国产小分子化学创新药临床药物相互作用研究现状

为了提高疗效或减少毒副作用,临床上常采用两种或两种以上药物联合的用药策略,这往往带来因联合而改变某一药物体内过程或疗效的新的用药问题。本文综述了我国自2000年1月至2021年3月批准上市自主研制的44种小分子化学创新药开展临床药物相互作用的研究现状。其中,创新药物作为代谢酶底物的临床药物相互作用试验占据主导地位（11/44）,且以CYP3A4酶底物研究为主（7/11）,结果表明创新药物多为CYP3A4的中等及以下敏感程度的底物,未发现高敏感底物。其次是基于协同增效或降低副作用而联合用药的药物相互作用试验,主要集中于肿瘤、糖尿病、病毒感染等领域,这些研究中也未表现出具有临床意义的药动学相互作用。以创新药物作为代谢酶调节剂开展的临床药物相互作用试验比例为7/44;基于转运体的药物相互作用临床试验报道较少,该方面研究主要以体外试验为主。随着药物体内外代谢/转运机制的深入研究,特别是放射性同位素标记药物的临床试验的开展以及计算机模拟的辅助,我国药物相互作用研究的整体水平也在逐步提高,这将为保障用药安全提供坚实的科学基础。

Current status of clinical drug-drug interactions research of innovative small molecule drugs in China

In order to improve the efficacy or reduce the side effects, the combination of two or more drugs is often used in clinical practice, which often brings new medication problems that change the process or efficacy of a drug in vivo due to combination. This article reviews the clinical drug-drug interaction (DDI) researches of 44 novel molecular entities which were approved to be launched in China from January 2000 to March 2021. Among them, clinical DDI trials based on test drugs as substrates of the metabolic enzymes (11/44) especially as the substrates of CYP3A4 (7/11) are dominant. The results show that most of test drugs were CYP3A4 substrates with a moderate or lower sensitivity, and no highly sensitive substrates were found. The second is the clinical DDI trials based on synergy or reducing side effects, which mainly focus on the fields of tumors, diabetes, and viral infections, and these studies have not shown pharmacokinetic interactions with clinical significance. The DDI trials of test drugs as metabolic enzyme modulators account for 7/44. And transporter-based DDI trials are relatively rare and most of them are in vitro studies. With the in-depth study of drug metabolism/transport mechanisms in vivo and in vitro, especially the development of clinical trials of radioisotope-labeled drugs and computer simulations, the overall level of DDI research in China is gradually improving, which will provide a solid scientific foundation to ensure drug safety.