Genentech Research and Early Development, South San Francisco, California 94080, USA.
Pharm Res. 2012 Sep;29(9):2354-66. doi: 10.1007/s11095-012-0800-y. Epub 2012 Jun 28.
Antibody drug conjugates (ADCs) are a class of therapeutics that combine the target specificity of an antibody with the potency of a chemotherapeutic. This therapeutic strategy can significantly expand the therapeutic index of a chemotherapeutic by minimizing the systemic exposure and associated toxicity of the chemotherapeutic agent, while simultaneously maximizing the delivery of the chemotherapeutic to the target. The abundance of antibody targets, coupled with advances in antibody engineering, conjugation chemistry, and examples of early clinical success, have stimulated interest in developing ADCs. However, developing and optimizing the highly complex components of ADCs remain challenging. Understanding the pharmacokinetics (PK) and consequently the pharmacokinetic-pharmacodynamic (PKPD) properties of ADCs is critical for their successful development. This review discusses the PK properties of ADCs, with a focus on ADC-specific characteristics, including molecular heterogeneity, in vivo processing, and the implications of multiple analytes. The disposition of ADCs and the utility of PKPD modeling are discussed in the context of providing guidance to assist in the successful development of these complex molecules.
抗体药物偶联物 (ADC) 是一类治疗药物，它将抗体的靶向特异性与化疗药物的效力结合在一起。这种治疗策略可以通过最小化化疗药物的全身暴露和相关毒性，同时最大限度地将化疗药物递送到靶标，显著扩大化疗药物的治疗指数。抗体靶标的丰富性，加上抗体工程、缀合化学和早期临床成功的例子的进步，激发了人们开发 ADC 的兴趣。然而，开发和优化 ADC 的高度复杂成分仍然具有挑战性。了解抗体药物偶联物的药代动力学 (PK)，进而了解药代动力学-药效动力学 (PKPD) 特性，对于它们的成功开发至关重要。本文讨论了 ADC 的 PK 特性，重点讨论了 ADC 的特异性特征，包括分子异质性、体内处理以及多个分析物的影响。还讨论了 ADC 的处置和 PKPD 建模的实用性，以提供指导，帮助成功开发这些复杂分子。
