Action And Clinical Pharmacology
Mechanism Of Action
There is evidence that calcitriol (1,25-(OH)2 D3) is the
biologically active form of vitamin D responsible, in part, for maintaining
calcium and phosphorous homeostasis.
Calcitriol stimulates the intestinal transport of
calcium. The active transport of calcium occurs primarily in the duodenum.
Although the exact mechanism by which this occurs is uncertain, most evidence
suggests that calcitriol enhances calcium movement across the brush border into
the intestinal cells. Evidence further suggests that a specific calcium-binding
protein, which is stimulated by calcitriol, acts to augment the entry of
calcium into the cell. In addition, calcitriol may exert a nuclear effect by
directing the synthesis of messenger RNA which in turn stimulates the synthesis
of new proteins which are thought to be involved in the calcium transport
Bone is the second tissue at which calcitriol acts to
mobilize calcium for circulation. Whether calcitriol can directly stimulate
bone mineralization or whether it leads to mineralization by increasing the
levels of calcium and phosphate in the extracellular fluid surrounding bone
remains unclear. Cytosolic receptor proteins for calcitriol in bone cells have
In acutely uremic rats, calcitriol has been shown to
stimulate intestinal calcium absorption. In bone, calcitriol, in conjunction
with parathyroid hormone, stimulates resorption of calcium; and in the kidney,
calcitriol increases the tubular reabsorption of calcium.
Calcitriol stimulates bone resorption which serves to
mobilize calcium for the circulation, when an intestinal credit of calcium is
absent. This effect is related to the role of vitamin D in maintaining the
homeostasis of calcium and phosphorous in plasma. In addition, calcitriol may
interact directly with osteoblasts.
The mechanism whereby calcitriol acts on the kidney and
parathyroid gland remains unclear. Evidence suggests that calcitriol may
enhance renal tubular calcium reabsorption. Recent studies in
parathyroidectomized animals suggest that calcitriol has a direct proximal
tubular action in regulating the secretion of PTH by the parathyroid gland.
Evidence suggests that calcitriol may affect the secretion of PTH through a
direct action on the parathyroid gland and may be involved in the regulation of
PTH synthesis and/or its secretion.
Calcitriol is the active form of vitamin D3
(cholecalciferol). The natural or endogenous supply of vitamin D in man mainly
depends on ultraviolet light for conversion of 7-dehydrocholesterol to vitamin
D3 in the skin. Vitamin D3 must be metabolically activated in the liver and the
kidney before it is fully active on its target tissues. The initial transformation
is catalyzed by a vitamin D3-25-hydroxylase enzyme present in the liver, and
the product of this reaction is 25-hydroxyvitamin D3 (calcifediol).
The latter undergoes hydroxylation in the mitochondria of
kidney tissue, and this reaction is activated by the renal 25-hydroxyvitamin
D3-1-alpha-hydroxylase to produce 1,25-dihydroxyvitamin D3 (calcitriol), the
active form of vitamin D3.
The known sites of action of calcitriol are intestine and
bone, but additional evidence suggests that it also acts on the kidney and the
parathyroid gland. Calcitriol is the most active known form of vitamin D3 in
stimulating intestinal calcium transport.
Not applicable as CALCIJEX® is an injectable drug.
Calcitriol, when administered by bolus injection, is
rapidly available in the blood stream. Vitamin D metabolites are known to be
transported in blood, bound to specific alpha2 globulins. The pharmacologic
activity of an administered dose of calcitriol is about 3 to 5 days.
Two metabolic pathways for calcitriol have been
identified: conversion to 1,24,25-(OH)3D3 and to calcitroic acid.
Study Demographics And Trial Design
Table 2: Summary of Patient Demographics for Clinical
Trials in Management of Hypocalcemia in Patients Undergoing Chronic Renal
||Dosage, Route of Administration and Duration
||Study Subjects (N=Number)
||Mean Age (Range)
||Gender (%M/F) Race (%B/C)
||Unblinded, multi-dose, three-period study
||Initial dose: 0.25-1.0 mcg 3 times weekly post-dialysis Dose increases: weekly increments of 0.25 to 0.50 mcg Maximum dose: 1.75-4.0 mcg 3 times weekly post-dialysis No comparator: each patient served as his/her own control Intravenous Period 1: pre-treatment (3 weeks)1 Period 2: treatment (4-8 weeks)2 Period 3: post-treatment (3 weeks)1
||48.3 years (21-67)
||Gender: 55/45 Race: 75/25
|1: No vitamin D therapy.
2: CALCIJEX® administered 3 times weekly, post-hemodialysis; 2 to 6 weeks of
dose adjustment followed by 2 weeks at optimal dose.
Definitions: B/C = Black / Caucasion; M/F = Male /
The safety and efficacy of CALCIJEX® (calcitriol
injection) in the management of hypocalcemia in patients undergoing maintenance
hemodialysis for chronic renal disease were investigated in Study 1. Twenty
patients received calcitriol; doses were titrated for each patient based upon
serum total calcium response.
