两种齐多夫定制剂在巴西健康志愿者中的生物等效性和药代动力学：一项开放标签、随机、单剂量、双向交叉研究。

Bioequivalence and pharmacokinetics of two zidovudine formulations in healthy Brazilian volunteers: an open-label, randomized, single-dose, two-way crossover study.

作者信息

Dos Reis Serra Cristina Helena, Mori Koono Eunice Emiko, Kano Eunice Kazue, Schramm Simone Grigoleto, Armando Yara Popst, Porta Valentina

机构信息

Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, Brazil.

出版信息

Clin Ther. 2008 May;30(5):902-8. doi: 10.1016/j.clinthera.2008.05.003.

DOI:10.1016/j.clinthera.2008.05.003

PMID:18555936

Abstract

BACKGROUND

Zidovudine is a thymidine nucleoside reverse transcriptase inhibitor with activity against HIV type 1. Some (approximately 8) generic formulations of zidovudine are available in Brazil; however, based on a literature search, information concerning their bioavailability and pharmacokinetic properties in the Brazilian population has not been reported.

OBJECTIVE

The aim of this study was to compare the bioavailability and pharmacokinetic properties of 2 capsule formulations of zidovudine 100 mg in healthy Brazilian volunteers.

METHODS

This open-label, randomized, 2-way crossover study utilized a 1-week washout period between doses. Blood samples were collected for 8 hours after a single dose of zidovudine 100-mg test (Zidovudina, Fundação para o Remédio Popular, São Paulo, Brazil) or reference formulation (Retrovir, GlaxoSmithKline, Philadelphia, Pennsylvania). Plasma zidovudine concentrations were determined using a validated high-performance liquid chromatography method with ultraviolet detection at 265 nm. C(max), T(max), AUC(0-t), AUC(0-infinity), t(1/2), and the elimination constant (k(e)) were determined using noncompartmental analysis. The formulations were considered bioequivalent if the 90% CIs for C(max), AUC(0-t), and AUC(0-infinity) fell within the interval of 80% to 125%,the regulatory definition set by the US Food and Drug Administration (FDA).

RESULTS

Twenty-four healthy volunteers (12 males, 12 females; mean age, 27 years; weight, 60 kg; height, 167 cm) were enrolled and completed the study. The 90% CIs of the treatment ratios for the logarithmic transformed values of C(max), AUC(max)0-t, and AUC(0-infinity) were 80.0% to 113.6%, 93.9% to 109.7%, and 93.6% to 110.1%, respectively. The values for the test and reference formulations were within the FDA bioequivalence definition intervals of 80% to 125%.

CONCLUSIONS

In this small study in healthy subjects, no statistically significant differences in C(max), AUC(0-t), and AUC(0-infinity) were found between the test and reference formulations of zidovudine 100-mg capsules. The 90% CIs for the mean ratio values for the test and reference formulations of AUC(0-t), AUC(0-infinity), and C(max) indicated that the reported data were entirely within the bioequivalence acceptance range proposed by the FDA of 80% to 125% (using log-transformed data).

摘要

背景

齐多夫定是一种胸腺嘧啶核苷逆转录酶抑制剂，对1型人类免疫缺陷病毒（HIV-1）具有活性。在巴西有大约8种齐多夫定的仿制药制剂；然而，根据文献检索，尚未有关于它们在巴西人群中的生物利用度和药代动力学特性的报道。

目的

本研究旨在比较100毫克齐多夫定两种胶囊制剂在健康巴西志愿者中的生物利用度和药代动力学特性。

方法

本开放标签、随机、双向交叉研究在剂量之间采用1周的洗脱期。在单次服用100毫克齐多夫定试验制剂（Zidovudina，巴西圣保罗大众药物基金会）或参比制剂（Retrovir，葛兰素史克公司，宾夕法尼亚州费城）后8小时采集血样。采用经过验证的高效液相色谱法，在265纳米处进行紫外检测，测定血浆齐多夫定浓度。使用非房室分析确定C(max)、T(max)、AUC(0 - t)、AUC(0 - ∞)、t(1/2)和消除常数(k(e))。如果C(max)、AUC(0 - t)和AUC(0 - ∞)的90%置信区间落在80%至125%的区间内（这是美国食品药品监督管理局（FDA）设定的监管定义），则认为这两种制剂具有生物等效性。

结果

24名健康志愿者（12名男性，12名女性；平均年龄27岁；体重60千克；身高167厘米）入组并完成了研究。C(max)、AUC(0 - t)和AUC(0 - ∞)对数转换值的治疗比值的90%置信区间分别为80.0%至113.6%、93.9%至109.7%和93.6%至110.1%。试验制剂和参比制剂的值均在FDA生物等效性定义的80%至125%区间内。

结论

在这项针对健康受试者的小型研究中，100毫克齐多夫定胶囊的试验制剂和参比制剂在C(max)、AUC(0 - t)和AUC(0 - ∞)方面未发现统计学上的显著差异。AUC(0 - t)、AUC(0 - ∞)和C(max)的试验制剂与参比制剂平均比值的90%置信区间表明，报告的数据完全在FDA提出的80%至125%生物等效性接受范围内（使用对数转换数据）。