Optimized chloroquine phosphate dosage regimens for early virological clearance of severe acute respiratory syndrome coronavirus 2 using Monte Carlo simulation

Abstract

Chloroquine (CQ) exhibited promising in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the optimal dosage regimens remain unknown. Our objective was to explore the optimal chloroquine phosphate (CQP) dosage regimens for early achievement of virological clearance within 48-72 hours to diminish in-hospital transmission to front-line healthcare workers. A 10,000-subject Monte Carlo simulation was performed to calculate both probability of efficacy and safety attainment (PTA) using pharmacokinetic (PK) parameters obtained from the published population PK study. Dosage regimens that early achieved PTA of efficacy (PTAeff) ≥90% within 48-72 hours, while maintained PTA of toxicity (PTAtox) ≤1% were considered optimal. For the previously proposed regimens in published guidelines and clinical studies, all dosage regimens could not achieve ≥90% PTAeff, except one with the highest dosage regimen. Our simulations suggested that large amount of loading dose was required for the early achievement. We designed three dosage regimens containing high loading dose (2-3 gram per day), which early achieved ≥90% PTAeff within 48-72 hours, while also maintained ≤1% PTAtox throughout the treatment course. Further clinical studies are needed to prove the efficacy and safety of our designed regimens.

Chloroquine dosage regimen simulation for pediatric patients with coronavirus disease 2019

“…On day 4, 22.2% of patients had negative NP swab which is likely lower than our reference outcome. Moreover, the MCS study by Tidwong et al 21 has investigated for the optimal dosage regimen in adult COVID-19. It was shown that high CQ dose was needed (such as the higher dosage regimen by Borba et al 9 or its own designed regimens of 2,000-3,000 mg LD in 1-2 days with 500 mg MD twice daily for total 10 days) which is quite different from our reference study regimen (CQP 500 mg twice daily for 10 days) 10 .…”

“…Thus, the difference of body composition and metabolic process between adults and children results in fairly contrasting PK parameters. Additionally, some adult COVID-19 regimens have been proposed in literature with relatively high dose of CQ 21 . Therefore, the recommended CQ in pediatrics converted from the "per kilogram" adult dose without adjustment for a PK parameter difference as seen in some CPGs 4 may lead to ineffective treatment or even toxicity resulting from lower or higher blood level than needed.…”