Ying Zhou1, Xiaomeng He1, Huqun Li1, Yang Ni1, Mingzhen Xu1, Haseeb Sattar1, Hui Chen2, Weiyong Li3. 1. Institute of Clinic Pharmacy, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. 2. Department of Infectious Disease, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. 3. Institute of Clinic Pharmacy, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. Electronic address: wenzhang_sci@163.com.
Abstract
PURPOSE:Minodronic acid is a third-generation bisphosphonate being developed for the treatment of osteoporosis. The aim of this study was to evaluate the pharmacokinetic profiles and tolerability of minodronic acid in healthy subjects, as well as to assess the effects of food and age on the pharmacokinetics. METHODS: This single-center, open-label, Phase I study was conducted in 4 parts. In part 1, minodronic acid tablets were administered to young volunteers at doses of 1, 2, and 4 mg. In part 2, after a single dose, young volunteers in the 1-mg dose group received repeated oral doses of minodronic acid once daily for 7 days. In part 3, a single oral dose of minodronic acid 1 mg was administered to elderly volunteers. In part 4, after a washout period of 8 days, volunteers in the 4-mg group received a single dose of 4-mg minodronic acid under fed conditions (administrated 30 minutes before a high-fat breakfast). Plasma samples were collected, and plasma concentrations of minodronic acid were analyzed by using a LC-MS/MS method. Tolerability was assessed throughout the study by physical examinations, measurement of vital signs, laboratory analyses, and monitoring of adverse events. FINDINGS:Thirty-six young volunteers (mean age, 22.1 years; mean weight, 58.6 kg) and 12 elderly volunteers (mean age, 62.3 years; mean weight, 62.4 kg) were enrolled in the study. After single doses of 1, 2, and 4 mg of minodronic acid, the dose-normalized AUC exhibited dose linearity over the range of 1 to 4 mg in the young subjects. The plasma concentration of minodronic acid reached a steady state on day 7 after oral administration once daily for 7 days, with a mean accumulation ratio of 1.3. After a single dose of minodronic acid 1 mg, plasma Cmax and AUC0-∞ were both 1.8-fold higher compared with those of the young subjects. In the 4-mg dose group, minodronic acid Cmax and AUC0-∞ were reduced by 55% and 72%, respectively, with a high-fat breakfast compared with fasted conditions. No clinically meaningful changes in vital signs, laboratory values, or ECGs were observed. IMPLICATIONS: Single dosing of minodronic acid exhibited linear pharmacokinetics over the range of 1 to 4 mg; there was no accumulation after repeated administration. Food, especially high-fat food, reduced the bioavailability of minodronic acid. In addition, the exposure of the drug was increased with age. Minodronic acid seemed to be well tolerated throughout the study. ClinicalTrials.gov Identifier: NCT02295436.
RCT Entities:
PURPOSE:Minodronic acid is a third-generation bisphosphonate being developed for the treatment of osteoporosis. The aim of this study was to evaluate the pharmacokinetic profiles and tolerability of minodronic acid in healthy subjects, as well as to assess the effects of food and age on the pharmacokinetics. METHODS: This single-center, open-label, Phase I study was conducted in 4 parts. In part 1, minodronic acid tablets were administered to young volunteers at doses of 1, 2, and 4 mg. In part 2, after a single dose, young volunteers in the 1-mg dose group received repeated oral doses of minodronic acid once daily for 7 days. In part 3, a single oral dose of minodronic acid 1 mg was administered to elderly volunteers. In part 4, after a washout period of 8 days, volunteers in the 4-mg group received a single dose of 4-mg minodronic acid under fed conditions (administrated 30 minutes before a high-fat breakfast). Plasma samples were collected, and plasma concentrations of minodronic acid were analyzed by using a LC-MS/MS method. Tolerability was assessed throughout the study by physical examinations, measurement of vital signs, laboratory analyses, and monitoring of adverse events. FINDINGS: Thirty-six young volunteers (mean age, 22.1 years; mean weight, 58.6 kg) and 12 elderly volunteers (mean age, 62.3 years; mean weight, 62.4 kg) were enrolled in the study. After single doses of 1, 2, and 4 mg of minodronic acid, the dose-normalized AUC exhibited dose linearity over the range of 1 to 4 mg in the young subjects. The plasma concentration of minodronic acid reached a steady state on day 7 after oral administration once daily for 7 days, with a mean accumulation ratio of 1.3. After a single dose of minodronic acid 1 mg, plasma Cmax and AUC0-∞ were both 1.8-fold higher compared with those of the young subjects. In the 4-mg dose group, minodronic acid Cmax and AUC0-∞ were reduced by 55% and 72%, respectively, with a high-fat breakfast compared with fasted conditions. No clinically meaningful changes in vital signs, laboratory values, or ECGs were observed. IMPLICATIONS: Single dosing of minodronic acid exhibited linear pharmacokinetics over the range of 1 to 4 mg; there was no accumulation after repeated administration. Food, especially high-fat food, reduced the bioavailability of minodronic acid. In addition, the exposure of the drug was increased with age. Minodronic acid seemed to be well tolerated throughout the study. ClinicalTrials.gov Identifier: NCT02295436.