Simulations Plus, Inc., 42505 10th Street West, Lancaster, CA, 93534, USA.
GlaxoSmithKline R&D, Stevenage, Hertfordshire, UK.
Clin Pharmacokinet. 2022 Feb;61(2):281-293. doi: 10.1007/s40262-021-01066-2. Epub 2021 Aug 30.
Physiologically based pharmacokinetic (PBPK) modelling has evolved to accommodate different routes of drug administration and enables prediction of drug concentrations in tissues as well as plasma. The inhalation route of administration has proven successful in treating respiratory diseases but can also be used for rapid systemic delivery, holding great promise for treatment of diseases requiring systemic exposure. The objective of this work was to develop a PBPK model that predicts plasma and tissue concentrations following inhalation administration of the PI3Kδ inhibitor nemiralisib.
A PBPK model was built in GastroPlus that includes a complete mechanistic description of pulmonary absorption, systemic distribution and oral absorption following inhalation administration of nemiralisib. The availability of clinical data obtained after intravenous, oral and inhalation administration enabled validation of the model with observed data and accurate assessment of pulmonary drug absorption. The PBPK model described in this study incorporates novel use of key parameters such as lung systemic absorption rate constants derived from human physiological lung blood flows, and implementation of the specific permeability-surface area product per millilitre of tissue cell volume (SpecPStc) to predict tissue distribution.
The inhaled PBPK model was verified using plasma and bronchoalveolar lavage fluid concentration data obtained in human subjects. Prediction of tissue concentrations using the permeability-limited systemic disposition tissue model was further validated using tissue concentration data obtained in the rat following intravenous infusion administration to steady state.
Fully mechanistic inhaled PBPK models such as the model described herein could be applied for cross molecule assessments with respect to lung retention and systemic exposure, both in terms of pharmacology and toxicology, and may facilitate clinical indication selection.
基于生理学的药代动力学（PBPK）模型已经发展到可以适应不同的给药途径，并能够预测药物在组织和血浆中的浓度。给药途径的吸入已被证明在治疗呼吸系统疾病方面是成功的，但也可用于快速全身给药，为治疗需要全身暴露的疾病提供了很大的希望。这项工作的目的是开发一种 PBPK 模型，用于预测吸入给药后 PI3Kδ 抑制剂 nemiralisib 的血浆和组织浓度。
在 GastroPlus 中构建了一个 PBPK 模型，该模型包括吸入给药后肺部吸收、全身分布和口服吸收的完整机制描述。静脉、口服和吸入给药后获得的临床数据的可用性使该模型能够用观察到的数据进行验证，并对肺部药物吸收进行准确评估。本研究中描述的 PBPK 模型纳入了一些关键参数的新用法，例如源自人体生理肺血流量的肺部系统吸收速率常数，以及实施每毫升组织细胞体积的特定渗透表面积产物（SpecPStc）来预测组织分布。
使用在人体受试者中获得的血浆和支气管肺泡灌洗液浓度数据验证了吸入 PBPK 模型。使用透性限制的全身处置组织模型预测组织浓度的方法，进一步通过静脉输注给药至稳态后在大鼠中获得的组织浓度数据进行了验证。
像本文描述的那样的完全基于生理学的吸入 PBPK 模型可以用于与肺部保留和全身暴露相关的跨分子评估，无论是在药理学还是毒理学方面，并且可能有助于临床适应证的选择。
