Pharmacology: Mechanism of Action:
The action of lbandronate on bone tissue is based on its affinity for hydroxyapatite, which is part
of the mineral matrix of bone. Ibandronate inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover,
leading to, on average, a net gain in bone mass.
Osteoporosis is characterized by decreased bone mass and increased fracture risk, most commonly at the spine, hip, and wrist. The diagnosis can be confirmed by a finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis indicative of vertebral fracture. While osteoporosis occurs in both men and women, it is most common among women following menopause. In healthy humans, bone formation and resorption are closely linked; old bone is resorbed and replaced by newly formed bone. In postmenopausal osteoporosis, bone resorption exceeds bone formation, leading to bone loss and increased risk of fracture. After menopause, the risk of fractures of the spine and hip increases; approximately 40% of 50-year-old women will experience an osteoporosis-related fracture during their remaining lifetimes.
In studies of postmenopausal women, Ibandronate sodium injection at doses of 0.5 mg to 3 mg produced biochemical changes indicative of inhibition of bone resorption, including decreases of biochemical markers of bone collagen degradation [cross-linked C-telopeptide of Type I collagen (CTX)]. Changes in markers of bone formation (osteocalcin) were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and formation.
Year 1 results from an efficacy and safety study comparing Ibandronate sodium injection 3 mg every 3 months and Ibandronate sodium 2.5 mg daily oral tablet demonstrated that both dosing regimens significantly suppressed serum CTX levels at Months 3, 6 and 12. The median pre-dose or trough serum CTX levels in the ITT population reached a nadir of 57% (Ibandronate sodium Injection) and 62% (Ibandronate sodium 2.5 mg tablets) below baseline values by Month 6, and remained stable at Month 12 of treatment.
Daily Oral Tablets:
The effectiveness and safety of Ibandronate sodium daily oral tablets were demonstrated in a
randomized, double-blind, placebo-controlled, multinational study (Treatment Study) of
2946 women aged 55-80 years, who were on average 21 years postmenopause, who had
lumbar spine bone mineral density (BMD) 2-5 SD below the premenopausal mean
(T-score) in at least 1 vertebra (Ll-L4), and who had 1-4 prevalent vertebral fractures. lbandronate sodium was evaluated at oral doses of 2.5 mg daily and 20 mg intermittently. The main outcome measure was the occurrence of new radiographically
diagnosed, vertebral fractures after 3 years of treatment. The diagnosis of an incident
vertebral fracture was based on both qualitative diagnosis by the radiologist and quantitative
morphometric criterion. The morphometric criterion required the dual occurrence of 2
events: A relative height ratio or relative height reduction in a vertebral body of at least 20%,
together with at least a 4 mm absolute decrease in height. All women received 400 IV
vitamin D and calcium 500 mg supplementation per day.
Quarterly IV Injection:
The effectiveness and safety of Ibandronate sodium injection 3 mg once every 3 months were
demonstrated in a randomized, double-blind, multinational, noninferiority study (DIVA Study) in
1358 women with postmenopausal osteoporosis (L2-L4 lumbar spine BMD, T-score below -2.5
SD at baseline). The control group received lbandronate sodium 2.5 mg daily oral tablets. The
primary efficacy parameter was the relative change from baseline to 1 year of treatment in
lumbar spine BMD, which was compared between the IV injection and the daily oral
treatment groups. All patients received vitamin D 400 IU and calcium 500 mg supplementation
Effect on Vertebral Fracture:
Ibandronate sodium 2.5 mg daily oral tablet significantly reduced the incidence of new vertebral
and of new and worsening vertebral fractures (Daily Oral Tablet-Treatment Study). Over the
course of the 3-year study, the risk for vertebral fracture was 9.6% in the placebo-treated women
and 4.7% in the women treated with lbandronate sodium 2.5 mg daily oral tablet (p<0.001) (see Table 1). In an unapproved regimen, intermittent oral administration of lbandronate sodium 20 mg, involving a 9- to 10-week drug-free interval, produced a statistically significant reduction (50%) in the incidence of new vertebral fractures, similar to that seen with the daily oral 2.5 mg regimen. (See Table 1.)
