Beran Kristian, Abrahamsson Bertil, Charoo Naseem, Cristofoletti Rodrigo, Holm René, Kambayashi Atsushi, Langguth Peter, Mehta Mehul, Parr Alan, Polli James E, Shah Vinod P, Dressman Jennifer
Fraunhofer Institute for Translational Medicine and Pharmacology, Frankfurt am Main, Germany.
Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca Gothenburg, Sweden.
J Pharm Sci. 2025 Feb;114(2):644-659. doi: 10.1016/j.xphs.2024.10.030. Epub 2024 Oct 23.
Lemborexant is a dual orexin receptor antagonist assigned to class II of the Biopharmaceutics Classification System (BCS). Thus, the ICH M9 Guideline excludes immediate-release (IR) solid oral dosage forms containing lemborexant from BCS-based biowaivers, irrespective of their in vitro dissolution behavior. By contrast, classification of lemborexant according to the refined Developability Classification System (rDCS) falls into class I, indicating few biopharmaceutics risks. Customized rDCS investigations identify dissolution as the main risk factor, in line with clinical data in humans which suggest that the absorption of lemborexant is limited neither by solubility nor by permeability. Instead, any risks lie in dissolution. Analysis by the rDCS coupled with biorelevant dissolution testing thus provides a way forward for manufacturers to mitigate the risks associated with changes in formulation or introduction of a generic version prior to running clinical bioequivalence (BE) studies. As a way forward regarding biowaivers for lemborexant and similar cases, where justifying BE based on the current BCS-based approach is not possible, a four-step pathway towards establishing BE virtually could be adopted as follows: (i) rDCS analysis to identify critical bioavailability attributes, (ii) comparative (biorelevant) dissolution testing, (iii) Physiologically Based Biopharmaceutics Modeling (PBBM), and (iv) virtual BE assessment.
伦博瑞生是一种双重食欲素受体拮抗剂，属于生物药剂学分类系统（BCS）的II类。因此，国际人用药品注册技术协调会（ICH）的M9指南将含有伦博瑞生的速释（IR）固体口服剂型排除在基于BCS的生物豁免范围之外，无论其体外溶出行为如何。相比之下，根据改进的可开发性分类系统（rDCS），伦博瑞生属于I类，表明生物药剂学风险较小。定制的rDCS研究确定溶出是主要风险因素，这与人体临床数据一致，表明伦博瑞生的吸收既不受溶解度限制，也不受渗透性限制。相反，任何风险都在于溶出。通过rDCS分析并结合生物相关溶出试验，为制造商在进行临床生物等效性（BE）研究之前降低与制剂变更或引入仿制药相关的风险提供了一条途径。对于伦博瑞生及类似情况的生物豁免，鉴于无法基于当前基于BCS的方法证明生物等效性，可采用以下四步途径来虚拟建立生物等效性：（i）rDCS分析以确定关键的生物利用度属性，（ii）比较（生物相关）溶出试验，（iii）基于生理的生物药剂学建模（PBBM），以及（iv）虚拟生物等效性评估。
