Agarwal Anju, Asif Muhammad, Deshmukh Rajeev, Vinchurkar Mohini, Singana Suresh B, Bhondave Pratik
ADVANZ PHARMA, Capital House, 85 King William Street, London, EC4N 7BL, United Kingdom.
Toxicol Res (Camb). 2022 Aug 13;11(5):743-749. doi: 10.1093/toxres/tfac047. eCollection 2022 Oct.
Following the introduction of new stability-indicating related substances methods, an unknown impurity was observed in levothyroxine (LeMI) and liothyronine (LiMI) tablets (ADVANZ PHARMA) in concentrations ≥1.0%, from 6 months of storage onwards. The impurity was identified as a Maillard condensation product between lactose and LeMI/LiMI in the LeMI and LiMI tablets, respectively.
To establish the toxicity profile of LeMI and LiMI in humans and to define appropriate shelf-life specification limits, a comprehensive nonclinical toxicological assessment was performed, including (Leadscope and Derek Nexus analyses), (Ames test), and tests (7-day dose range finding and 90-day dose repeat studies in rats). analyses indicated that potential LeMI and LiMI structures should not be considered bacterial mutagens or / clastogens, and that at the low oral exposure levels expected, the impurities are unlikely to cause harm.
testing showed that neither LeMI nor LiMI were cytotoxic or mutagenic at up to 5000 μg/plate, both in the presence and absence of metabolic activation. The 2 studies further confirmed that no systemic toxicity or other notable negative effects were evident at up to 200 μg/kg/day for LeMI and 45 μg/kg/day for LiMI, the highest doses tested. These doses represent 120-122 times the maximum daily exposures of LeMI and LiMI, based on body surface area (μg/m).
Based on these results, a proposal has been formulated to increase the limits of Maillard condensation products to ≤8.0% for LeMI and ≤6.0% for LiMI at shelf life.
在引入新的稳定性指示相关物质方法后，从储存6个月起，在左甲状腺素（LeMI）和三碘甲状腺原氨酸（LiMI）片剂（ADVANZ PHARMA）中观察到浓度≥1.0%的未知杂质。该杂质分别被鉴定为LeMI和LiMI片剂中乳糖与LeMI/LiMI之间的美拉德缩合产物。
为确定LeMI和LiMI在人体中的毒性特征并确定合适的保质期规格限度，进行了全面的非临床毒理学评估，包括（Leadscope和Derek Nexus分析）、（艾姆斯试验）和试验（大鼠7天剂量范围查找和90天剂量重复研究）。分析表明，潜在的LeMI和LiMI结构不应被视为细菌诱变剂或/断裂剂，并且在预期的低口服暴露水平下，这些杂质不太可能造成危害。
试验表明，在有和没有代谢活化的情况下，LeMI和LiMI在高达5000μg/平板时均无细胞毒性或诱变性。两项研究进一步证实，在高达200μg/kg/天的LeMI和45μg/kg/天的LiMI（测试的最高剂量）下，没有明显的全身毒性或其他显著的负面影响。根据体表面积（μg/m），这些剂量分别是LeMI和LiMI最大每日暴露量的120 - 122倍。
基于这些结果，已制定一项提议，将保质期时美拉德缩合产物的限度提高到LeMI≤8.0%，LiMI≤6.0%。
