Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Alendronate Sodium
Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone-resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover.
Daily oral doses of alendronate (5, 20, and 40 mg for six weeks) in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases in urinary calcium and urinary markers of bone collagen degradation (such as deoxypyridinoline and cross- linked N-telopeptides of type I collagen). These biochemical changes tended to return toward baseline values as early as 3 weeks following the discontinuation of therapy with alendronate and did not differ from placebo after 7 months.
Long-term treatment of osteoporosis with FOSALAN 10 mg/day (for up to five years) reduced urinary excretion of markers of bone resorption, deoxypyridinoline and cross-linked N-telopeptides of type l collagen, by approximately 50% and 70%, respectively, to reach levels similar to those seen in healthy premenopausal women. The decrease in the rate of bone resorption indicated by these markers was evident as early as one month and at three to six months reached a plateau that was maintained for the entire duration of treatment with FOSALAN. In osteoporosis treatment studies FOSALAN 10 mg/day decreased the markers of bone formation, osteocalcin and bone specific alkaline phosphatase by approximately 50%, and total serum alkaline phosphatase by approximately 25 to 30% to reach a plateau after 6 to 12 months. Similar reductions in the rate of bone turnover were observed in postmenopausal women during one-year studies with once weekly FOSALAN 70 mg for the treatment of osteoporosis. These data indicate that the rate of bone turnover reached a new steady-state, despite the progressive increase in the total amount of alendronate deposited within bone.
As a result of inhibition of bone resorption, asymptomatic reductions in serum calcium and phosphate concentrations were also observed following treatment with FOSALAN. In the long-term studies, reductions from baseline in serum calcium (approximately 2%) and phosphate (approximately 4 to 6%) were evident the first month after the initiation of FOSALAN 10 mg. No further decreases in serum calcium were observed for the five-year duration of treatment; however, serum phosphate returned toward prestudy levels during years three through five. In one-year studies with once weekly FOSALAN 70 mg, similar reductions were observed at 6 and 12 months. The reduction in serum phosphate may reflect not only the positive bone mineral balance due to FOSALAN but also a decrease in renal phosphate reabsorption.
Osteoporosis in Men
Treatment of men with osteoporosis with FOSALAN 10 mg/day for two years reduced urinary excretion of cross-linked N-telopeptides of type I collagen by approximately 60% and bone-specific alkaline phosphatase by approximately 40%. Similar reductions were observed in a one-year study in men with osteoporosis receiving once weekly FOSALAN 70 mg.
Cholecalciferol
Vitamin D is required for normal bone formation. Vitamin D insufficiency is associated with negative calcium balance, leading to increased parathyroid hormone levels and worsening of bone loss associated with osteoporosis. When taken without vitamin D, alendronate is also associated with a reduction in serum calcium concentrations and increased parathyroid hormone levels. In a 15-week trial, 717 postmenopausal women and men, mean age 67 years, with osteoporosis (lumbar spine bone mineral density [BMD] of at least 2.5 standard deviations below the premenopausal mean) were randomized to receive either weekly FOSAVANCE 70 mg/2800 IU vitamin D or weekly FOSALAN 70 mg alone with no vitamin D supplementation. Patients who were vitamin D deficient (25-hydroxyvitamin D less than 9 ng/mL) at baseline were excluded. Treatment with FOSAVANCE 70 mg/ 2800 IU resulted in a smaller reduction in serum calcium levels (-0.9%) when compared to FOSALAN 70 mg alone (-1.4%). As well, treatment with FOSAVANCE 70 mg/ 2800 IU resulted in a significantly smaller increase in parathyroid hormone levels when compared to FOSALAN 70 mg alone (14% and 24%, respectively).
The sufficiency of patients’ vitamin D status is best assessed by measuring 25-hydroxyvitamin D levels.