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Effect on Nonvertebral Fractures:
There was a similar number of nonvertebral osteoporotic fractures at 3 years reported in women treated with lbandronate sodium 2.5 mg daily oral tablet [9.1 %, (95% CI: 7.1%, 11.1 %)] and placebo [8.2%, (95% CI: 6.3%, 10.2%)]. The two treatment groups were also similar with regard to the number of fractures reported at the individual non-vertebral sites: pelvis, femur, wrist, forearm, rib, and hip (Daily Oral Tablet-Treatment Study).
Effect on Bone Mineral Density (BMD): Daily Oral Tablet-Treatment Study:
Ibandronate sodium 2.5 mg daily oral tablet significantly increased BMD at the lumbar spine and hip relative to treatment with placebo. In the 3-year osteoporosis treatment study, lbandronate sodium 2.5 mg daily oral tablet produced increases in lumbar spine BMD that were progressive over 3 years of treatment and were statistically significant relative to placebo at 6 months and at all later time points. Lumbar spine BMD increased by 6.4% after 3 years of treatment with Ibandronate sodium 2.5 mg daily oral tablet compared with 1.4% in the placebo group. Table 2 displays the significant increases in BMD seen at the lumbar spine, total hip, femoral neck, and trochanter compared to placebo. (See Table 2.)
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Quarterly IV Injection DIVA Study:
In the ITT efficacy analysis, the least-squares mean increase at 1 year in lumbar spine BMD in patients (n=429) treated with Ibandronate sodium injection 3 mg once every 3 months (4.5%) was statistically superior to that in patients (n=434) treated with daily oral tablets (3.5%). The mean difference between groups was 1.05% (95% CI: 0.53%, 1.57%; p<0.001; see Figure). The mean increases from baseline in total hip BMD at 1 year were 2.1% in the Ibandronate sodium injection 3 mg once every 3 months group and 1.5% in the Ibandronate sodium 2.5 mg daily oral tablet group. Consistently higher BMD increases at the femoral neck and trochanter were also observed following Ibandronate sodium injection 3 mg once every 3 months compared to Ibandronate sodium 2.5 mg daily oral tablet. (See Figure.)
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The effects of Ibandronate sodium 2.5 mg daily oral tablet on bone histology were evaluated in iliac crest biopsies from 16 women after 22 months of treatment and 20 women after 34 months of treatment. The histological analysis of bone biopsies showed bone of normal quality and no indication of osteomalacia or a mineralization defect.
The histological analysis of bone biopsies after 22 months of treatment with IV Ibandronate 3 mg every 3 months (n=30) or 23 months of treatment with IV Ibandronate 2 mg every 2 months (n=27) in women with postmenopausal osteoporosis showed bone of normal quality and no indication of a mineralization defect.
Animal studies have shown that Ibandronate is an inhibitor of osteoclast-mediated bone resorption. In the Schenk assay in growing rats, Ibandronate inhibited bone resorption and increased bone volume, based on histologic examination of the tibial metaphyses. There was no evidence of impaired mineralization at the highest dose of 5 mg/kg/day (SC), which is 1000 times the lowest antiresorptive dose of 0.005 mg/kg/day in this model, and 5000 times the optimal antiresorptive dose of 0.001 mg/kg/day in the aged ovariectomized rat. This indicates that Ibandronate sodium injection administered at a therapeutic dose is unlikely to induce osteomalacia.