The primary parameter for determining efficacy was serum
total calcium. Serum levels of ionized calcium, phosphorus, magnesium, and
alkaline phosphatase were also measured to determine the effect, if any, of
calcitriol on these parameters. A significant increase (p < 0.001) in serum
total calcium (CaT) of 1.7 ± 0.2 mcg/dL was observed during the last two weeks
of treatment compared with the last week of the pre-treatment period, where CaT
decreased by 1.2 ± 0.2 mcg/dL (p < 0.001). Mean serum C-terminal parathyroid
hormone (PTH) levels decreased to 50% of pre-treatment values during Period 2
and returned to pre-treatment levels by the end of Period 3.
In human studies, calcitriol is rapidly absorbed from the
intestine. Vitamin D metabolites are known to be transported in blood, bound to
a specific alpha2 globulin.
A vitamin D-resistant state may exist in uremic patients
because of the failure of the kidney to adequately convert precursors to the
active compound, calcitriol.
Recent reports have indicated that vitamin D analogues
may cause a deterioration of renal function in chronic renal failure patients
who are not on renal dialysis.
Calcitriol administered intravenously or intraperitonealy
was found to be a simple and effective means to suppress secondary
hyperparathyroidism in patients undergoing hemodialysis or ambulatory
The acute toxicity of calcitriol administered by a
variety of routes was studied in mice and rats. The lethal dosages are shown in
Table 3: Acute Toxicity of CALCIJEX® in Mice and Rats
Median Lethal Dosages
|Definition: LD50 = Lethal dose that killed 50% of the
The primary signs of toxicity included decreased
lacrimation, ataxia, body temperature decrease and somnolence.
Neonatal rats (15/sex/dose) were administered calcitriol
once daily for 14 to 16 days at oral doses of 0, 0.06, 0.19 and 0.64
mcg/kg/day. Five controls, four low-dose, two mid-dose, and fifteen high-dose
pups died during the two-week treatment period. Some of the deaths were
attributed to dosing accidents, but more than half of the deaths in the
high-dose group were drug-related. An additional 6 high-dose pups died during a
7-week “recovery” period. Drug-related deaths resulted from
metastatic calcification alone or in combination with the stress imposed by
Many high-dose pups were considerably smaller than pups
in the other groups, exhibited subcutaneous white patches on head and lower jaw
and developed splayed limbs, and had higher serum calcium levels than controls.
Gross and histologic changes reflective of metastatic calcification were seen
in a number of organs including kidney and heart. Nephrocalcinosis was the most
consistent histologic lesion noted.
No significant signs of toxicity were noted in low-dose
pups examined soon after final treatment, but 3 of 8 low-dose animals examined
after the 7-week “recovery” period exhibited a minimal degree of
renal calcification. The observed effects, were deemed to be entirely
attributable to the induction of hypercalcemia in previously normocalcemic
Neonatal rats (15/sex/dose) were treated intramuscularly
once daily for 14 to 16 consecutive days with calcitriol at doses of 0, 0.13,
0.38 and 1.28 mcg/kg/day. The majority of the animals were killed following the
last treatment, but a number of pups were maintained on a 7-week
One control, one mid-dose and two high-dose pups died
during the two-week treatment period; six additional mid-dose and seven
additional high-dose pups died during the “recovery” period.
Drug-related deaths resulted from metastatic calcification or renal tubular
Subcutaneous white patches on the head and splayed limbs
were observed at the high-dose, 1.28 mcg/kg/day. Mean body weights of males in
all groups were significantly less than the control mean. Serum calcium levels
were elevated in all animals receiving calcitriol.
Gross pathologic changes included white streaks of spots
on the liver, heart and diaphragm. Metastatic calcification was the principal
treatment-related histologic lesion found in all treatment groups.
Nephrocalcinosis, gastric mineralization and calcium deposition in heart, aorta
and respiratory system were consistently seen. Residual calcium deposits tended
to be less severe in the tissues of the recovery animals.
Rats (10/sex/dose) were injected intramuscularly with
calcitriol at dosage levels of 0, 0.03, 0.13 and 0.64 mcg/kg/day for 14 days.
Dosage groups consisted of 10 males and 10 females. There were six deaths at
0.64 mcg/kg/day during the study. Apparent signs of toxicity observed at 0.13
and 0.64 mcg/kg/day included labored breathing, reduced motor activity, corneal
opacities, decreased defecation and elevated serum calcium levels.
Elevation in blood urea nitrogen (BUN) and decreases in
total serum protein and potassium, body weight and food consumption were noted
at 0.64 mcg/kg/day. Microscopic lesions found included calcification of the
myocardial fibers, arteriosclerosis of the coronary and aortic arteries,
nephrolithiasis, calcification of the stomach and the large intestine and
thymus hypoplasia. The only histopathological change observed at 0.03 and 0.13
mcg/kg/day was an increase in phagocytosis by the large cortical cells of the
thymus. The thymus hypoplasia was considered to be attributable to a high
degree of stress consequent upon debilitation and possibly severe electrolyte changes.
