Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, 410 North 12th Street, P.O. Box 980533, Richmond, VA, 23298, USA.
Biopharm Drug Dispos. 2020 Feb;41(1-2):32-43. doi: 10.1002/bdd.2210. Epub 2019 Dec 10.
The kinetic clarification of lung disposition for inhaled drugs in humans via pharmacokinetic (PK) modeling aids in their development and regulation for systemic and local delivery, but remains challenging due to its multiplex nature. This study exercised our lung delivery and disposition kinetic model to derive the kinetic descriptors for the lung disposition of four drugs [calcitonin, tobramycin, ciprofloxacin and fluticasone propionate (FP)] inhaled via different inhalers from the published PK profile data. With the drug dose delivered to the lung (DTL) estimated from the corresponding γ-scintigraphy or in vivo predictive cascade impactor data, the model-based curve-fitting and statistical moment analyses derived the rate constants of lung absorption (k ) and non-absorptive disposition (k ). The k values differed substantially between the drugs (0.05-1.00 h ), but conformed to the lung partition-based membrane diffusion except for FP, and were inhaler/delivery/deposition-independent. The k values also varied widely (0.03-2.32 h ), yet appeared to be explained by the presence or absence of non-absorptive disposition in the lung via mucociliary clearance, local tissue degradation, binding/sequestration and/or phagocytosis, and to be sensitive to differences in lung deposition. For FP, its k value of 0.2 h was unusually low, suggesting solubility/dissolution-limited slow lung absorption, but was comparable between two inhaler products. Thus, the difference in the PK profile was attributed to differences in the DTL and the k value, the latter likely originating from different aerosol sizes and regional deposition in the lung. Overall, this empirical, rather simpler model-based analysis provided a quantitative kinetic understanding of lung absorption and non-absorptive disposition for four inhaled drugs from PK profiles in humans.
通过药代动力学 (PK) 建模对吸入药物在人体内的肺部处置动力学进行澄清，有助于开发和调节全身和局部输送系统，但由于其复杂性，仍然具有挑战性。本研究运用我们的肺部输送和处置动力学模型，从已发表的 PK 曲线数据中，为四种通过不同吸入器吸入的药物[降钙素、妥布霉素、环丙沙星和丙酸氟替卡松（FP）]的肺部处置推导动力学描述符。根据相应的γ闪烁扫描或体内预测级联撞击器数据估算的肺部药物输送量（DTL），模型拟合和统计矩分析得出了肺部吸收（k）和非吸收处置（k）的速率常数。k 值在药物之间有很大差异（0.05-1.00 h），但符合基于肺部分配的膜扩散，除了 FP 外，与吸入器/输送/沉积无关。k 值也变化很大（0.03-2.32 h），但似乎可以通过肺部的非吸收处置来解释，如黏液纤毛清除、局部组织降解、结合/隔离和/或吞噬作用，并且对肺部沉积的差异敏感。对于 FP，其 k 值为 0.2 h，异常低，表明溶解度/溶解限制的肺部吸收缓慢，但在两种吸入器产品之间具有可比性。因此，PK 曲线的差异归因于 DTL 和 k 值的差异，后者可能源自不同的气溶胶大小和肺部的区域性沉积。总体而言，这种经验性、更简单的基于模型的分析，为从人体 PK 曲线中了解四种吸入药物的肺部吸收和非吸收处置提供了定量动力学认识。
