Clinical trial of risedronate in Japanese volunteers: a study on the effects of timing of dosing on absorption

Abstract

Because of its chemical structure, risedronate was thought to form a complex with divalent cations, e.g., Ca(2+), and to be likely to show changes in the efficiency of absorbance from the gastrointestinal tract according to the presence of food. Therefore, we conducted a crossover study using healthy Japanese adults to examine the effects of food intake on absorption after the oral administration of risedronate and to choose the best timing of regimen for risedronate. Using single doses of 5 mg risedronate, the following four dose times were investigated: (a) in the morning under a fasting condition without breakfast; (b) 30 min before breakfast; (c) 30 min after breakfast; and (d) 3 h after breakfast. The results showed that the C(max) and AUC(0-24) of the plasma risedronate concentrations and its cumulative urinary excretions decreased in the following order: fasting without breakfast >>30 min before breakfast >>3 h after breakfast >>30 min after breakfast. In other words, it was demonstrated that the absorption of risedronate decreases due to the effects of food. Several adverse events, whose causality with risedronate was unknown or possibly related, were observed, including headaches, diarrhea, increased CK-BB, and an increased urinary Beta(2)-microglobulin excretion rate, but none of these events was clinically significant, and none differed in frequency or severity from the events after a single oral administration. In consideration of the optimal practical timings required to administer risedronate for Japanese patients, therefore, it was found that ingesting the drug immediately after waking up in the morning, when the stomach is empty, was optimal, and that it was necessary to refrain from eating and drinking for at least 30 min after drug ingestion. Therefore, we determined that the optimal time for risedronate to be administered in Japanese patients is 30 min before breakfast.

In Vitro Dissolution/Permeation System to Predict the Oral Absorption of Poorly Water-Soluble Drugs: Effect of Food and Dose Strength on It

“…The oral drug absorption under the fed state can be more or less than that under the fasted state, which are often called positive and negative food effects, respectively. [5][6][7][8] Fleisher et al stated that drugs classified into class I, class II and class III using the biopharmaceutics classification system (BCS) are likely to be not affected by food, be positively affected by food and be negatively affected by food, respectively, while the effects are unclear for class IV drugs. …”

“…The oral drug absorption under the fed state can be more or less than that under the fasted state, which are often called positive and negative food effects, respectively. [5][6][7][8] Fleisher et al stated that drugs classified into class I, class II and class III using the biopharmaceutics classification system (BCS) are likely to be not affected by food, be positively affected by food and be negatively affected by food, respectively, while the effects are unclear for class IV drugs. 9) As the main cause of the positive food effect, it is considered that the ingestion of food stimulates the secretion of bile juice into the gastrointestinal tract, which accelerates the solubility and dissolution of poorly water-soluble drugs and then enhances oral absorption.…”

The Effects of Low-Dose Bisphosphonate Treatment on Bone Mineral Density and Bone Turnover Markers in Elderly Patients With Osteoporosis

“…Recently, some studies reported that a low dose of bisphosphonates can be as effective as higher doses, particularly in Asians when compared with Caucasians 25) . Gertz et al 26) reported that the cumulative urinary clearance rate of a 10-mg dose of alendronate was 0.4% in Caucasian women, which was similar to the values in Korean (0.48%) and Japanese (0.43%) women who were administered half the dose (5 mg) of alendronate 27,28) .…”

Higher Efficacy of Urinary Bone Resorption Marker Measurements in Assessing Response to Treatment for Osteoporosis in Postmenopausal Women

“…Osteoporosis in Japanese women may be adequately treated with smaller risedronate doses than those used to treat Caucasian women . This difference in the effectiveness of risedronate treatment between two ethnicities may be due to differences in the pharmacokinetics of risedronate (Ogura et al 2004) and/or genetic factors (Eisman 1999).…”

“…The maximum plasma concentration and the area under the plasma concentration-time curve up to 24 hr after oral administration of risedronate were previously reported to be 2-3-fold higher in Japanese subjects than in Caucasian subjects (Ogura et al 2004). Therefore, the recommended dosage of risedronate is 2.5 mg for Japanese, compared with 5.0 mg for Caucasians.…”