Ryu Hyo-Jeong, Moon Hyun-Ki, Lee Junho, Yang Gi-Hyeok, Yang Sung-Yoon, Yun Hwi-Yeol, Chae Jung-Woo, Kang Won-Ho
Gwangkyo R&D Center, Medytox Inc., Suwon 16506, Korea.
College of Pharmacy, Chungnam National University, Daejeon 34134, Korea.
Pharmaceuticals (Basel). 2021 Jul 7;14(7):654. doi: 10.3390/ph14070654.
MT921 is a new injectable drug developed by Medytox Inc. to reduce submental fat. Cholic acid is the active pharmaceutical ingredient, a primary bile acid biosynthesized from cholesterol, endogenously produced by liver in humans and other mammals. Although individuals treated with MT921 could be administered with multiple medications, such as those for hypertension, diabetes, and hyperlipidemia, the pharmacokinetic drug-drug interaction (DDI) has not been investigated yet. Therefore, we studied in vitro against drug-metabolizing enzymes and transporters. Moreover, we predicted the potential DDI between MT921 and drugs for chronic diseases using physiologically-based pharmacokinetic (PBPK) modeling and simulation. The magnitude of DDI was found to be negligible in in vitro inhibition and induction of cytochrome P450s and UDP-glucuronosyltransferases. Organic anion transporting polypeptide (OATP)1B3, organic anion transporter (OAT)3, Na-taurocholate cotransporting polypeptide (NTCP), and apical sodium-dependent bile acid transporter (ASBT) are mainly involved in MT921 transport. Based on the result of in vitro experiments, the PBPK model of MT921 was developed and evaluated by clinical data. Furthermore, the PBPK model of amlodipine was developed and evaluated. PBPK DDI simulation results indicated that the pharmacokinetics of MT921 was not affected by the perpetrator drugs. In conclusion, MT921 could be administered without a DDI risk based on in vitro study and related in silico simulation. Further clinical studies are needed to validate this finding.
MT921是Medytox公司研发的一种新型注射用药物，用于减少颏下脂肪。胆酸是其活性药物成分，是一种由胆固醇生物合成的初级胆汁酸，由人类和其他哺乳动物的肝脏内源性产生。尽管接受MT921治疗的个体可能同时服用多种药物，如治疗高血压、糖尿病和高脂血症的药物，但尚未对其药代动力学药物-药物相互作用（DDI）进行研究。因此，我们针对药物代谢酶和转运体进行了体外研究。此外，我们使用基于生理的药代动力学（PBPK）建模和模拟预测了MT921与慢性疾病药物之间潜在的DDI。结果发现，在体外对细胞色素P450和尿苷二磷酸葡萄糖醛酸转移酶的抑制和诱导作用中，DDI的程度可忽略不计。有机阴离子转运多肽（OATP）1B3、有机阴离子转运体（OAT）3、牛磺胆酸钠共转运多肽（NTCP）和顶端钠依赖性胆汁酸转运体（ASBT）主要参与MT921的转运。基于体外实验结果，利用临床数据建立并评估了MT921的PBPK模型。此外，还建立并评估了氨氯地平的PBPK模型。PBPK DDI模拟结果表明，MT921的药代动力学不受肇事药物的影响。总之，基于体外研究和相关的计算机模拟，MT921可以在无DDI风险的情况下给药。需要进一步的临床研究来验证这一发现。
