Fluvoxamine for the treatment of COVID-19
Authors: Michael G Dodds, Eileen B Doyle, Angela M Reiersen, Fran Brown, Craig R Rayner
Journal: The Lancet Global Health (2022)

The clinical efficacy of fluvoxamine observed in the TOGETHER trial1Reis G Dos Santos Moreira-Silva EA Silva DCM et al.Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.Lancet Glob Health. 2022; 10: e42-e51Summary Full Text Full Text PDF PubMed Scopus (83) Google Scholar (although no change in virological outcomes was observed) might be related to anti-inflammatory effects via sigma-1 receptor agonism,2Fred SM Kuivanen S Ugurlu H et al.Antidepressant and antipsychotic drugs reduce viral infection by SARS-CoV-2 and fluoxetine show antiviral activity against the novel variants in vitro.bioRxiv. 2021; (published online March 23.) (preprint).https://doi.org/10.1101/2021.03.22.436379Google Scholar but several other possible mechanisms warrant further investigation.3Sukhatme VP Reiersen AM Vayttaden SJ Sukhatme VV Fluvoxamine: a review of its mechanism of action and its role in COVID-19.Front Pharmacol. 2021; 12652688Crossref PubMed Scopus (55) Google Scholar After the clinical success of fluvoxamine, extrapolation of other therapeutics is inevitable. A logical candidate is fluoxetine, another selective serotonin reuptake inhibitor. To translate in-vitro findings to the clinic, we apply pharmacokinetic modelling to compare free-drug concentration (unbound to plasma proteins) to in-vitro potency.2Fred SM Kuivanen S Ugurlu H et al.Antidepressant and antipsychotic drugs reduce viral infection by SARS-CoV-2 and fluoxetine show antiviral activity against the novel variants in vitro.bioRxiv. 2021; (published online March 23.) (preprint).https://doi.org/10.1101/2021.03.22.436379Google Scholar, 4Brimson JM Prasanth MI Malar DS Brimson S Thitilertdecha P Tencomnao T Drugs that offer the potential to reduce hospitalization and mortality from SARS-CoV-2 infection: the possible role of the sigma-1 receptor and autophagy.Expert Opin Ther Targets. 2021; 25: 435-449Crossref PubMed Scopus (11) Google Scholar Pharmacokinetic parameter estimates for fluvoxamine and fluoxetine were obtained from US prescribing information (Luvox, Solvay pharmaceuticals, US Food and Drug Administration, 1994; and Prozac, Eli Lilly and Company, US Food and Drud Administration, 1987), with additional fluoxetine parameter estimates from a study by Panchaud and colleagues.5Panchaud A Garcia-Bournissen F Csajka C et al.Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine exposure.Clin Pharmacol Ther. 2011; 89: 830-836Crossref PubMed Scopus (20) Google Scholar One-compartment models with first-order absorption were built and used to simulate fluvoxamine (association constant [Ka]=0·356 1/h, oral clearance [CL/F]=30·2 L/h, volume of distribution [V/F]=928 L) and fluoxetine (Ka=0·3 1/h, CL/F=8·42 L/h, V/F=690 L) plasma concentrations. The models were used to simulate dosing over 10 days. Free plasma concentrations were calculated for fluvoxamine (20% free) and fluoxetine (5·5% free). Ratio of plasma concentrations to sigma-1 receptor inhibitor constant4Brimson JM Prasanth MI Malar DS Brimson S Thitilertdecha P Tencomnao T Drugs that offer the potential to reduce hospitalization and mortality from SARS-CoV-2 infection: the possible role of the sigma-1 receptor and autophagy.Expert Opin Ther Targets. 2021; 25: 435-449Crossref PubMed Scopus (11) Google Scholar and the half-maximal inhibitory concentration2Fred SM Kuivanen S Ugurlu H et al.Antidepressant and antipsychotic drugs reduce viral infection by SARS-CoV-2 and fluoxetine show antiviral activity against the novel variants in vitro.bioRxiv. 2021; (published online March 23.) (preprint).https://doi.org/10.1101/2021.03.22.436379Google Scholar of HEK293T cell lines expressing ACE2 and TMPRSS2 are reported (appendix). Unbound fluvoxamine concentration is predicted to be three times greater than sigma-1 receptor binding affinity, suggesting anti-inflammatory fluvoxamine concentrations can be reached clinically, in alignment with outcomes from the TOGETHER trial.1Reis G Dos Santos Moreira-Silva EA Silva DCM et al.Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.Lancet Glob Health. 