McKeand William
Pfizer Inc, Collegeville, Pennsylvania.
Clin Ther. 2017 Sep;39(9):1769-1779. doi: 10.1016/j.clinthera.2017.07.012. Epub 2017 Jul 26.
Bazedoxifene is a selective estrogen receptor modulator that has estrogen agonist effects on bone and lipid metabolism while having neutral or estrogen antagonist effects on the breast and endometrium. The present report describes findings from 3 Phase I clinical studies that evaluated the single-dose pharmacokinetics (study 1; n = 84), multiple-dose pharmacokinetics (study 2; n = 23), and absolute bioavailability (study 3; n = 18) of bazedoxifene.
All 3 studies enrolled healthy postmenopausal women who were either naturally postmenopausal or had undergone bilateral oophorectomy at least 6 months before the start of the study.
Study 1 showed that unconjugated and total (unconjugated and conjugated) bazedoxifene levels increased proportionally with ascending oral doses of bazedoxifene (through the dose range of 5-120 mg). Evaluation with or without food intake was conducted at the 10-mg dose, with no clinically relevant effect on pharmacokinetic parameters. Study 2 showed that bazedoxifene achieved steady state in 1 week and exhibited linear pharmacokinetics in doses of 5 to 40 mg with no unexpected accumulation over the dose range. In accordance with a linear pharmacokinetic profile, mean maximum plasma concentration values increased with increasing dose, with values of 1.6, 6.2, and 12.5 ng/mL for the 5-, 20-, and 40-mg doses, respectively. In study 3, tablet and capsule formulations of bazedoxifene formulations had an estimated oral bioavailability of ~6%. The clearance of bazedoxifene was 0.4 (0.1) L/h/kg based on intravenous administration. The oral formulations had comparable exposure profiles with respect to AUC and AUC0-t, and the 90% CIs for these values were within the bioequivalence limits of 80% to 125%. Bazedoxifene was safe and well tolerated in all 3 studies.
These pharmacokinetic evaluations in healthy postmenopausal women found that bazedoxifene displayed linear pharmacokinetics with doses ranging from 5 to 40 mg, with no unexpected accumulation. Food did not seem to have any clinically relevant impact on pharmacokinetic parameters. Bazedoxifene had an estimated oral bioavailability of ~6% and was safe and well tolerated in the range of doses evaluated.
巴多昔芬是一种选择性雌激素受体调节剂，对骨骼和脂质代谢具有雌激素激动剂作用，而对乳腺和子宫内膜具有中性或雌激素拮抗剂作用。本报告描述了3项I期临床研究的结果，这些研究评估了巴多昔芬的单剂量药代动力学（研究1；n = 84）、多剂量药代动力学（研究2；n = 23）和绝对生物利用度（研究3；n = 18）。
所有3项研究均纳入了健康的绝经后女性，她们要么是自然绝经，要么在研究开始前至少6个月接受了双侧卵巢切除术。
研究1表明，未结合型和总（未结合型和结合型）巴多昔芬水平随巴多昔芬口服剂量的增加而成比例增加（剂量范围为5 - 120 mg）。在10 mg剂量下进行了有无食物摄入的评估，对药代动力学参数无临床相关影响。研究2表明，巴多昔芬在1周内达到稳态，在5至40 mg剂量下表现出线性药代动力学，在该剂量范围内无意外蓄积。根据线性药代动力学特征，平均最大血浆浓度值随剂量增加而升高，5 mg、20 mg和40 mg剂量的平均最大血浆浓度值分别为1.6 ng/mL、6.2 ng/mL和12.5 ng/mL。在研究3中，巴多昔芬片剂和胶囊制剂的口服生物利用度估计约为6%。基于静脉给药，巴多昔芬的清除率为0.4（0.1）L/h/kg。口服制剂在AUC和AUC0 - t方面具有可比的暴露特征，这些值的90%置信区间在生物等效性限度80%至125%之内。在所有3项研究中，巴多昔芬均安全且耐受性良好。
这些对健康绝经后女性的药代动力学评估发现，巴多昔芬在5至40 mg剂量范围内表现出线性药代动力学，无意外蓄积。食物似乎对药代动力学参数无任何临床相关影响。巴多昔芬的口服生物利用度估计约为6%，在评估的剂量范围内安全且耐受性良好。
