Applied BioMath, LLC, Concord, MA, USA.
MAbs. 2023 Jan-Dec;15(1):2192251. doi: 10.1080/19420862.2023.2192251.
Early assessment of dosing requirements should be an integral part of developability assessments for a discovery program. If a very high dose is required to achieve the desired pharmacological effect, it may not be clinically feasible or commercially desirable to develop the biotherapeutic for the selected target unless extra measures are taken to develop a high concentration formulation or maximize yield during manufacturing. A quantitative understanding of the impact of target selection, biotherapeutic format, and optimal drug properties on potential dosing requirements to achieve efficacy can affect many early decisions. Early prediction of dosing requirements for biotherapeutics, as opposed to small molecules, is possible due to a strong influence of target biology on pharmacokinetics and dosing. Mechanistic pharmacokinetic/pharmacodynamic (PK/PD) models leverage knowledge and competitor data available at an early stage of drug development, including biophysics of the target(s) and disease physiology, to rationally inform drug design criteria. Here we review how mathematical mechanistic PK/PD modeling can and has been applied to guide early drug development decisions.
早期评估剂量需求应成为发现计划可开发性评估的一个组成部分。如果为了达到预期的药理作用需要很高的剂量，那么除非采取额外措施开发高浓度制剂或在制造过程中最大化产量，否则为选定的靶标开发生物治疗药物在临床上可能不可行或商业上不可取。对目标选择、生物治疗制剂和最佳药物特性对实现疗效的潜在剂量需求的影响的定量理解可能会影响许多早期决策。与小分子不同，由于靶标生物学对药代动力学和剂量有很强的影响，因此可以对生物治疗药物的剂量需求进行早期预测。基于机制的药代动力学/药效动力学（PK/PD）模型利用药物开发早期阶段的知识和竞争产品数据，包括（多个）靶标的生物物理学和疾病生理学，来合理地告知药物设计标准。在这里，我们回顾了数学机制 PK/PD 模型如何以及已经被应用于指导早期药物开发决策。
