使用单剂量和多剂量数据评估纳多洛尔两种片剂制剂的生物等效性：采用立体特异性和非立体特异性分析方法

Bioequivalence of two tablet formulations of nadolol using single and multiple dose data: assessment using stereospecific and nonstereospecific assays.

作者信息

Srinivas N R, Barr W H, Shyu W C, Mohandoss E, Chow S, Staggers J, Balan G, Belas F J, Blair I A, Barbhaiya R H

机构信息

Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.

出版信息

J Pharm Sci. 1996 Mar;85(3):299-303. doi: 10.1021/js950442m.

DOI:10.1021/js950442m

PMID:8699333

Abstract

Nadolol, a nonspecific beta-blocker, is a racemate composed of equal amounts of four stereoisomers, namely, SQ-12148, SQ-12149, SQ-12150, and SQ-12151. In an open-label, randomized, four-period crossover study, the pharmacokinetics of nadolol and its stereoisomers and the bioequivalence of two formulations of nadolol were assessed in 20 healthy male subjects following a single dose (80 mg) and multiple doses (80 mg; once daily for 7 days). A standard granulated tablet and direct compressed tablet formulations, each containing 80 mg of nadolol, with different in vitro dissolution profiles that met current USP requirements were used. The four treatments were single and multiple doses of granulated tablet, and single and multiple doses of compressed tablet. There was a 7 day washout period between successive treatments. All doses of nadolol were administered after an overnight fast. Serial blood samples were collected up to 72 h following the single dose and during multiple dose treatments, following day 6 and 7 doses. Validated high-performance liquid chromatographic assays were applied to measure nadolol and its stereoisomers in the study samples. Plasma concentration data were subjected to noncompartmental pharmacokinetic analysis. Both C(max) and AUC values were significantly greater for SQ-12150 when compared to other nadolol stereoisomers obtained after a single dose or at steady state. However, T(max) and T1/2 values were similar among the four isomers. The observed steady state AUC tau values for nadolol (2278-2331 ng h/ML) or its stereoisomers (550-874 ng h/ML) were significantly greater than those predicted from the single dose AUCinf values (nadolol, 1840-1845 ng h/ML; isomers, 450-713 ng h/ML). The intrasubject variability, computed from multiple dose data, was generally greater for the stereoisomers (17-40%) than for nadolol (10-32%). The two formulations were bioequivalent for nadolol (C(max) = 0.98 [84%, 117%]; AUCinf = 1.03 [93%, 116%]) and SQ-12150 (C(max) = 1.12 [89%, 122%]; AUCinf = 0.98 [82%, 119%]) after a single dose, and only for nadolol (C(max) = 1.07 [84%, 118%]; AUCinf = 1.02 [91%, 113%]) at steady state.

摘要

纳多洛尔是一种非选择性β受体阻滞剂，是一种由等量的四种立体异构体组成的外消旋体，即SQ - 12148、SQ - 12149、SQ - 12150和SQ - 12151。在一项开放标签、随机、四周期交叉研究中，对20名健康男性受试者单次给药（80mg）和多次给药（80mg；每日一次，共7天）后纳多洛尔及其立体异构体的药代动力学以及两种纳多洛尔制剂的生物等效性进行了评估。使用了标准颗粒片和直接压片制剂，每种制剂均含有80mg纳多洛尔，它们具有不同的体外溶出曲线，但均符合现行美国药典要求。四种治疗分别为单次和多次剂量的颗粒片，以及单次和多次剂量的压片。连续治疗之间有7天的洗脱期。所有剂量的纳多洛尔均在过夜禁食后给药。在单次给药后长达72小时以及多次给药治疗期间，在第6和第7剂给药后采集系列血样。采用经过验证的高效液相色谱法测定研究样本中的纳多洛尔及其立体异构体。血浆浓度数据进行非房室药代动力学分析。与单次给药后或稳态时获得的其他纳多洛尔立体异构体相比，SQ - 12150的C(max)和AUC值均显著更高。然而，四种异构体之间的T(max)和T1/2值相似。观察到的纳多洛尔（2278 - 2331 ng h/ML）或其立体异构体（550 - 874 ng h/ML）的稳态AUC tau值显著高于根据单次剂量AUCinf值预测的值（纳多洛尔，1840 - 1845 ng h/ML；异构体，450 - 713 ng h/ML）。根据多次给药数据计算得出的立体异构体的受试者内变异性（17 - 40%）通常大于纳多洛尔（10 - 32%）。两种制剂在单次给药后对于纳多洛尔（C(max)=0.98 [84%，117%]；AUCinf = 1.03 [93%，116%]）和SQ - 12150（C(max)=1.12 [89%，122%]；AUCinf = 0.98 [82%，119%]）具有生物等效性，而在稳态时仅对于纳多洛尔（C(max)=1.07 [84%，118%]；AUCinf = 1.02 [91%，113%]）具有生物等效性。