The action of ibandronate on bone 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.
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 (ibandronate) every 3 months and ibandronate sodium 2.5 mg (ibandronate) 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 intent-to-treat population reached a nadir of 57% (ibandronate sodium injection) and 62% (ibandronate sodium 2.5 mg (ibandronate) tablets) below baseline values by Month 6, and remained stable at Month 12 of treatment.
Area under the serum ibandronate concentrations versus time curve increases in a dose proportional manner after administration of 2 mg to 6 mg ibandronate by intravenous 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. In one study, in vitro 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 intravenous bolus administration).
There is no evidence that ibandronate is metabolized in humans. Ibandronate does not inhibit human P450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 isozymes in vitro.
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.
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 intravenous 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 hours after intravenous 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 intravenous 2 and 4 mg ibandronate after 2 hours of infusion ranges from 4.6 to 15.3 hours and 5 to 25.5 hours, 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.
Pharmacokinetics in Specific Populations
The pharmacokinetics of ibandronate have not been studied in patients less than 18 years of age.
The pharmacokinetics of ibandronate are 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 Use in Specific Populations (8.5) ] .
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 (CLcr).
Following a single dose of 0.5 mg ibandronate by intravenous administration, patients with creatinine clearance 40 to 70 mL/min had 55% higher exposure (AUC 8 ) than the exposure observed in patients with creatinine clearance higher than 90 mL/min. Patients with severe renal impairment (creatinine clearance below 30 mL/min) had more than a two-fold increase in exposure compared to the exposure for patients with creatinine clearance equal to or higher than 80 mL/min [see Dosage and Administration (2.6) and Use in Specific Populations (8.6) ] .
No studies have been performed to assess the pharmacokinetics of ibandronate in patients with hepatic impairment since ibandronate is not metabolized in the human liver.
A pharmacokinetic interaction study in multiple myeloma patients demonstrated that intravenous melphalan (10 mg/m 2 ) and oral prednisolone (60 mg/m 2 ) did not interact with 6 mg ibandronate upon intravenous coadministration. Ibandronate did not interact with melphalan or prednisolone.
A pharmacokinetic interaction study in healthy postmenopausal women demonstrated that there was no interaction between oral 30 mg tamoxifen and intravenous 2 mg ibandronate.
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