Corneal opacities observed were not considered by the authors to be
drug-related. The maximum tolerated dosage was 0.03 mcg/kg/day in this study.
Immature rats (10/sex/dose) were administered calcitriol
once daily for a minimum of six weeks beginning on postnatal Day 15. At doses
of 0, 0.02, 0.06 and 0.20 mcg/kg/day, no evidence of toxicity attributable to
calcitriol administration was noted. The “no-effect” level was
determined to be 0.20 mcg/kg/day in these animals.
Dogs (3/sex/dose) were injected intramuscularly with
calcitriol at dosage levels of 0, 0.02, 0.06 and 0.21 mcg/kg/day for 14 days.
There were no deaths in the study. Thinness, dehydration, decreased activity,
ocular discharge, decreased body weight and food consumption were observed at
0.06 and 0.21 mcg/kg/day. Significantly elevated serum calcium levels were
noted at the two higher dosage levels (0.06 and 0.21 mcg/kg/day). Calcium
deposition was not evident in the tissues at any dosage level. Therefore, a
dosage of 0.02 mcg/kg/day was considered to be the maximum-tolerated dose in
Mutagenicity And Carcinogenicity
There was no evidence of mutagenicity as studied by the
Ames Method. Concentrations as high as 1000 mcg were found to be non mutagenic
to Salmonella strain.
Long-term studies in animals have not been performed to
evaluate the carcinogenic potential of calcitriol.
Reproduction And Teratology
Fertility and General Reproductive Performance
Calcitriol was administered orally to male rats for 60
days prior to mating and to female rats (24/dosage) from 14 days prior to
mating until sacrifice of the females either on gestation Day 13 or on
lactation day 21. Dosages tested were 0, 0.002, 0.08 and 0.30 mcg/kg/day. No
adverse effects on either fertility or neonatal development were noted. All F0 generation
animals survived. It was concluded that under the conditions of this study
there were no adverse effects observed on either reproductive parameters or the
pups themselves at dosages as great as 0.30 mcg/kg/day of calcitriol.
Calcitriol was orally administered to pregnant rats
(20/dosage) from gestation Day 7 to gestation Day 15. Dosages tested were 0
(control), 0.02, 0.08 and 0.30 mcg/kg/day. Numbers of fetuses, implantation
sites and resorption sites were counted. Fetuses were weighed and examined for
external abnormalities. One-third of the fetuses in each litter were examined
for visceral abnormalities, two-thirds of the fetuses in each litter were
prepared for skeletal evaluation.
Maternal weight gain was significantly reduced in dams
receiving 0.3 mcg/kg/day. No biologically significant adverse effects on rat
embryonic or fetal development were observed at any of the tested dosages.
There was no evidence that calcitriol was teratogenic in rats.
Calcitriol was orally administered to pregnant rabbits
from gestation Day 7 to gestation Day 18. Dosages tested were 0, 0.02, 0.08 and
0.30 mcg/kg/day for 31, 16, 15 and 16 rabbits respectively. Numbers of live or
dead pups, resorption sites, corpora lutea and implantation sites were
recorded. Fetuses were examined for external abnormalities, dissected to check
for visceral abnormalities and prepared for skeletal evaluation.
Marked weight loss occurred among high-dose dams; 3
high-dose animals died (2 clearly as a result of hypervitaminosis D). The mean
litter size was reduced and the resorption frequency was increased among
high-dose dams. Although not statistically significant, these changes were
considered to be biologically significant by the authors. The percentage of
viable pups that survived 24 hours of incubation was significantly decreased at
the highest dose. The average fetal body weight was slightly reduced at this
dosage as well. While the overall incidence of external, visceral and skeletal
anomalies was comparable among all groups, one entire litter in each of the
0.08 and 0.30 mcg/kg groups exhibited multiple external malformations. These
malformations included open eyelids, microphthalmia, cleft palate, reduced long
bones, gnarled paws, pes caves, shortened ribs and sternebral defects in 9
mid-dose fetuses and open eyelids, reduced long bones and shortened ribs in 6
high-dose fetuses. The authors concluded that while the low incidence of litters involved, the lack of clear
dose-response and the lack of statistical significance made it uncertain that
these abnormalities were related to calcitriol administration, this possibility
could not be discounted.
Perinatal and Postnatal Studies
Calcitriol was orally administered to pregnant rats
(20/dosage) from gestation Day 15 through Day 21 of lactation. Dosages tested
were 0, 0.02, 0.08 and 0.30 mcg/kg/day. Hypercalcemia and hypophosphatemia were
noted in dams receiving 0.08 and 0.30 mcg/kg/day. Serum sampled from pups on
postnatal Day 21 was hypercalcemic in both the mid- and high-dose groups. Aside
from this no adverse effects on reproduction or pup growth and survival were
observed at the tested dosages.
Calcitriol was given intravenously into an ear vein in
rabbits at doses of 5 mcg/kg which is ten times the proposed maximum dosage.
Calcitriol was found not to be irritating to veins.
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