In the 15-week trial mentioned above, baseline 25-hydroxyvitamin D levels were 22.2 ng/mL in the FOSAVANCE group and 22.1 ng/mL in the FOSALAN only group. After 15 weeks of treatment, the mean levels were 23.1 ng/mL and 18.4 ng/mL in the FOSAVANCE and FOSALAN only groups, respectively. The final levels of 25-hydroxyvitamin D at Week 15 are summarized in Table 4.

Table 4: 25-hydroxyvitamin D Levels after Treatment with FOSAVANCE (70 mg/2800 IU) or FOSALAN 70 mg at Week 15*
Number (%) of Patients
25-hydroxyvitamin D Ranges            <9           9-14         15-19         20-24        25-29     30-62
(ng/mL)
FOSAVANCE                          4 (1.1)       37 (10.4)     87 (24.4)    84 (23.5)     82 (23.0) 63 (17.7) (70 mg/2800 Iu)
(N=357)
FOSALAN 70 mg                     46 (13.1)      66 (18.8)    108 (30.8)    58 (16.5)     37 (10.5) 36 (10.3) (N=351)
*
Patients who were vitamin D deficient (25-hydroxyvitamin D less than 9 ng/mL) at baseline were excluded.

Patients (n=652) who completed the above 15-week trial continued in a 24-week extension in which all received FOSAVANCE (70 mg/2800 IU) and were randomly assigned to receive either additional once weekly vitamin D3 2800 IU (Vitamin D3 5600 IU group) or matching placebo (Vitamin D3 2800 IU group).
After 24 weeks of extended treatment (Week 39 from original baseline), the mean levels of 25- hydroxyvitamin D were 27.9 ng/mL and 25.6 ng/mL in the vitamin D3 5600 IU group and vitamin D3 2800 IU group, respectively. The percentage of patients with hypercalciuria at Week 39 was not statistically different between treatment groups.
The distribution of the final levels of 25-hydroxyvitamin D at Week 39 is summarized in Table 5.
Table 5: 25-hydroxyvitamin D Levels after Treatment with FOSAVANCE at Week 39 Number (%) of Patients
25-hydroxyvitamin D Ranges               <9          9-14          15-19         20-24         25-29         30-59
(ng/mL)
FOSAVANCE (Vitamin D3 5600               0          10 (3.1)      29 (9.0)      79 (24.6)     87 (27.1)    116 (36.1) IU group)*
(N=321)
FOSAVANCE (Vitamin D3 2800             1 (0.3)      17 (5.3)      56 (17.5)     80 (25.0)     74 (23.1)    92 (28.8) IU group)†
(N=320)
*
Patients received FOSALAN 70 mg or FOSAVANCE (70 mg/2800 IU) for the 15-week base study followed by FOSAVANCE (70 mg/2800 IU) and 2800 IU additional vitamin D3 for the 24-week extension study.
†
Patients received FOSALAN 70 mg or FOSAVANCE (70 mg/2800 IU) for 15-week base study followed by FOSAVANCE (70 mg/2800 IU) and placebo for the additional vitamin D3 for 24-week extension study.

Pharmacokinetic Properties

12.3 Pharmacokinetics
Absorption
Alendronate Sodium
Relative to an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10-mg tablet in men (0.59%) was similar to that in women when administered after an overnight fast and 2 hours before breakfast.
In a study, the alendronate in the FOSAVANCE 70 mg/5600 IU tablets was found to be equally bioavailable to the alendronate in the FOSALAN (alendronate sodium) 70-mg tablets.
A study examining the effect of timing of a meal on the bioavailability of alendronate was performed in 49 postmenopausal women. Bioavailability was decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast.
Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.
Cholecalciferol
Following administration of FOSAVANCE 70 mg/5600 IU Tablets after an overnight fast and two hours before a standard meal, the baseline adjusted mean area under the serum-concentration-time curve (AUC0- 80 hrs) and baseline adjusted mean maximal serum concentration (Cmax) for vitamin D3 were 355.6 ng-hr/mL and 10.8 ng/mL, respectively. The baseline adjusted mean time to maximal serum concentration (Tmax) was 9.2 hrs. The bioavailability of the 5600 IU vitamin D3 in the FOSAVANCE 70 MG/ 5600 IU TABLETS is similar to 5600 IU vitamin D3 administered as two 2800 IU vitamin D3 tablets.
