Division of Biochemical Toxicology, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, AR 72079, USA.
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, AR 72079, USA.
Biochem Pharmacol. 2021 Jul;189:114468. doi: 10.1016/j.bcp.2021.114468. Epub 2021 Feb 10.
Physiologically based pharmacokinetic (PBPK) modeling is a powerful tool with many demonstrated applications in various phases of drug development and regulatory review. RNA interference (RNAi)-based therapeutics are a class of drugs that have unique pharmacokinetic properties and mechanisms of action. With an increasing number of RNAi therapeutics in the pipeline and reaching the market, there is a considerable amount of active research in this area requiring a multidisciplinary approach. The application of PBPK models for RNAi therapeutics is in its infancy and its utility to facilitate the development of this new class of drugs is yet to be fully evaluated. From this perspective, we briefly discuss some of the current computational modeling approaches used in support of efficient development and approval of RNAi therapeutics. Considerations for PBPK model development are highlighted both in a relative context between small molecules and large molecules such as monoclonal antibodies and as it applies to RNAi therapeutics. In addition, the prospects for drawing upon other recognized avenues of PBPK modeling and some of the foreseeable challenges in PBPK model development for these chemical modalities are briefly discussed. Finally, an exploration of the potential application of PBPK model development for RNAi therapeutics is provided. We hope these preliminary thoughts will help initiate a dialogue between scientists in the relevant sectors to examine the value of PBPK modeling for RNAi therapeutics. Such evaluations could help standardize the practice in the future and support appropriate guidance development for strengthening the RNAi therapeutics development program.
基于生理学的药代动力学（PBPK）建模是一种强大的工具，在药物开发和监管审查的各个阶段都有许多应用。RNA 干扰（RNAi）治疗药物是一类具有独特药代动力学特性和作用机制的药物。随着越来越多的 RNAi 治疗药物进入研发管线并推向市场，该领域的研究非常活跃，需要采用多学科方法。PBPK 模型在 RNAi 治疗药物中的应用还处于起步阶段，其在促进这类新药开发中的效用尚未得到充分评估。从这个角度出发，我们简要讨论了目前支持 RNAi 治疗药物高效开发和审批所使用的一些计算建模方法。在小分子和大分子（如单克隆抗体）之间的相对背景下，以及在适用于 RNAi 治疗药物的情况下，都强调了 PBPK 模型开发的注意事项。此外，还简要讨论了借鉴其他公认的 PBPK 建模途径以及在这些化学模式下开发 PBPK 模型的一些可预见挑战的前景。最后，还探讨了 PBPK 模型开发在 RNAi 治疗药物中的潜在应用。我们希望这些初步想法将有助于在相关领域的科学家之间展开对话，以检验 PBPK 建模在 RNAi 治疗药物中的价值。这种评估有助于为未来的实践标准化提供支持，并为加强 RNAi 治疗药物开发计划提供适当的指导原则。
