Takeda Development Center Americas, Cambridge, Massachusetts, USA.
Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA.
J Clin Pharmacol. 2022 Dec;62 Suppl 2:S79-S94. doi: 10.1002/jcph.2141.
Recombinant adeno-associated virus (AAV) is currently the most widely used platform for in vivo gene therapy. Clinical pharmacology is a central field for AAV gene therapy, represented by the pillars of pharmacokinetics, pharmacodynamics/efficacy, and safety. In this review, we provide a comprehensive summary of clinical pharmacology considerations for recombinant AAV. The main topics covered are biodistribution and shedding, dose-exposure-response relationship, safety, immune and stress response, and clinical dose selection strategies. We highlight how the cumulative knowledge of AAV gene therapy could help with guiding clinical trial design and assessing and mitigating risks, as well as planning and executing pharmacokinetic/pharmacodynamic /safety data analyses. In addition, we discuss the major gaps and areas of growth in clinical pharmacology understanding of recombinant AAV. These include the mechanisms of the durability of treatment response and variability in biodistribution, transduction, and immunogenicity, as well as a potential influence on AAV's safety and efficacy profiles by drug product characteristics and patient intrinsic/extrinsic factors.
重组腺相关病毒（AAV）是目前应用最广泛的体内基因治疗平台。临床药理学是 AAV 基因治疗的一个核心领域，其支柱包括药代动力学、药效动力学/疗效和安全性。在这篇综述中，我们全面总结了重组 AAV 的临床药理学考虑因素。主要涵盖的主题有生物分布和脱落、剂量-暴露-反应关系、安全性、免疫和应激反应以及临床剂量选择策略。我们强调了 AAV 基因治疗的累积知识如何有助于指导临床试验设计、评估和减轻风险，以及规划和执行药代动力学/药效动力学/安全性数据分析。此外，我们还讨论了重组 AAV 临床药理学理解方面的主要差距和增长领域。这些包括治疗反应持久性和生物分布、转导和免疫原性变异性的机制，以及药物产品特性和患者内在/外在因素对 AAV 安全性和疗效的潜在影响。
