| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T1 |
130-233 |
DRI_Background |
denotes |
Hydroxychloroquine (HCQ) is a promising candidate for Coronavirus Disease of 2019 (COVID-19) treatment. |
| T2 |
234-271 |
DRI_Approach |
denotes |
The optimal dosing of HCQ is unknown. |
| T3 |
272-434 |
DRI_Challenge |
denotes |
Our goal was to integrate historic and emerging pharmacological and toxicity data to understand safe and efficacious HCQ dosing strategies for COVID-19 treatment. |
| T4 |
435-859 |
DRI_Outcome |
denotes |
The data sources included were 1) longitudinal clinical, pharmacokinetic, and virologic data from patients with severe acute respiratory syndrome-2 (SARS-CoV-2) infection who received HCQ with or without azithromycin (n=116), 2) in vitro viral replication data and SARS-CoV-2 viral load inhibition by HCQ, 3) a population pharmacokinetic model of HCQ and 4) a model relating chloroquine pharmacokinetics to QTc prolongation. |
| T5 |
860-1009 |
DRI_Challenge |
denotes |
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. |
| T6 |
1087-1408 |
DRI_Outcome |
denotes |
The extrapolated patient EC50 was 4.7 µM, comparable to the reported in vitro EC50 's. HCQ doses > 400 mg BID 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 to lower dose (≤400 mg daily) regimens. |
| T7 |
1409-1485 |
DRI_Background |
denotes |
However, HCQ doses >600 mg BID were also predicted to prolong QTc intervals. |
| T8 |
1486-1572 |
DRI_Approach |
denotes |
This prolongation may have clinical implications warranting further safety assessment. |
| T9 |
1573-1680 |
DRI_Background |
denotes |
Due to COVID-19's variable natural history, lower dose HCQ regimens may be indistinguishable from controls. |
| T10 |
1681-1761 |
DRI_Background |
denotes |
Evaluation of higher HCQ doses is needed to ensure adequate safety and efficacy. |