Park Wan-Su, Park Gab-Jin, Han Seunghoon, Ban Sooho, Park Moon-Young, Kim San-Ho, Kim Seon-Myung, Kim Yong-Chul, Kim Hyung Sik, Shin Young G, Yim Dong-Seok
Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary's Hospital, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Korea.
PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul, Korea.
Cancer Chemother Pharmacol. 2017 Aug;80(2):363-369. doi: 10.1007/s00280-017-3373-y. Epub 2017 Jun 28.
AGM-130 is a cyclin-dependent kinase inhibitor that exhibits dose-dependent efficacy in xenograft mouse models. During preclinical pharmacokinetic (PK) studies, mice and rats showed comparable PK parameters while dogs showed unusually high clearance (CL), which has made human PK prediction challenging. To address this discrepancy, we performed a human microdosing PK and developed a mouse PK/PD model in order to guide the first-in-human studies.
A microdose of AGM-130 was given via intravenous injection to healthy subjects. Efficacy data obtained using MCF-7 breast cancer cells implanted in mice was analyzed using pre-existing tumor growth inhibition models. We simulated a human PK/PD profile with the PK parameters obtained from the microdose study and the PD parameters estimated from the xenograft PK/PD model.
The human CL of AGM-130 was 3.08 L/h/kg, which was comparable to CL in mice and rats. The time-courses of tumor growth in xenograft model was well described by a preexisting model. Our simulation indicated that the human doses needed for 50 and 90% inhibition of tumor growth were about 100 and 400 mg, respectively.
This is the first report of using microdose PK and xenograft PK/PD model to predict efficacious doses before the first-in-human trial in cancer patients. In addition, this work highlights the importance of integration of all of information in PK/PD analysis and illustrates how modeling and simulation can be used to add value in the early stages of drug development.
AGM - 130是一种细胞周期蛋白依赖性激酶抑制剂，在异种移植小鼠模型中表现出剂量依赖性疗效。在临床前药代动力学（PK）研究中，小鼠和大鼠显示出可比的PK参数，而犬类显示出异常高的清除率（CL），这使得预测人体PK具有挑战性。为了解决这一差异，我们进行了人体微剂量PK研究并建立了小鼠PK/PD模型，以指导首次人体研究。
对健康受试者静脉注射微剂量的AGM - 130。使用预先存在的肿瘤生长抑制模型分析了将MCF - 7乳腺癌细胞植入小鼠所获得的疗效数据。我们用从微剂量研究中获得的PK参数和从异种移植PK/PD模型估算的PD参数模拟了人体PK/PD曲线。
AGM - 130的人体CL为3.08 L/h/kg，与小鼠和大鼠的CL相当。预先存在的模型很好地描述了异种移植模型中肿瘤生长的时间进程。我们的模拟表明，抑制肿瘤生长50%和90%所需的人体剂量分别约为100和400毫克。
这是关于在癌症患者首次人体试验之前使用微剂量PK和异种移植PK/PD模型预测有效剂量的首次报告。此外，这项工作突出了在PK/PD分析中整合所有信息的重要性，并说明了如何在药物开发的早期阶段利用建模和模拟来增加价值。
