BBSG Pharm Associates, LLC, 7641 Summer Day Drive, Corona, California 92883, United States.
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 125 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
Mol Pharm. 2024 Sep 2;21(9):4191-4198. doi: 10.1021/acs.molpharmaceut.4c00479. Epub 2024 Aug 12.
Pharmacokinetic bioequivalence of orally inhaled drug products is a critical component of the US FDA's "weight of evidence" approach, and it can serve as the sole indicator of safety and effectiveness of follow-on inhalation products approved in Europe and some other geographic areas. The approved labels of the orally inhaled drug products recommend the maximum number of actuations that can be administered in a single dose on one occasion. This single maximum dose may consist of one or more inhalations depending upon the product. Bioequivalence studies for the inhalation drug product registrations in the US and EU have employed single and multiple actuation doses, in some cases over and above the approved single maximum labeled doses, thus, inconsistent with the approved labeling of the reference products. Pharmacokinetics of inhaled drug products after single and multiple doses may be different, with implications for bioequivalence determined at single and multiple doses. Scientific literature indicates that the relative bioavailability of the Test and Reference products may differ between administrations of doses in one and multiple inhalations. Multiple doses not only alter the pharmacokinetics but also may reduce the sensitivity of the bioassay to actual differences between the Test and Reference product performances. Ability of the pharmacokinetic bioassay to accurately determine the extent of difference between two products may also be substantially reduced at high doses. Therefore, in our opinion, pharmacokinetic bioequivalence to support regulatory approvals of inhalation products at doses above the recommended single maximum dose should be avoided. Furthermore, the bioequivalence of products (if any) established at doses exceeding the approved single maximum doses should be revisited to determine if the products maintain bioequivalence when evaluated at the clinically relevant single maximum doses.
经口吸入药物产品的药代动力学生物等效性是美国 FDA“证据权重”方法的关键组成部分，它可以作为欧洲和其他一些地区批准的后续吸入产品的安全性和有效性的唯一指标。经口吸入药物产品的批准标签建议单次剂量可使用的最大喷雾次数。单次最大剂量可能由一次吸入或多次吸入组成，具体取决于产品。在美国和欧盟进行的吸入药物产品注册的生物等效性研究采用了单次和多次喷雾剂量，在某些情况下超过了批准的单次最大标签剂量，因此与参比产品的批准标签不一致。单次和多次剂量后的吸入药物产品的药代动力学可能不同，单次和多次剂量的生物等效性决定了其结果。科学文献表明，在一次和多次吸入剂量中，受试和参比产品的相对生物利用度可能不同。多次剂量不仅改变了药代动力学，而且可能降低生物测定对受试和参比产品性能实际差异的敏感性。在高剂量下，药代动力学生物测定准确确定两种产品之间差异程度的能力也可能大大降低。因此，我们认为，应避免在推荐的单次最大剂量以上的剂量下进行药代动力学生物等效性研究，以支持吸入产品的监管批准。此外，应重新评估超过批准的单次最大剂量的产品（如果有）的生物等效性，以确定在评估临床相关的单次最大剂量时，产品是否仍具有生物等效性。