2022; 10: e42-e51Summary Full Text Full Text PDF PubMed Scopus (83) Google Scholar By contrast, predicted fluoxetine concentrations were ten times lower than sigma-1 receptor inhibitory constant, suggesting fluoxetine treatment at clinically approved doses might not be successful (appendix). Comparing plasma concentrations to half-maximal inhibitory concentrations of pseudotyped virus, neither fluvoxamine nor fluoxetine appeared promising (concentration or half-maximal inhibitory concentration ratios <1; appendix), which reflects primarily on the relevance of the potential mechanism of action assessed in these experiments. These observations underscore the challenge of translation of in-vitro experience to clinic. It is important to use non-clinical data that inform the hypothesised primary pharmacology and use pharmacokinetic modelling of anticipated unbound concentrations relative to the non-clinical evaluations in translational efforts. In conclusion, although the available pharmacological data do not provide a strong translational rationale for fluoxetine for treatment of SARS-CoV-2, available scientific data are very scarce. As such, further exploration of mechanistic and clinical potential of fluoxetine is warranted. Clinical potential should be established within the context of clinical trials where posology can be properly investigated and appropriate safeguards are in place for patients and off-label use should be discouraged. MGD, EBD, FB, CRR are employed by Certara. Certara scientific support into the TOGETHER study was funded by the Bill and Melinda Gates Foundation. AMR is a co-applicant on a patent application filed by Washington University for the public use of generic selective serotonin reuptake inhibitors for COVID-19. Download .pdf (.3 MB) Help with pdf files Supplementary appendix Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trialTreatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital. Full-Text PDF Open AccessFluvoxamine for the treatment of COVID-19We congratulate Gilmar Reis and colleagues (January, 2022)1 on their randomised, platform clinical trial (TOGETHER trial) investigating the effects of early treatment with fluvoxamine for patients with COVID-19. In the study, the impressive 5% absolute risk reduction in hospitalisation or prolonged emergency setting observation equates to a number needed to treat of 20, meaning for every 20 individuals treated, one will have this benefit from the treatment.1 At a US wholesale pharmacy cost of US$4·66, which equates to $93 (95%CI 56–285) to prevent one emergency setting visit or hospitalisation among all participants. Full-Text PDF Open AccessFluvoxamine for the treatment of COVID-19In the TOGETHER study,1 Gilmar Reis and colleagues showed a benefit of early treatment with fluvoxamine with notably a reduction in the need for hospitalisation, which was defined as retention in a COVID-19 emergency setting for more than 6 h or transfer to a tertiary hospital.1 The authors mentioned that the findings of their study, together with fluvoxamine's safety, tolerability, ease of use, low cost, and widespread availability, might influence national and international guidelines on the clinical management of COVID-19. Full-Text PDF Open AccessFluvoxamine for the treatment of COVID-19 – Author's replyWe are grateful for the communications pertaining to our trial.1 After publication, we noticed that some decision-making groups might not have the correct understanding of composite endpoints. Composite endpoint guidance is well-established. Strictly speaking, all clinical endpoints are a form of composite (eg, death can be from different reasons).2 If we apply the same composite endpoint (hospitalisation or emergency care >24 h) used in the paxlovid trial3 and molnupiravir trial,4 our effect size does not change importantly (relative risk [RR] 0·74 [95% CI 0·56–0·98]). Full-Text PDF Open AccessFluvoxamine for the treatment of COVID-19We read with interest the investigation by Gilmar Reis and colleagues1 who studied the repurposing of fluvoxamine for the mitigation of hospitalisation risk among acutely symptomatic patients with COVID-19 in Brazil. Although impressive, their observation that a 10-day course of fluvoxamine resulted in an absolute risk reduction of 5% and a relative risk reduction of 32% for hospitalisations might be an underestimate of its potential efficacy. Full-Text PDF Open Access