Zhou Ying, He Xiaomeng, Li Huqun, Ni Yang, Xu Mingzhen, Sattar Haseeb, Chen Hui, Li Weiyong
Institute of Clinic Pharmacy, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Department of Infectious Disease, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Clin Ther. 2015 Apr 1;37(4):869-76. doi: 10.1016/j.clinthera.2015.01.015. Epub 2015 Mar 5.
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.
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.
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.
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.
米诺膦酸是一种正在研发用于治疗骨质疏松症的第三代双膦酸盐。本研究的目的是评估米诺膦酸在健康受试者中的药代动力学特征和耐受性，并评估食物和年龄对药代动力学的影响。
本单中心、开放标签的I期研究分4部分进行。在第1部分中，米诺膦酸片以1、2和4毫克的剂量给予年轻志愿者。在第2部分中，单次给药后，1毫克剂量组的年轻志愿者每天口服一次米诺膦酸，重复给药7天。在第3部分中，向老年志愿者单次口服1毫克米诺膦酸。在第4部分中，经过8天的洗脱期后，4毫克组的志愿者在进食条件下（在高脂早餐前30分钟给药）接受4毫克米诺膦酸的单次给药。采集血浆样本，采用液相色谱-串联质谱法分析米诺膦酸的血浆浓度。在整个研究过程中，通过体格检查、生命体征测量、实验室分析和不良事件监测来评估耐受性。
36名年轻志愿者（平均年龄22.1岁；平均体重58.6千克）和12名老年志愿者（平均年龄62.3岁；平均体重62.4千克）参与了本研究。年轻受试者单次给予1、2和4毫克米诺膦酸后，剂量标准化的AUC在1至4毫克范围内呈剂量线性关系。每天口服一次，连续7天，米诺膦酸的血浆浓度在第7天达到稳态，平均蓄积比为1.3。单次给予1毫克米诺膦酸后，血浆Cmax和AUC0-∞均比年轻受试者高1.8倍。在4毫克剂量组中，与禁食条件相比，高脂早餐后米诺膦酸的Cmax和AUC0-∞分别降低了55%和72%。未观察到生命体征、实验室值或心电图有临床意义的变化。
米诺膦酸单次给药在1至4毫克范围内呈现线性药代动力学；重复给药后无蓄积。食物，尤其是高脂食物，会降低米诺膦酸的生物利用度。此外，药物暴露量随年龄增加。在整个研究过程中，米诺膦酸似乎耐受性良好。ClinicalTrials.gov标识符：NCT02295436。
