Yu Lawrence X, Straughn Arthur B, Faustino Patrick J, Yang Yongsheng, Parekh Ameeta, Ciavarella Anthony B, Asafu-Adjaye Ebenezer, Mehta Mehul U, Conner Dale P, Lesko Larry J, Hussain Ajaz S
Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, Maryland 20857, USA.
Mol Pharm. 2004 Sep-Oct;1(5):357-62. doi: 10.1021/mp0499407.
The purpose of this study is to test the hypothesis that rapidly dissolving immediate-release (IR) solid oral products containing a highly soluble and highly permeable drug [biopharmaceutical classification system (BCS) class I] are bioequivalent under fed conditions. Metoprolol and propranolol (BCS class I) as well as hydrochlorothiazide (BCS class III) were selected as model drugs. The relative bioavailability of two FDA approved (Orange Book AB rating) solid oral dosage forms of metoprolol and propranolol/hydrochlorothiazide (combination tablets) was evaluated in human volunteers under fed conditions using a two-way crossover design. Equal numbers of male and female volunteers were recruited, and racial and/or ethnic minorities were not excluded. The plasma concentrations of metoprolol, propranolol, and hydrochlorothiazide were determined using validated high-performance liquid chromatography (HPLC) methods. Eighteen subjects completed the metoprolol study while 17 subjects completed the propranolol/hydrochlorothiazide combination tablet study. In the metoprolol study, the 90% confidence intervals of Cmax and AUC(inf) were 98-118% and 92-115%, respectively. For propranolol, the 90% confidence intervals of Cmax and AUC(inf) were 91-121% and 89-117%, and for hydrochlorothiazide, the 90% confidence intervals for Cmax and AUC(inf) were 96-107% and 97-106%, respectively. These study results appear to support the hypothesis that rapidly dissolving IR solid oral products containing a BCS class I drug are likely to be bioequivalent under fed conditions. In addition, BCS class III drugs may have the potential to be bioequivalent under fed conditions.
含有高溶解性和高渗透性药物（生物药剂学分类系统（BCS）I类）的速溶即释（IR）固体口服制剂在进食条件下具有生物等效性。选择美托洛尔和普萘洛尔（BCS I类）以及氢氯噻嗪（BCS III类）作为模型药物。采用双向交叉设计，在进食条件下对两种经美国食品药品监督管理局（FDA）批准（橙皮书AB评级）的美托洛尔和普萘洛尔/氢氯噻嗪（复方片剂）固体口服剂型在人类志愿者中的相对生物利用度进行了评估。招募了数量相等的男性和女性志愿者，且未排除种族和/或少数族裔。使用经过验证的高效液相色谱（HPLC）方法测定美托洛尔、普萘洛尔和氢氯噻嗪的血浆浓度。18名受试者完成了美托洛尔研究，17名受试者完成了普萘洛尔/氢氯噻嗪复方片剂研究。在美托洛尔研究中，Cmax和AUC(inf)的90%置信区间分别为98 - 118%和92 - 115%。对于普萘洛尔，Cmax和AUC(inf)的90%置信区间为91 - 121%和89 - 117%，对于氢氯噻嗪，Cmax和AUC(inf)的90%置信区间分别为96 - 107%和97 - 106%。这些研究结果似乎支持了以下假设：含有BCS I类药物的速溶IR固体口服制剂在进食条件下可能具有生物等效性。此外，BCS III类药物在进食条件下可能具有生物等效性的潜力。
