Abstract
Background.Recentin vitrostudies have shown fluoxetineinhibitsthe severe acute respiratory syndrome coronavirus2 (SARS-CoV-2)pathogen, including variants B.1.1.7 and B.1.351, SARS-CoV-2 spike mutations (E484K,K417N,N501Y),and oneretrospectiveclinical study reported fluoxetine exposureat a median dose of 20mgin patientswith theSARS-CoV-2coronavirus disease 2019 (COVID-19) had asignificantlylower risk of intubation and death. The aim of this study is to conductin silicopopulationpharmacokineticdosing simulations to quantify the percentage of patientsachieving atroughlevelforthe effective concentration resulting in 90% inhibition(EC90)of SARS-CoV-2as reportedinCalu-3human lungcells. Methods.Population pharmacokineticparameterestimates fora structural one-compartmentmodel with first-order absorption wereused to simulate fluoxetinepharmacokineticdata.Apopulationof1,000 individualswere simulatedat standard fluoxetinedoses(20mg/day, 40mg/day, and 60mg/day)to estimate the percentage ofthe patientsachieving atroughplasmalevel forthe EC90SARS-CoV-2inhibitory concentrationfora10daytreatment period. All analyseswereconductedvia statistical programming inR. Results.Standard fluoxetineantidepressantdoses resulted ina range of81% to 97%of thepatientpopulationachieving atroughtargetplasma concentration of23.2ng/mlat day10 andtranslates toalung-tissuedistribution coefficient of 60-times higher(EC90 of 4.02mM).At adose of 40mg per day, at least 87% of patients will reach thetroughtarget EC90 concentrationwithinthreedays. Conclusion.Overall, the findings of this population pharmacokineticdosing studycorroborates in vitroandobservationalclinicalstudies reportingthe first selective serotonin reuptake inhibitor fluoxetineinhibits theSARS-CoV-2pathogenat commonly treated doses in the practice of psychiatry.
Highlights
The selective serotonin reuptake inhibitor (SSRI) fluoxetine is a racemic mixture of two stereoisomers, R-fluoxetine and S-fluoxetine, and maintains regulatory approvals for a wide-array of clinical indications in the practice of psychiatry
Schloer et al found that fluoxetine significantly decreases SARS-Cov-2 titers, after a 48-hour incubation period, in both African green monkey kidney epithelial Vero E6 cells (EC50 = 0.69 μM and 90% maximal effective concentration [effective concentration resulting in 90% inhibition (EC90)] = 1.81 μM, multiplicity of infection (MOI) = 0.01) and human-lung Calu-3 cells (EC50 = 0.82 μM and EC90 = 4.02 μM, MOI = 0.1) (Schloer et al, 2020)
The fluoxetine SARS-CoV-2 in vitro findings were corroborated by Hoertel et al who showed in a multicenter observational retrospective cohort study of patients who were treated with fluoxetine and diagnosed with COVID-19, experienced a lower risk of intubation and death at a median fluoxetine dose of 20 mg (Hoertel et al, 2020)
Summary
The selective serotonin reuptake inhibitor (SSRI) fluoxetine is a racemic mixture of two stereoisomers, R-fluoxetine and S-fluoxetine, and maintains regulatory approvals for a wide-array of clinical indications in the practice of psychiatry. The fluoxetine SARS-CoV-2 in vitro findings were corroborated by Hoertel et al who showed in a multicenter observational retrospective cohort study of patients who were treated with fluoxetine and diagnosed with COVID-19, experienced a lower risk of intubation and death (hazard ratio = 0.32; 95% confidence interval, 0.14–0.73, p = 0.007) at a median fluoxetine dose of 20 mg (standard deviation [SD] = 4.82) (Hoertel et al, 2020) In this context, the aim of this study is to conduct in silico population pharmacokinetic dosing simulations to quantify the percentage of patients expected to achieve the trough effective concentration resulting in 90% inhibition of SARS-CoV-2.
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