Development of a Physiologically-Based Pharmacokinetic (PBPK) Model of Nebulized Hydroxychloroquine for Pulmonary Delivery to COVID-19 Patients

Abstract

Despite inconclusive evidence, chloroquine (CQ) and hydroxychloroquine (HCQ)are commonly used for the treatment of Corona virus Disease 2019(COVID-19) in critically ill patients.It was hypothesized that HCQ as an aerosol application can reach the antiviral concentration of ~1–5 μM in the alveolar cells which has been proven effective in vitro. A physiologically-based pharmacokinetic (PBPK) model of nebulized HCQ for pulmonary delivery to COVID-19 patients using the Nasal-Pulmonary Module in GastroPlus® V9.7 simulator, in order to calculate the necessary inhalation dose regimen of HCQ, was developed. The physiological, drug disposition, and pharmacokinetic parameters were obtained from the literature and used during model building after optimization using Optimization Module, while oral data was used for validation. The 25 mg BID inhalation dosing was predicted to lead to alveolar HCQ levels of 7 µM (above EC50 of ~1–5 µM), and small plasma levels of 0.18 µM (as compared to plasma levels of 3.22 µM after 200 mg BID oral dosing). However, average contact time (>1 µM) is around 0.5 h in lung parts, suggesting indirect exposure response effect of HCQ.The developed PBPK model herein predicted HCQ levels in plasma and different lung parts of adults after multiple inhalation dosing regimens for 5 days. This in-silico work needs to be tested in vivo on healthy subjects and COVID-19 patients using 12.5 mg BID and 25 mg BID inhalation doses.

Predicting the systemic exposure and lung concentration of nafamostat using physiologically-based pharmacokinetic modeling

“…Rajoli et al [ 25 ] developed a whole-body PBPK model for nitazoxanide, an anthelmintic drug, and used an in vitro half maximal effective concentration for SARS-CoV-2 to design an optimal dosage regimen for COVID-19 treatment. In a study by Idkaidek et al [ 26 ], the PBPK model for hydroxychloroquine was utilized to design the dose for the inhalation formulation required to maintain an effective concentration in the alveolus. The PBPK model built using in vitro absorption data and a mathematical function can be used to predict the first-in-human PK profile, the PK profile in a particular population, and assess the effect of formulation changes.…”

Nebulised Isotonic Hydroxychloroquine Aerosols for Potential Treatment of COVID-19

“…The model featured droplets with a VMD of 5.6 µm. The proportions depositing in the trachea, bronchioles, and alveoli were 10, 13, and 30% by mass, respectively [80]. Their sum (53%) could be interpreted as the proportion of the emitted aerosol < 5 µm because they theoretically deposited in the lungs.…”

“…High drug levels in the airways can be maintained by multiple daily inhalations. Idkaidek et al employed a physiologically based pharmacokinetic model to estimate the inhaled dose needed for COVID-19 based on this concentration range [80]. The model featured droplets with a VMD of 5.6 µm.…”

“…Their sum (53%) could be interpreted as the proportion of the emitted aerosol < 5 µm because they theoretically deposited in the lungs. It was found that inhaling 25 mg of hydroxychloroquine twice a day could achieve a maximum concentration (C max ) ≥ 7 µM in the various parts of the lungs, while the plasma C max was only 0.18 µM [80]. If the inhaled dose was doubled to 50 mg hydroxychloroquine twice a day, then the lung C max reached ≥ 13 µM and plasma C max increased to 0.35 µM.…”

Hydroxychloroquine is Metabolized by Cytochrome P450 2D6, 3A4, and 2C8, and Inhibits Cytochrome P450 2D6, while its Metabolites also Inhibit Cytochrome P450 3Ain vitro

“…Manuscript for Drug Metabolism & Disposition, October 2022 24 Because of the complex pharmacokinetics of HCQ and the wide variability in its concentration profile, it has been difficult to relate measured HCQ concentrations to its therapeutic and adverse effects (Rainsford et al, 2015). Nevertheless, several pharmacokinetic and physiologically-based pharmacokinetic (PBPK) models have been developed for HCQ, in particular after the outbreak of COVID-19 (Collins et al, 2018;Themans et al, 2020;Idkaidek et al, 2021). Our data can be used to update these models, and to simulate the effects of CYP-mediated drug-drug interactions and variants in CYP genes.…”