Long-term daily or intermittent administration of Ibandronate to ovariectomized rats or monkeys was associated with suppression of bone turnover and increases in bone mass. Vertebral BMD, trabecular density, and biomechanical strength were increased dose-dependently in rats and monkeys, at doses up to 8 to 4 times the human IV dose of 3 mg every 3 months, based on cumulative dose normalized for body surface area (mg/m2
) and AUC comparison, respectively. Ibandronate maintained the positive correlation between bone mass and strength at the ulna and femoral neck. New bone formed in the presence of Ibandronate had normal histologic structure and did not show mineralization defects.
Area under the serum Ibandronate concentrations versus time curve increases in a dose proportional manner after administration of 2 mg to 6 mg by IV injection.
After administration, Ibandronate either rapidly binds to bone or is excreted into urine. In humans, the apparent terminal volume of distribution is at least 90 L, and the amount of dose removed from the circulation into the bone is estimated to be 40% to 50% of the circulating dose.
protein binding in human serum was approximately 86% over an Ibandronate concentration range of 20 to 2000 ng/mL (approximate range of maximum serum Ibandronate concentrations upon IV bolus administration) in 1 study.
There is no evidence that Ibandronate is metabolized in humans. Ibandronate does not inhibit human P450 1A2, 2A6, 2C9, 2Cl9, 2D6, 2El, and 3A4 isozymes in vitro
The portion of Ibandronate that is not removed from the circulation via bone absorption is eliminated unchanged by the kidney (approximately 50% to 60% of the administered IV dose).
The plasma elimination of Ibandronate is multiphasic. Its renal clearance and distribution into bone accounts for a rapid and early decline in plasma concentrations, reaching 10% of Cmax
within 3 or 8 hrs after IV or oral administration, respectively. This is followed by a slower clearance phase as Ibandronate redistributes back into the blood from bone. The observed apparent terminal half-life for Ibandronate is generally dependent on the dose studied and on assay sensitivity. The observed apparent terminal half-life for IV 2 and 4 mg Ibandronate alter 2 hrs of infusion ranges from 4.6 to 15.3 hrs and 5 to 25.5 hrs, respectively.
Following intravenous administration, total clearance of Ibandronate is low, with average values in the range 84 to 160 mL/min. Renal clearance (about 60 mL/min in healthy postmenopausal women) accounts for 50% to 60% of total clearance and is related to creatinine clearance. The difference between the apparent total and renal clearances likely reflects bone uptake of the drug.
Special Populations: Children:
The pharmacokinetics of Ibandronate has not been studied in patients <18 years.
The pharmacokinetics of lbandronate is similar in both men and women.
Since Ibandronate is not known to be metabolized, the only difference in Ibandronate elimination for geriatric patients versus younger patients is expected to relate to progressive age-related changes in renal function (see Special Populations: Renal Impairment).
Pharmacokinetic differences due to race have not been studied.
Renal clearance of Ibandronate in patients with various degrees of renal impairment is linearly related to creatinine clearance (CrCl).
Following a single dose of Ibandronate 0.5 mg by IV administration, patients with CrCl 40-70 mL/min had 55% higher exposure (AUC∞
) than the exposure observed in subjects with CrCl >90 mL/min. Patients with CrCl <30 mL/min had more than a 2-fold increase in exposure compared to the exposure for healthy subjects (see Renal Impairment under Dosage & Administration).
No studies have been performed to assess the pharmacokinetics of Ibandronate in patients with hepatic impairment since lbandronate is not metabolized in the human liver.
Ibandronate does not undergo hepatic metabolism and does not inhibit the hepatic cytochrome P450 system. Ibandronate is eliminated by renal excretion. Based on a rat study, the Ibandronate secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other drugs.
A pharmacokinetic interaction study in multiple myeloma patients demonstrated that IV melphalan (10 mg/m2
) and oral prednisolone (60 mg/m2
) did not interact with Ibandronate 6 mg upon IV co-administration. Ibandronate did not interact with melphalan or prednisolone.
A pharmacokinetic interaction study in healthy postmenopausal women demonstrated that there was no interaction between oral tamoxifen 30 mg and IV Ibandronate 2 mg.