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.
Key words
hyrdoxychloroquine - PBPK - gastroplus - COVID-19 - pulmonary
