Drug Metab Dispos. 2022 Mar 4:DMD-AR-2021-000789. doi: 10.1124/dmd.121.000789. Online ahead of print.
Oral inhalation (OI) of drugs is the route of choice to treat respiratory diseases or for recreational drug use (e.g., cannabis). Following 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 (OID). Since 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 OID, morphine and nicotine. Further, 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. Further, our model could be used to establish the bioequivalence of generic OID 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 OID, 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. Further, 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.
Source: ncbi 2