key: cord-0845015-o8a0jhx2
authors: Mégarbane, Bruno; Scherrmann, Jean-Michel
title: Comment on: Rationale of a loading dose initiation for hydroxychloroquine treatment in COVID-19 infection in the DisCoVeRy trial
date: 2020-08-07
journal: J Antimicrob Chemother
DOI: 10.1093/jac/dkaa327
sha: 5de78f88e3b53892b4dc82ea31073d1833663249
doc_id: 845015
cord_uid: o8a0jhx2

nan

concentrations up to 1000-fold the extracellular concentrations), are driven by the lysosomotropic mechanism of its main anti-SARS-CoV-2 activity consisting of acidotic intra-organelle pH modulation (e.g. the endosomes, lysosomes and Golgi apparatus). No correlation between blood exposure to hydroxychloroquine and the resulting autophagy inhibition is expected with such incomplete PBPK models. 4 Thirdly, using in vitro anti-SARS-CoV-2 activity and drug exposure at the putative target site of action to determine the effective regimen in vivo is misleading. 6 Antiviral EC 50 determined in culture media should be compared with in vivo free drug plasma concentrations, likely to be equal to free extracellular tissue concentrations. If assuming that cell accumulation is equivalent in vivo to in vitro studies, free lung concentrations that would result from the proposed regimen would be far below the in vitro EC 50 values, questioning its clinical effectiveness. Given its complex tissue distribution, attempts to simulate lung hydroxychloroquine levels should be cautiously considered. 4 Interestingly, one mechanistic PK/virological/QTc model developed to predict SARS-CoV-2 decline rate and QTc prolongation suggested that only elevated hydroxychloroquine regimens (>400 mg twice daily for 5 days) are predicted to rapidly decrease viral loads, reduce the infected patient proportion and shorten the treatment course, compared with routine regimens (400 mg daily). 7 Suboptimal regimens such as that of Lê et al. 1 have been predicted to be non-efficient, resulting in wasted time and resources.

In a randomized trial, hydroxychloroquine did not increase the probability of negating SARS-CoV-2 conversion, despite a higherdose regimen (loading dose of 1200 mg daily for 3 days followed by maintenance dose of 800 mg daily for 2 weeks in mild-tomoderate patients and 3 weeks in severe patients). 8 The Recovery trial (NCT04381936) data monitoring committee recommended stopping enrolling patients to the hydroxychloroquine arm due to the absence of benefit based on the primary endpoint of 28 day mortality. Yet, the hydroxychloroquine regimen (loading dose of 2400 mg including initial 800 mg followed by 800, 400 and 400 mg administered 6, 12 and 24 h later, respectively, and maintenance dose of 400 mg/12 h for 9 days) was much higher than that recommended by Lê et al. 1 Therefore, consistent with the models and negative results from the released trials, studies investigating higher doses up to 600 mg twice daily have been launched such as the PATCH trial (NCT04329923). However, safety hazards have become likely when reinforcing hydroxychloroquine regimens, given SARS-CoV-2-infected patient conditions with advanced age, comorbidities, possible myocarditis and kidney injuries and drugdrug interactions. 9 Models suggested that doses >600 mg twice daily may prolong QTc intervals with consequences warranting safety considerations. 7 With a 400 mg loading dose followed by a 10 day 200 mg thrice daily course, toxic blood concentrations were reached despite normal renal function. 10 Unsurprisingly, side effects were also observed at therapeutic concentrations.

Since no safe and suitable regimen is expected, the synergistic azithromycin/hydroxychloroquine co-administration should be V C The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. rationally considered, allowing reduction of the minimum hydroxychloroquine concentration to negate SARS-CoV-2 load by 29-fold. 10 Lastly, the time at which hydroxychloroquine is initiated in the disease course is also another issue as highlighted by the difficulties in reaching intracellular steady-state in the predictive models.

To conclude, prediction of the effective hydroxychloroquine regimen to treat the SARS-CoV-2-infected patient is doomed due to uncertainties related to the lack of in vitro model reliability and EC 50 pertinence and to the weakness of used PBPK models that did not mirror hydroxychloroquine PK complexity at the intracellular target level.

None to declare.

Rationale of a loading dose initiation for hydroxychloroquine treatment in COVID-19 infection in the DisCoVeRy trial

In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Hydroxychloroquine for treatment of SARS-CoV-2 infection? Improving our confidence in a model-based approach to dose selection

Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics

Connecting hydroxychloroquine in vitro antiviral activity to in vivo concentration for prediction of antiviral effect: a critical step in treating COVID-19 patients

Optimizing hydroxychloroquine dosing for patients with COVID-19: an integrative modeling approach for effective drug repurposing

Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial

Hydroxychloroquine pharmacokinetic in COVID-19 critically ill patients: an observational cohort study

Hydroxychloroquine and azithromycin as potential treatments for COVID-19; clinical status impacts the outcome