Pharmacokinetics and Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Rm. N525, 20 N. Pine St., Baltimore, MD, 21201, USA.
Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, University of Charleston, Charleston, WV, USA.
Clin Pharmacokinet. 2018 Jun;57(6):687-703. doi: 10.1007/s40262-017-0619-0.
Antibody-drug conjugates are an emerging class of biopharmaceuticals changing the landscape of targeted chemotherapy. These conjugates combine the target specificity of monoclonal antibodies with the anti-cancer activity of small-molecule therapeutics. Several antibody-drug conjugates have received approval for the treatment of various types of cancer including gemtuzumab ozogamicin (Mylotarg), brentuximab vedotin (Adcetris), trastuzumab emtansine (Kadcyla), and inotuzumab ozogamicin, which recently received approval (Besponsa). In addition to these approved therapies, there are many antibody-drug conjugates in the drug development pipeline and in clinical trials, although these fall outside the scope of this article. Understanding the pharmacokinetics and pharmacodynamics of antibody-drug conjugates and the development of pharmacokinetic/pharmacodynamic models is indispensable, albeit challenging as there are many parameters to incorporate including the disposition of the intact antibody-drug conjugate complex, the antibody, and the drug agents following their dissociation in the body. In this review, we discuss how antibody-drug conjugates progressed over time, the challenges in their development, and how our understanding of their pharmacokinetics/pharmacodynamics led to greater strides towards successful targeted therapy programs.
抗体药物偶联物是一类新兴的生物制药，正在改变靶向化疗的格局。这些偶联物将单克隆抗体的靶向特异性与小分子治疗药物的抗癌活性结合在一起。有几种抗体药物偶联物已被批准用于治疗各种类型的癌症，包括吉妥珠单抗奥佐米星（Mylotarg）、本妥昔单抗维达汀（Adcetris）、曲妥珠单抗恩美曲妥珠（Kadcyla）和伊妥珠单抗奥佐米星（Besponsa），后者最近获得批准。除了这些已批准的疗法外，还有许多抗体药物偶联物处于药物开发管道和临床试验中，尽管这些不在本文的讨论范围内。了解抗体药物偶联物的药代动力学和药效动力学以及开发药代动力学/药效动力学模型是必不可少的，尽管这具有挑战性，因为有许多参数需要纳入，包括完整抗体药物偶联物复合物、抗体和药物在体内解离后的处置。在这篇综述中，我们讨论了抗体药物偶联物是如何随着时间的推移而发展的，以及它们在开发过程中面临的挑战，以及我们对它们的药代动力学/药效动力学的理解如何使我们朝着成功的靶向治疗方案迈出了更大的步伐。