          Distribution
Alendronate Sodium
Preclinical studies (in male rats) show that alendronate transiently distributes to soft tissues following 1 mg/kg intravenous administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL) for analytical detection. Protein binding in human plasma is approximately 78%.
Cholecalciferol
Following absorption, vitamin D3 enters the blood as part of chylomicrons. Vitamin D3 is rapidly distributed mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D3, the major storage form. Lesser amounts are distributed to adipose tissue and stored as vitamin D3 at these sites for later release into the circulation. Circulating vitamin D3 is bound to vitamin D-binding protein.
Metabolism
Alendronate Sodium
There is no evidence that alendronate is metabolized in animals or humans.
Cholecalciferol
Vitamin D3 is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D3, and subsequently metabolized in the kidney to 1,25-dihydroxyvitamin D3, which represents the biologically active form. Further hydroxylation occurs prior to elimination. A small percentage of vitamin D3 undergoes glucuronidation prior to elimination.
Excretion
Alendronate Sodium
Following a single intravenous dose of [14C] alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the feces. Following a single 10-mg intravenous dose, the renal clearance of alendronate was 71 mL/min (64, 78; 90% confidence interval [CI]), and systemic clearance did not exceed 200 mL/min. Plasma concentrations fell by more than 95% within 6 hours following intravenous administration. The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Based on the above, it is estimated that after 10 years of oral treatment with FOSALAN (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.
Cholecalciferol
When radioactive vitamin D3 was intravenously administered to healthy subjects, the mean urinary excretion of radioactivity after 48 hours was 2.4% of the administered dose, and the mean fecal excretion of radioactivity after 48 hours was 4.9% of the administered dose. In both cases, the excreted radioactivity was almost exclusively as metabolites of the parent. The mean half-life of baseline adjusted vitamin D3 in the serum following an oral dose of FOSAVANCE 70 MG/ 5600 IU TABLETS is approximately 14 hours.
Specific Populations
Gender: Bioavailability and the fraction of an intravenous dose of alendronate excreted in urine were similar in men and women.
Geriatric:
Alendronate Sodium
Bioavailability and disposition of alendronate (urinary excretion) were similar in elderly and younger patients. No dosage adjustment of alendronate is necessary.
Cholecalciferol
Dietary requirements of vitamin D3 are increased in the elderly.
Race: Pharmacokinetic differences due to race have not been studied.
Renal Impairment:
Alendronate Sodium
Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after 3 weeks dosing with cumulative intravenous doses of 35 mg/kg in young male rats. Although no formal renal impairment pharmacokinetic study has been conducted in patients, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function.
No dosage adjustment is necessary for patients with creatinine clearance 35 to 60 mL/min.
FOSAVANCE 70 MG/ 5600 IU TABLETS are not recommended for patients with creatinine clearance less than 35 mL/min due to lack of experience with alendronate in renal failure.
Cholecalciferol
Patients with renal insufficiency will have decreased ability to form the active 1,25-dihydroxyvitamin D3 metabolite.
              Hepatic Impairment:
Alendronate Sodium
As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary.
Cholecalciferol
Vitamin D3 may not be adequately absorbed in patients who have malabsorption due to inadequate bile production.
Drug Interactions
Alendronate Sodium
Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H2-antagonists is unknown.
In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 to 44%).
Products containing calcium and other multivalent cations are likely to interfere with absorption of alendronate.
Cholecalciferol
Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g., cholestyramine, colestipol) may impair the absorption of vitamin D. Anticonvulsants, cimetidine, and thiazides may increase the catabolism of vitamin D.