Yannovits N, Zintzaras E, Pouli A, Koukoulis G, Lyberi S, Savari E, Potamianos S, Triposkiadis F, Stefanidis I, Zartaloudis E, Benakis A
Skylab-Med Laboratories, Halandri, Athens, Greece.
Eur J Drug Metab Pharmacokinet. 2006 Apr-Jun;31(2):73-8. doi: 10.1007/BF03191122.
Probably for genetic reasons a substantial part of the Greek population requires Levothyroxine treatment. Since commercially available Levothyroxine was first marketed, the manufacture and storage of the drug in tablet form has been complicated and difficult; and as cases of therapeutic failure have frequently been reported following treatment with this medicinal agent, quality control is an essential factor. Due to the unreliability of Levothyroxine-based commercial products, in the present study we decided to follow the Food and Drug Administration (FDA) guidelines*, and use a Levothyroxine solution as reference product. The bioavailability of the Levothyroxine sodium tablet formulation THYROHORMONE/Ni-The Ltd (0.2 mg/tab) and that of a reference oral solution (0.3 mg/100 ml) under fasting conditions were compared in an open, randomized, single-dose two-way crossover study. Twenty four healthy Caucasian volunteers (M/F=15/9, mean age=32.9+/-7.4yr) participated in the study. Bioavailability was assessed by pharmacokinetic parameters such as the area under plasma concentration-time curve from time zero up to the measurable last time point (AUC(last)) and the maximum plasma concentration (Cmax). Heparinized venous blood samples were collected pre-dose and up to a 48-hour period post-dose. Levothyroxine sodium in plasma samples was assayed by a validated electrochemiluninescent immunoassay technique. Statistical analysis showed that the post-dose thyrotropin-stimulating hormone (TSH) levels decreased significantly (p<0.05). Regarding Levothyroxine (T4), the point estimate of the test formulation to the reference formulation ratios (T/R) for AUC(last) and Cmax was 0.92 with 90% confidence limits (0.90, 0.94) and 0.93 with 90% confidence limits (0.91, 0.94), respectively. Regarding triiodo-L-thyronine (T3), the point estimate for the T/R ratios of AUC(last) and Cmax was 0.92 with 90% confidence limits (0.90, 0.95) and 0.94 with 90% confidence limits (0.92, 0.95), respectively. The 90% confidence limits for the pharmacokinetic parameters AUC(last) and Cmax lie within the acceptance limits for bioequivalence (0.80, 1.25), for both T3 and T4.
可能由于遗传原因，希腊相当一部分人口需要左甲状腺素治疗。自从市售左甲状腺素首次上市以来，该药物片剂形式的生产和储存一直复杂且困难；而且由于使用这种药物治疗后经常有治疗失败的病例报告，质量控制是一个关键因素。由于基于左甲状腺素的商业产品不可靠，在本研究中我们决定遵循美国食品药品监督管理局（FDA）的指导原则*，并使用左甲状腺素溶液作为参比制剂。在一项开放、随机、单剂量双向交叉研究中，比较了甲状腺激素/Ni-The有限公司（0.2mg/片）的左甲状腺素钠片制剂和一种参比口服溶液（0.3mg/100ml）在禁食条件下的生物利用度。24名健康的白种人志愿者（男/女=15/9，平均年龄=32.9±7.4岁）参与了该研究。通过药代动力学参数如从零时间到可测量的最后时间点的血浆浓度-时间曲线下面积（AUC（last））和最大血浆浓度（Cmax）来评估生物利用度。在给药前和给药后长达48小时内采集肝素化静脉血样。血浆样本中的左甲状腺素钠通过经过验证的电化学发光免疫分析技术进行测定。统计分析表明，给药后促甲状腺激素（TSH）水平显著下降（p<0.05）。关于左甲状腺素（T4），受试制剂与参比制剂的AUC（last）和Cmax比值（T/R）的点估计分别为0.92，90%置信区间为（0.90，0.94）和0.93，90%置信区间为（0.91，0.94）。关于三碘-L-甲状腺原氨酸（T3），AUC（last）和Cmax的T/R比值的点估计分别为0.92，90%置信区间为（0.90，0.95）和0.94，90%置信区间为（0.92，0.95）。对于T3和T4，药代动力学参数AUC（last）和Cmax的90%置信区间均在生物等效性的接受限度（0.80，1.25）内。
