Pharmacokinetics and Bioequivalence Study of Hydroxychloroquine Sulfate Tablets in Chinese Healthy Volunteers by LC-MS/MS
Pharmacokinetics and Bioequivalence Study of Hydroxychloroquine Sulfate Tablets in Chinese Healthy Volunteers by LC-MS/MS
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DOI：
10.1007/s40744-015-0012-0
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发表时间：
2015-12-01
影响因子：
3.8
通讯作者：
Li, Ying-bin
中科院分区：
文献类型：
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作者：
Fan, Hong-wei;Ma, Zhi-xiang;Li, Ying-bin
简介：羟氯喹（HCQ），4-氨基喹啉，是一种抗疟药，已成为治疗风湿病的基本疗法。通过其免疫抑制功能和抗炎作用，可以稳定SLE患者的病情，减少患者复发的机会。该药口服吸收完全、迅速，但消除半衰期较长。本研究的目的是评估新仿制药（试验）制剂与 HCQ 品牌（参比）制剂在健康中国男性志愿者中的药代动力学参数和相对生物等效性。本研究旨在获得监管机构对测试配方的批准。方法：本研究采用随机、单剂量、两阶段和交叉设计进行。男性受试者按 1:1 的比例随机分为两组，在 3 个月的洗脱期后分别接受两种制剂的 0.2 g 硫酸羟氯喹片剂（0.1 g/片），然后服用替代制剂。研究药物是在禁食过夜（超过 10 小时）后施用的。通过经过验证的 LC-MS/MS 方法测量羟氯喹的血浆浓度。以下药代动力学特性通过非房室药代动力学方法测定：C-max、T-max、AUC(0)-t、AUC(0-无穷大)和t(1/2)。使用方差分析方法根据以下参数评估受试品和参比产品之间的生物等效性：C-max、AUC0-60d 和 AUC(0-无穷大)。如果 AUC(0-t) 的 90% CI 在 SFDA 提出的统计区间的 80-125% 范围内且 C-max 在 70-143% 范围内，则认为两种制剂具有生物等效性。针对羟氯喹作为长半衰期药物的主要药代动力学特征，根据FDA确定了0-72 h的药代动力学参数。此外，还比较了0-60天和0-72小时的参数，以评估是否可以应用截断AUC方法来估计HCQ的相对生物利用度。通过监测生命体征和实验室测试以及询问受试者有关不良事件的情况来评估耐受性。结果：HCQ 的 Cmax 90% CI 为 103.8-142.3%； AUC0-60 为 100-114.2%，AUC(0-无穷大) 100-115.5%。两者均符合 SFDA 生物等效性指南的标准。相对生物利用度为109.5%（根据AUC0-60d）和110.7%（根据AUC(0-无穷大））。未观察到严重或意外的不良事件。结论：在本研究中，进行了药代动力学研究和结果，使得HCQ的受试制剂和参比制剂符合中国生物等效性标准。两种制剂在人群研究中均具有良好的耐受性。
Introduction: Hydroxychloroquine (HCQ), 4-aminoquinoline, is an antimalarial drug and has become a basic therapy for rheumatic disease treatment. It can stabilize the condition of SLE patients and reduce the chances of patient relapse through its immunosuppressive function and antiinflammatory effects. This drug was absorbed completely and rapidly by oral administration, but has a prolonged half-life for elimination. The objective of this study was to evaluate the pharmacokinetic parameters and relative bioequivalence of a new generic (test) formulation with the branded (reference) formulation of HCQ in healthy Chinese male volunteers. This study was designed to acquire regulatory approval for the test formulation.Methods: This study was conducted with a randomized, single-dose, two-period, and crossover design. The male subjects were randomly assigned to two groups at a 1: 1 ratio to receive 0.2 g hydroxychloroquine sulfate tablets (0.1 g/piece) of the two formulations after a 3-month washout period then administered the alternate formulation. Study drugs were administered after overnight fasting (over 10 h). Plasma concentrations of hydroxychloroquine were measured by a validated LC-MS/MS method. The following pharmacokinetic properties were determined by a noncompartmental pharmacokinetic method: C-max, T-max, AUC(0)-t, AUC(0-infinity), and t(1/2). The bioequivalence between the test and reference products was assessed based on the following parameters: C-max, AUC0-60d, and AUC(0-infinity) using the ANOVA method. If the 90% CI for AUC(0-t) was within 80-125% and for C-max was within 70-143% of the statistical interval proposed by the SFDA, the two formulations were assumed bioequivalent. Concerning the main pharmacokinetic charateristics of hydroxychloroquine, a long half-life drug, the pharmacokinetic parameters of 0-72 h were determined according to the FDA. Furthermore, a comparison was made between the parameters at 0-60 days and 0-72 h to evaluate whether a truncated AUC method can be applied to estimate the relative bioavailability of HCQ. Tolerability was assessed by monitoring vital signs and laboratory tests and by questioning subjects about adverse events.Results: The 90% CI of Cmax for HCQ is 103.8-142.3%; the AUC0-60 is 100-114.2% and AUC(0-infinity) 100-115.5%. Both met the criteria according to the SFDA's guidelines for bioequivalence. The relative bioavailability was 109.5% (according to AUC0-60d) and 110.7% (according to AUC(0-infinity)). No serious or unexpected adverse events were observed.Conclusions: In this study, the pharmacokinetic studies and results were conducted so that the test and reference formulations of HCQ met the Chinese criteria for assuming bioequivalence. Both formulations were well tolerated in the population studies.