Mechanistic PK/PD modeling to address early-stage biotherapeutic dosing feasibility questions.
Mechanistic PK/PD modeling to address early-stage biotherapeutic dosing feasibility questions.
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DOI：
10.1080/19420862.2023.2192251
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发表时间：
2023-01
期刊：
影响因子：
5.3
通讯作者：
Marcantonio, Diana H.
中科院分区：
文献类型：
--
作者：
Grant, Joshuaine;Hua, Fei;Apgar, Joshua F.;Burke, John M.;Marcantonio, Diana H.
剂量要求的早期评估应该是发现计划可开发性评估的一个组成部分。如果需要非常高的剂量来实现所需的药理学作用，则开发用于所选靶标的生物素可能在临床上不可行或在商业上不可取，除非采取额外措施来开发高浓度制剂或在制造期间使产量最大化。定量了解靶点选择、生物等效性形式和最佳药物性质对实现疗效的潜在给药要求的影响可能会影响许多早期决策。由于靶生物学对药代动力学和给药的强烈影响，与小分子药物相反，可以早期预测生物治疗药物的给药要求。机制药代动力学/药效学（PK/PD）模型利用药物开发早期阶段可用的知识和竞争对手数据，包括靶标的生物物理学和疾病生理学，以合理地告知药物设计标准。在这里，我们回顾数学机制PK/PD模型可以和已经被应用于指导早期药物开发决策。
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.
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