Abstract
AimsChloroquine (CQ) has been repurposed to treat coronavirus disease 2019 (COVID-19). Understanding the pharmacokinetics (PK) in COVID-19 patients is essential to study its exposure–efficacy/safety relationship and provide a basis for a possible dosing regimen optimization.Subject and methodsIn this study, we used a population-based meta-analysis approach to develop a population PK model to characterize the CQ PK in COVID-19 patients. An open-label, single-center study (ethical review approval number: PJ-NBEY-KY-2020-063-01) was conducted to assess the safety, efficacy, and pharmacokinetics of CQ in patients with COVID-19. The sparse PK data from 50 COVID-19 patients, receiving 500 mg CQ phosphate twice daily for 7 days, were combined with additional CQ PK data from 18 publications.ResultsA two-compartment model with first-order oral absorption and first-order elimination and an absorption lag best described the data. Absorption rate (ka) was estimated to be 0.559 h−1, and a lag time of absorption (ALAG) was estimated to be 0.149 h. Apparent clearance (CL/F) and apparent central volume of distribution (V2/F) was 33.3 l/h and 3630 l. Apparent distribution clearance (Q/F) and volume of distribution of peripheral compartment (Q3/F) were 58.7 l/h and 5120 l. The simulated CQ concentration under five dosing regimens of CQ phosphate were within the safety margin (400 ng/ml).ConclusionModel-based simulation using PK parameters from the COVID-19 patients shows that the concentrations under the currently recommended dosing regimen are below the safety margin for side-effects, which suggests that these dosing regimens are generally safe. The derived population PK model should allow for the assessment of pharmacokinetics–pharmacodynamics (PK-PD) relationships for CQ when given alone or in combination with other agents to treat COVID-19.
Highlights
The outbreak of coronavirus disease 2019 (COVID-19) has quickly become a global pandemic since December 2019. no treatment has demonstrated clinical efficacy against COVID-19, various drugs are being repositioned to treat COVID-19 and are being tested clinically
Preliminary data from clinical trials demonstrate its beneficial effect such as reducing the deterioration of pneumonia, improving the lungimaging results, decreasing the viral load, and shortening the disease duration [3]. This drug is recommended in the guidelines for the prevention, diagnosis, and treatment of pneumonia caused by COVID-19, issued by the National Health Commission of the People’s Republic of China [4]
These patients received CQ phosphate administration unless they had one or more of the following exclusion criteria: 1) female patients in pregnancy, 2) patients with a clear history of allergies to chloroquine, 3) patients suffering from diseases of the blood system, 4) patients suffering from chronic liver or kidney diseases and reaching the terminal stage, 5) patients suffering from arrhythmia or chronic heart disease patients, 6) patients with known retinal diseases or hearing loss, 7) patients with known mental illness, and 8) patients who have to use digitalis drugs for existing underlying diseases
Summary
The outbreak of coronavirus disease 2019 (COVID-19) has quickly become a global pandemic since December 2019. no treatment has demonstrated clinical efficacy against COVID-19, various drugs are being repositioned to treat COVID-19 and are being tested clinically. Preliminary data from clinical trials demonstrate its beneficial effect such as reducing the deterioration of pneumonia, improving the lungimaging results, decreasing the viral load, and shortening the disease duration [3]. This drug is recommended in the guidelines for the prevention, diagnosis, and treatment of pneumonia caused by COVID-19, issued by the National Health Commission of the People’s Republic of China [4]. The US Food and Drug Administration has issued an emergency use authorization (EUA) to permit the emergency use of chloroquine phosphate in patients with COVID-19 under certain conditions [5]
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