Impact of Disease on Plasma and Lung Exposure of Chloroquine, Hydroxychloroquine and Azithromycin: Application of PBPK Modeling
Karen Rowland Yeo, Mian Zhang, Xian Pan, Alice Ban Ke, Hannah M Jones, David Wesche, Lisa M Almond
Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.1955
We use a mechanistic lung model to demonstrate that accumulation of chloroquine (CQ), hydroxychloroquine (HCQ), and azithromycin (AZ) in the lungs is sensitive to changes in lung pH, a parameter that can be affected in patients with coronavirus disease 2019 (COVID-19). A reduction in pH from 6.7 to 6 in the lungs, as observed in respiratory disease, led to 20-fold, 4.0-fold, and 2.7-fold increases in lung exposure of CQ, HCQ, and AZ, respectively. Simulations indicated that the relatively high concentrations of CQ and HCQ in lung tissue were sustained long after administration of the drugs had stopped. Patients with COVID-19 often present with kidney failure. Our simulations indicate that renal impairment (plus lung pH reduction) caused 30-fold, 8.0-fold, and 3.4-fold increases in lung exposures for CQ, HCQ, and AZ, respectively, with relatively small accompanying increases (20 to 30%) in systemic exposure. Although a number of different dosage regimens were assessed, the purpose of our study was not to provide recommendations for a dosing strategy, but to demonstrate the utility of a physiologically-based pharmacokinetic modeling approach to estimate lung concentrations. This, used in conjunction with robust in vitro and clinical data, can help in the assessment of COVID-19 therapeutics going forward.
Coronavirus disease 2019 (COVID-19 ) has rapidly become a global pandemic, since the outbreak was initially identified in Wuhan, China, in December 2019. The virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect the lower respiratory tract causing fevers, cough, and pneumonia. As new drug candidates are being investigated for treatment of COVID-19, efforts are being made to repurpose existing antimalarial drugs, as they are readily available, and have a known safety profile. Specifically, it has been reported that chloroquine (CQ) has been successful in treating SARS-CoV-2 infections in China. 1 In vitro studies have since confirmed that hydroxychloroquine (HCQ), an analog of CQ, is a more potent inhibitor of SARS-CoV-2 (5-fold to 7-fold). 2 Given that HCQ also has a more favorable safety profile than CQ during chronic dosing, a clinical study was conducted in France to determine whether HCQ (600 mg daily; 465 mg base) could be a more viable option for COVID-19
SUPPORTING INFORMATION Supplementary information accompanies this paper on the Clinical Pharmacology & Therapeutics website (www.cpt-journal.com).
CONFLICT OF INTEREST All authors are paid employees of Certara UK Limited (Simcyp Division) or Certara Inc.
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