Ibonate Mechanism of Action

Therapeutic/Pharmacologic Class of Drug: Ibonate is a nitrogen containing bisphosphonate.
Pharmacology: Pharmacodynamics: The pharmacodynamic action of ibandronic acid is inhibition of bone resorption.
Ibandronic acid is a highly potent bisphosphonate belonging to the nitrogen containing group of bisphosphonates, which act on bone tissue and specifically inhibit osteoclast activity. It does not interfere with osteoclast recruitment. The selective action of ibandronic acid on bone tissue is based on the high affinity of this compound for hydroxyapatite, which represents the mineral matrix of the bone.
Ibandronic acid reduces bone resorption, with no direct effect on bone formation. In postmenopausal women, it reduces the elevated rate of bone turnover towards premenopausal levels, leading to a progressive net gain in bone mass.
Daily or intermittent administration of ibandronic acid results in reduced bone resorption as reflected in reduced levels of serum and urinary biochemical markers of bone turnover, increased BMD and a decreased incidence of fractures.
Pharmacokinetics: The pharmacological effects of ibandronic acid are not directly related to actual plasma concentrations. This was demonstrated by various studies in animals and in humans, in which equivalent efficacy of ibandronic acid was demonstrated following either daily or intermittent regimens, consisting of a drug-free interval of several weeks (at least 6 weeks in rats, at least 11 weeks in dogs, at least 30 days in monkeys, and at least 9.5 weeks in humans) provided the same total dose was administered over this period.
Absorption: The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administration and plasma concentrations increase in a dose-proportional manner up to 50 mg oral intake, with greater than dose-proportional increases seen above this dose. Maximum observed plasma concentration were reached within 0.5 to 2 hours (median 1 hour) in the fasted state and absolute bioavailability was about 0.6%. The extent of absorption is impaired when taken together with food or beverages (other plain water). Bioavailability is reduced by about 90% when ibandronic acid is administered with a standard breakfast in comparison with bioavailability seen in fasted subjects. There is no meaningful reduction in bioavailability provided ibandronic acid is taken 60 minutes before a meal.
Both bioavailability and BMD gains are reduced when food or beverage are taken less than 60 minutes after ibandronic acid.
Distribution: After initial systemic exposure, ibandronic acid 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 reaching the bone is estimated to be 40-50% of the circulating dose. Protein binding in human plasma is low (approximately 85% bound at therapeutic concentrations), and thus there is a low potential for drug-drug interaction due to displacement.
Metabolism: There is no evidence that ibandronic acid is metabolized in animals or humans.
Elimination: The absorbed fraction of ibandronic acid is removed from the circulation via bone absorption (40-50%) and the remainder is eliminated unchanged by the kidney. The unabsorbed fraction of ibandronic acid is eliminated unchanged in the feces. The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but the apparent terminal half-life is generally in the range of 10-72 hours. Early plasma levels fall quickly reaching 10% of peak values within 3 and 8 hours after intravenous or oral administration respectively.
Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min. Renal clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60% of total clearance and is related to creatinine clearance. The difference between the apparent total and renal clearances is considered to reflect the uptake by bone.
Phamacokinetics in Special Populations: Gender: Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.
Race: There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in ibandronic acid disposition. There are few data available on patients of African origin.
Patients with renal impairment: Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr).
No dosage adjustment is necessary for patients with mild or moderate renal impairment (CLcr  ml/min).
Patients with hepatic impairment: There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid which is not metabolized but is cleared by renal excretion and by uptake into bone. Therefore, dosage adjustment is not necessary in patients with hepatic impairment. Further, as protein binding of ibandronic acid is low (85%) at therapeutic concentrations, hypoproteinemia in severe liver disease is unlikely to lead to clinically significant increases in free plasma concentration.
Elderly: In a multivariate analysis age was not found to be an independent factor of any of the pharmacokinetic parameters studied. As renal function decreases with age, this is the only factor to take into consideration (see Patients with renal impairment, as mentioned in the previous text).
Children: There are no data on the use of Ibonate in patients less than 18 years old.