Pharmacology: Pharmacodynamics: The drug is rapidly absorbed in blood from the intestinal tube after intake and 25-hydroxylated by 25-hydroxylase of hepatic microsome to be metabolized into an active substance. 1α, 25-(OH)2D3 and distributed to target tissues such as intestinal tube, bone, etc. It binds to a receptor and then exerts its physiological activities such as stimulation of Ca absorption from intestinal tube, bone resorption and bone formation.
Ca absorption from intestinal tube and elevation of serum Ca level: In animal studies using vitamin D-defficient rats and nephrectomized rats, alfacalcidol was found to stimulate Ca absorption from intestinal tube and elevate serum Ca level.
Bone formation: Bone tissue culture: In culture tests on fetal tissue from 9-day old, 1α, 25-(OH)2D3 was proved to be indispensable for normal bone formation.
Nephrectomized rat: In rats with a lot of bone resorption areas and osteoid tissues and remarkable hypo-calcification due to sub-total nephrectomy, the 30-day administration of alfacalcidol resulted in an increase in bone formation area.
Osteoporosis model (ovarlectomized rat): In a long-term breeding after ovartectomy, the serum level of 1α, 25-(OH)2D3 decreases, trabecular bone decreases in its mass and the percentage of calcium deposition reduces. These changes were improved after 6-month treatment with alfacalcidol at 0.1 mcg/kg/day.
Rat model of osteoporosis (hydrocortisone-treated rats): Trabecular bone, bone cortex width and bone mineral content decrease following a long-term administration of hydrocortisone. These changes were improved after the 12-week treatment with alfacalcidol at 0.02 mcg/kg/day to 0.1 mcg/kg/day.
Senile osteoporosis (human, observation under electron microscope and optical microscope): Ilium biopsy was performed before and after treatment with Bon-One and the sampled materials were observed under electron microscope and optical microscope. Active osteoblast, calcified bone cell and bone cell increases in their numbers and osteohistological improvements were confirmed.
Ca-intake and bone resorption/bone formation: Vitamin D-defficient rats were bred with Ca-containing food at various doses, and alfacalcidol was administered to these rats. At a low dose of Ca, bone resorption was noted and with a sufficient intake of Ca, bone formation was remarkable.
Pharmacokinetics: Metabolic Fate: The drug is absorbed in the small intestine and rapidly metabolized to be 1α, 25-(OH)2D3 in the liver.
In normal subjects, the blood level of 1α, 25-(OH)2D3 reaches its peak 8 to 24 hours after oral administration at a dose of 4 mcg/day, and its half life is 2 to 4 days.
Clinical Trials: Clinical effect: Clinical trials including three double-blind trials were performed in a total of 1,017 patients in 152 Institutes in Japan. The clinical effects of the drug were the following: Chronic renal failure, hypoparathyroidism, vitamin D-resistant rickets, osteomalacia of 583 patients included in the efficacy evaluation, the drug was judged as very effective or effective in 76.2% (444/583), and in 89.0% (519/583) including the result "fairly effective", In double-blind trials, the usefulness of the drug was confirmed.
Osteoporosis: Of 434 patients included in efficacy evaluation, the drug was evaluated as very effective or effective in 46.5% (202/434), and in 84.1% (365/434) including the result "fairly effective", In double-blind trials, the usefulness of the drug was confirmed.
Side effects and laboratory findings: The safety of the drug was studied in a total of 9,802 patients in 1,356 institutes in Japan (including clinical studies for development, such as phase I-III studies, and a 8-year survey on clinical safety after authorization).
Chronic renal failure, etc: Of 707 patients included in the clinical studies for development, side effects were reported in 66 patients (9.34%). The main symptoms were feeling of pruritus (20 events, 1.66%), nausea and vomiting (10 events, 0.83%) and elevation of GPT (8 events, 0.66%).
Osteoporosis: According to 3-year surgery after authorization (October 1983 to October 1986), side effects were reported in 100 (1.35%) of a total of 7,405 patients. The main symptoms were elevation of BUN and creatinine (22 events, 0.30%), increase in GPT (13 events, 0.18%), elevation of GPT (11 events, 0.15%), increase in gamma-GTP (8 events, 0.11%) and stomach discomfort (7 events, 0.09%).
Toxicology: Animal Studies: Acute toxicity (LD50 mg/kg): see Table.
Click on icon to see table/diagram/image
Subacute toxicity, Chronic toxicity: Wistar rats were treated with the drug at doses up to 50 mcg/kg for one month, up to 5.0 mcg/kg for three months and up to 2.5 mcg/kg for six months, and Beagle dogs at doses up to 10 mcg/kg for one month and 0.08 mcg/kg for 12 months. In rats treated at 2.5 mcg/kg for one month and at 0.1 mcg/kg for three to six months, and Beagle dogs treated at 0.04 mcg/kg for one month and at 0.02 mcg/kg for 12 months, no abnormal findings were noted. In animals at massive doses, some secondary changes to overdose of alfacalcidol, such as atrophy of thymus and sexual gland and degeneration of myocardium and renal tubule, were observed, but these symptoms were recovered after discontinuation of treatment.
Reproduction test: A fertility test, a teratologic test and a perinatal test were performed in rats at doses up to 2.5 mcg/kg and a teratologic test, in rats at doses up to 2.5 mcg/kg and a teratologic test, in rabbits at doses up to 0.5 mcg/kg.
No abnormal findings were noted at 0.5 mcg/kg in rats and at 0.02 mcg/kg in rabbits. In animals treated at massive doses, delayed ossification and some influence upon sexual gland were noted, and the rate of pregnancy decreased, fetal mortality increased, fetal development was supposed and lactating ability increased.
Special toxicity: No abnormality was found in antigenicity test, nor in mutagenicity test.
Absorption and excretion in animal (rat): About 72% of dosed amount of the drug was excreted in urine and feces within 48 hours after oral administration at 0.4 mcg/kg, and almost 100% was excreted in 7 days.
No tendency of accumulation in any organ was noted after a 14-day successive administration.