National University of Singapore, Department of Pharmacy, Faculty of Science, Singapore.
Fraunhofer-Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology, Frankfurt, Germany; Goethe University, Institute of Pharmaceutical Technology, Frankfurt, Germany.
Eur J Pharm Biopharm. 2020 Aug;153:257-272. doi: 10.1016/j.ejpb.2020.06.004. Epub 2020 Jun 24.
Over the years, a wide variety of nanomedicines has entered global markets, providing a blueprint for the emerging generics industry. They are characterized by a unique pharmacokinetic behavior difficult to explain with conventional methods. In the present approach a physiologically-based nanocarrier biopharmaceutics model has been developed. Providing a compartmental framework of the distribution and elimination of nanocarrier delivery systems, this model was applied to human clinical data of the drug products Doxil®, Myocet®, and AmBisome® as well as to the formulation prototypes Foslip® and NanoBB-1-Dox. A parameter optimization by differential evolution led to an accurate representation of the human data (AAFE < 2). For each formulation, separate half-lives for the carrier and the free drug as well as the drug release were calculated from the total drug concentration-time profile. In this context, a static in vitro set-up and the dynamic in vivo situation with a continuous infusion and accumulation of the carrier were simulated. For Doxil®, a total drug release ranging from 0.01 to 22.1% was determined. With the time of release exceeding the elimination time of the carrier, the major fraction was available for drug targeting. NanoBB-1-Dox released 76.2-77.8% of the drug into the plasma, leading to an accumulated fraction of approximately 20%. The mean residence time of encapsulated doxorubicin was 128 h for Doxil® and 0.784 h for NanoBB-1-Dox, giving the stealth liposomes more time to accumulate at the intended target site. For all other formulations, Myocet®, AmBisome®, and Foslip®, the major fraction of the dose was released into the blood plasma without being available for targeted delivery.
多年来，各种纳米药物已进入全球市场，为新兴仿制药行业提供了蓝图。它们具有独特的药代动力学行为，难以用传统方法解释。在本研究中，建立了一种基于生理学的纳米载体生物药剂学模型。该模型提供了纳米载体递药系统分布和消除的隔室框架，应用于多柔比星脂质体（Doxil®）、米托蒽醌脂质体（Myocet®）、两性霉素 B 脂质体（AmBisome®）药物产品的人体临床数据以及 Foslip®和 NanoBB-1-Dox 的制剂原型。通过微分进化进行参数优化，使模型能够准确地再现人体数据（AAFE<2）。对于每种制剂，从总药物浓度-时间曲线计算了载体和游离药物以及药物释放的单独半衰期。在此背景下，模拟了静态的体外设置和具有载体连续输注和积累的动态体内情况。对于 Doxil®，确定了 0.01%至 22.1%的总药物释放。由于释放时间超过载体消除时间，大部分药物可用于靶向药物。NanoBB-1-Dox 有 76.2%至 77.8%的药物释放到血浆中，导致累积分数约为 20%。Doxil®中封装的多柔比星的平均驻留时间为 128 小时，NanoBB-1-Dox 为 0.784 小时，使隐形脂质体有更多的时间在预期的靶部位积累。对于其他所有制剂，米托蒽醌脂质体（Myocet®）、两性霉素 B 脂质体（AmBisome®）和 Foslip®，大部分剂量的药物释放到血液中，无法用于靶向递送。
