Clinical trial of risedronate in Japanese volunteers: single and multiple oral dose studies

Abstract

The tolerability and pharmacokinetics of risedronate after a single oral administration and during multiple oral administrations were examined in healthy adult male volunteers. In the single dose study, the dose was increased gradually from 1 mg to 2.5, 5, 10, or 20 mg. Subsequently, risedronate was given by multiple administration, 5 mg per dosing, once daily, for 7 days. The observed adverse events, whose causality was possibly related or unknown, included headache, diarrhea, increased body temperature, increased CK-BB, and increased urinary Beta(2)-microglobulin excretion rate. However, none of these adverse events was clinically significant. The results thus showed that risedronate was well tolerated when delivered as a single administration of up to 20 mg or as a multiple administration of up to 5 mg/day. In the multiple dose study, changes in urinary deoxypyridinoline suggested the bone antiresorptive activity of risedronate. In the single dose study, AUC and C(max), after the administration of risedronate at 1, 2.5, 5, 10, and 20 mg, increased dose dependently, and the T(max), t(1/2), and urinary excretion rates were nearly constant. Therefore, the pharmacokinetic profile of risedronate was considered to show linearity in a dosage range of up to 20 mg. Furthermore, the results obtained in the multiple administration study indicated that the plasma concentrations of risedronate reached a steady state on day 4 of administration. The plasma concentrations of risedronate after the administration of 2.5 mg risedronate to the Japanese population were nearly comparable to the serum concentrations after the administration of 5 mg risedronate to the United Kingdom study population.

Comparison of treatment effects of teriparatide and the bisphosphonate risedronate in an aged, osteopenic, ovariectomized rat model under various clinical conditions

“…With respect to bisphosphonates, the dosing regimen of 3.0 μg/kg of risedronate (as determined in our dose-finding experiments) three times weekly for a total of 9 μg/kg weekly is similar to that used in previous studies involving rats (5 μg/kg two times weekly [19,22,23] or 3 μg/kg three times weekly [20,21]). Additionally, the results of previous AUC comparisons indicate that the risedronate dosing regimen in the present study is almost the same as the clinical weekly dose [37,38]. We therefore consider our dosing regimen (5.6 μg/kg of teriparatide and 3.0 μg/kg of risedronate administered subcutaneously three times weekly for 4 months) to be highly applicable to the clinical setting.…”

Induction of creatine kinase release from cultured osteoclasts via the pharmacological action of aminobisphosphonates

“…An increase in the serum CK level has been observed in clinical studies of N-BPs. The frequency of CK elevation was between 1% and less 5% in a trial of 5 mg alendronate (in Japanese package insert), while increases of CK-BB and CK-MB were found in single and multiple oral dose phase I studies of risedronate in Japanese healthy adult male subjects (Ogura et al 2004 ). Minodronic acid treatment at 1 mg has been found to elevate CK at a frequency of less 1% (in Japanese package insert).…”

Clinical Efficacy on Fracture Risk and Safety of 0.5 mg or 1 mg/month Intravenous Ibandronate Versus 2.5 mg/day Oral Risedronate in Patients with Primary Osteoporosis

“…Oral risedronate (2.5 or 5 mg daily) also significantly reduced the risk of new vertebral fracture by 46 and 65 %, respectively, compared with placebo in the VERT-NA (Vertebral Efficacy with Risedronate Therapy North America) study, and reduced the fracture risk by similar amounts in postmenopausal women with prevalent vertebral fractures in the VERT-MN (VERT-Multinational) study [14]. The plasma concentrations of risedronate attained while on treatment with 2.5 mg oral risedronate in Japanese subjects were almost comparable with those of 5 mg dosing in white subjects [15]. Furthermore, BMD increases at the lumbar spine and changes in bone turnover markers (BTMs) were comparable in Japanese subjects who received 2.5 mg/day risedronate and in white patients who received 5 mg/day risedronate [13, 16].…”