clinical manifestations are alleviated by Calcitriol (Rocaltrol) therapy.
In patients with vitamin D-dependent rickets, serum levels of calcitriol are low or absent. As the endogenous production of calcitriol in the kidney is insufficient, Calcitriol (Rocaltrol) is considered as a replacement therapy.
In patients with vitamin D-resistant rickets and hypophosphatemia in whom plasma calcitriol levels are reduced, treatment with Calcitriol (Rocaltrol) reduces tubular elimination of phosphates and, in conjunction with concurrent phosphate treatment, normalizes bone development.
Patients with various other forms of rickets, e.g. in association with neonatal hepatitis, biliary atresia, cystinosis and dietary calcium and vitamin D deficiency, have also benefited from Calcitriol (Rocaltrol) therapy.
Pharmacokinetics: Absorption: Peak plasma concentrations following a single oral dose of 0.25-1.0 mcg Calcitriol (Rocaltrol) were reached within 2-6 hours.
Distribution: During transport in the blood, calcitriol and other vitamin D metabolites are bound to specific plasma proteins.
Metabolism: Calcitriol is hydroxylated and oxidized in the kidney and in the liver by a specific cytochrome P450 isoenzyme; CYP24A1.
Several metabolites with different degrees of vitamin D activity have been identified.
Elimination: The elimination half-life of calcitriol in plasma ranges between 5 to 8 hours.
The elimination and absorption kinetics of calcitriol remain linear in a very broad dose range up to 165 μg single oral dose.
The pharmacological effect of a single dose of calcitriol lasts at least 4 days.
Calcitriol is excreted in the bile and may undergo an enterohepatic circulation.
Pharmacokinetics in Special Populations: In patients with nephrotic syndrome or in those undergoing hemodialysis, serum levels of calcitriol were reduced and time to peak levels was prolonged.
Toxicology: Preclinical Safety: Subchronic toxicity studies in rats and dogs indicated that calcitriol at an oral dose of 20 ng/kg/day (twice the usual human dosage) for up to 6 months produced no or minimal adverse effects. A dose of 80 ng/kg/day (8 times the usual human dosage) for up to 6 months produced moderate adverse effects; changes seen appeared to be primarily the result of prolonged hypercalcemia.
Impairment of Fertility: Reproductive toxicity studies in rats indicated that oral doses up to 300 ng/kg/day (30 times the usual human dose) did not adversely affect reproduction. In rabbits, multiple foetal abnormalities were observed in two litters at an oral maternally toxic dose of 300 ng/kg/day and one litter at 80 ng/kg/day, but not at 20 ng/kg/day (twice the usual human dose). Although there were no statistically significant differences between treated groups and controls in the numbers of litters or foetuses showing abnormalities, the possibility that these findings were due to calcitriol administration could not be discounted.