Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington.
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
Drug Metab Dispos. 2022 May;50(5):519-528. doi: 10.1124/dmd.121.000789. Epub 2022 Mar 4.
Oral inhalation (OI) of drugs is the route of choice to treat respiratory diseases or for recreational drug use (e.g., cannabis). After OI, the drug is deposited in and systemically absorbed from various regions of the respiratory tract. Measuring regional respiratory tissue drug concentrations at the site of action is important for evaluating the efficacy and safety of orally inhaled drugs (OIDs). Because such a measurement is routinely not possible in humans, the only alternative is to predict these concentrations, for example by physiologically based pharmacokinetic (PBPK) modeling. Therefore, we developed an OI-PBPK model to integrate the interplay between regional respiratory drug deposition and systemic absorption to predict regional respiratory tissue and systemic drug concentrations. We validated our OI-PBPK model by comparing the simulated and observed plasma concentration-time profiles of two OIDs, morphine and nicotine. Furthermore, we performed sensitivity analyses to quantitatively demonstrate the impact of key parameters on the extent and pattern of regional respiratory drug deposition, absorption, and the resulting regional respiratory tissue and systemic plasma concentrations. Our OI-PBPK model can be applied to predict regional respiratory tissue and systemic drug concentrations to optimize OID formulations, delivery systems, and dosing regimens. Furthermore, our model could be used to establish the bioequivalence of generic OIDs for which systemic plasma concentrations are not measurable or are not a good surrogate of the respiratory tissue drug concentrations. SIGNIFICANCE STATEMENT: Our OI-PBPK model is the first comprehensive model to predict regional respiratory deposition, as well as systemic and regional tissue concentrations of OIDs, especially at the drug's site of action, which is difficult to measure in humans. This model will help optimize OID formulations, delivery systems, dosing regimens, and bioequivalence assessment of generic OID. Furthermore, this model can be linked with organs-on-chips, pharmacodynamic and quantitative systems pharmacology models to predict and evaluate the safety and efficacy of OID.
口服吸入（OI）是治疗呼吸道疾病或娱乐性药物使用（例如大麻）的首选途径。OI 后，药物沉积在呼吸道的各个部位，并从这些部位系统吸收。在作用部位测量局部呼吸道组织的药物浓度对于评估口服吸入药物（OIDs）的疗效和安全性非常重要。由于在人体中通常无法进行这种测量，唯一的替代方法是预测这些浓度，例如通过基于生理学的药代动力学（PBPK）建模。因此，我们开发了一种 OI-PBPK 模型，将局部呼吸道药物沉积与全身吸收之间的相互作用整合在一起，以预测局部呼吸道组织和全身药物浓度。我们通过比较两种 OIDs（吗啡和尼古丁）的模拟和观察到的血浆浓度-时间曲线来验证我们的 OI-PBPK 模型。此外，我们进行了敏感性分析，以定量证明关键参数对局部呼吸道药物沉积、吸收的程度和模式以及由此产生的局部呼吸道组织和全身血浆浓度的影响。我们的 OI-PBPK 模型可用于预测局部呼吸道组织和全身药物浓度，以优化 OID 配方、输送系统和给药方案。此外，我们的模型可用于建立不能测量或不能很好地替代呼吸道组织药物浓度的通用 OID 的生物等效性。意义陈述：我们的 OI-PBPK 模型是第一个全面的模型，可以预测 OIDs 的局部呼吸道沉积以及全身和局部组织浓度，特别是在药物的作用部位，这在人体中很难测量。该模型将有助于优化 OID 配方、输送系统、给药方案以及通用 OID 的生物等效性评估。此外，该模型可以与器官芯片、药效动力学和定量系统药理学模型相结合，用于预测和评估 OID 的安全性和疗效。
