Abstract：
This work is the second in a series of publications outlining the fundamental principles and proposed design of a biopharmaceutics classifications system for inhaled drugs and drug products (the iBCS). Here, a mechanistic computer-based model has been used to explore the sensitivity of the primary biopharmaceutics functional output parameters: (i) pulmonary fraction dose absorbed (Fabs) and (ii) drug half-life in lumen (t1/2) to biopharmaceutics-relevant input attributes including dose number (Do) and effective permeability (Peff). Results show the nonlinear sensitivity of primary functional outputs to variations in these attributes. Drugs with Do < 1 and Peff > 1 × 10-6 cm/s show rapid (t1/2 < 20 min) and complete (Fabs > 85%) absorption from lung lumen into lung tissue. At Do > 1, dissolution becomes a critical drug product attribute and Fabs becomes dependent on regional lung deposition. The input attributes used here, Do and Peff, thus enabled the classification of inhaled drugs into parameter spaces with distinctly different biopharmaceutic risks. The implications of these findings with respect to the design of an inhalation-based biopharmaceutics classification system (iBCS) and to the need for experimental methodologies to classify drugs need to be further explored.
摘要：
这项工作是一系列出版物中的第二篇，这些出版物概述了吸入药物和药物产品（iBCS）的基本原理和拟议的生物制药分类系统的设计。这里,已经使用基于机械计算机的模型来探索主要生物制药功能输出参数的敏感性:(i)肺部分吸收剂量(Fabs)和(ii)管腔内药物半衰期(t1/2)与生物制药相关的输入属性,包括剂量数(Do)和有效通透性(Peff)。结果表明，主要功能输出对这些属性变化的非线性敏感性。具有Do<1和Peff>1×10-6cm/s的药物显示从肺腔快速(t1/2<20分钟)和完全(Fabs>85%)吸收到肺组织中。在Do>1时,溶解成为关键的药物产品属性,并且Fab变得依赖于局部肺沉积。这里使用的输入属性，Do和Peff,因此能够将吸入药物分类到具有明显不同生物制药风险的参数空间中.这些发现对基于吸入的生物制药分类系统（iBCS）的设计以及对药物分类的实验方法的需求的影响需要进一步探讨。
