Optimizing Hydroxychloroquine Dosing for Patients With COVID‐19: An Integrative Modeling Approach for Effective Drug Repurposing

Abstract

Hydroxychloroquine (HCQ) is a promising candidate for Coronavirus disease of 2019 (COVID-19) treatment. The optimal dosing of HCQ is unknown. Our goal was to integrate historic and emerging pharmacological and toxicity data to understand safe and efficacious HCQ dosing strategies for COVID-19 treatment. The data sources included were (i) longitudinal clinical, pharmacokinetic (PK), and virologic data from patients with severe acute respiratory syndrome-2 (SARS-CoV-2) infection who received HCQ with or without azithromycin (n = 116), (ii) in vitro viral replication data and SARS-CoV-2 viral load inhibition by HCQ, (iii) a population PK model of HCQ, and (iv) a model relating chloroquine PKs to corrected QT (QTc) prolongation. A mechanistic PK/virologic/QTc model for HCQ was developed and externally validated to predict SARS-CoV-2 rate of viral decline and QTc prolongation. SARS-CoV-2 viral decline was associated with HCQ PKs (P < 0.001). The extrapolated patient half-maximal effective concentration (EC 50 ) was 4.7 µM, comparable to the reported in vitro EC 50s . HCQ doses > 400 mg b.i.d. for ≥5 days were predicted to rapidly decrease viral loads, reduce the proportion of patients with detectable SARS-CoV-2 infection, and shorten treatment courses, compared with lower dose (≤ 400 mg daily) regimens. However, HCQ doses > 600 mg b.i.d. were also predicted to prolong QTc intervals. This prolongation may have clinical implications warranting further safety assessment. Due to COVID-19's variable natural history, lower dose HCQ regimens may be indistinguishable from controls. Evaluation of higher HCQ doses is needed to ensure adequate safety and efficacy.

Finding the Dose for Hydroxychloroquine Prophylaxis for COVID‐19: The Desperate Search for Effectiveness

“…There are no scientifically established doses for SARS‐CoV‐2. Although pharmacometric modeling and simulation has been used by several groups to propose potential regimens, 3–5 these are targeted for hospitalized patients with advanced disease and no models have specifically evaluated regimens in the context of prophylaxis.…”

Hydroxychloroquine and Azithromycin to Treat Patients With COVID‐19: Both Friends and Foes?

“…The exact clinically effective hydroxychloroquine dose is still undetermined. Given the weaknesses of Gautret's 1 and Chen's 2 studies along with the negative results of the recently released US veterans study 5 (Table 1), improving effectiveness by increasing hydroxychloroquine doses has been questioned by different modeling approaches including a physiologically based pharmacokinetic study 15 and a pharmacokinetic/virology/QT model 21 . Both studies concluded that hydroxychloroquine doses >400 mg twice daily for at least 5 days are needed to ensure efficacy on viral load decline and cardiac safety.…”

Ayurveda botanicals in COVID-19 management: An in silico- multitarget approach

“…Therefore, it is required to have safe pharmacotherapy for COVID-19 that can be co-prescribed with WHO solidarity trial drugs and commonly prescribed drugs such as anti-hypertensive, anti-asthmatic and anti-diabetic. Administering plasma of a recovered patient to the critically ill COVID-19 patients seems promising 12 .Currently there is limited evidence on the safety and e cacy of Hydroxychloroquine which is being used in many countries for COVID-19 treatmentunder emergency circumstances 13,14 .There is a great rush to nd vaccines and therapeutics against SARS-CoV-2. Several pharmaceutical companies have announced clinical trials for drug and vaccine candidates.…”