Fluoxetine pharmacokinetics and tissue distribution quantitatively supports a therapeutic role in COVID-19 at a minimum dose of 20 mg per day

Abstract

Background. Various in vitro studies have shown fluoxetine inhibits multiple variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen causing the coronavirus disease 2019 (COVID-19) worldwide pandemic and multiple observational clinical studies have shown that patients receiving fluoxetine experienced clinical benefit by lowering the risk of intubation and death. The aim of this study is to conduct population pharmacokinetic dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 50% (EC50) and 90% (EC90) inhibition of SARS-CoV-2 as reported in Calu-3 human lung cells. Methods. Pharmacometric parameter estimates used in this study were obtained from the U.S. FDA website from a new drug application for fluoxetine hydrochloride. A population of 1,000 individuals were simulated at standard fluoxetine antidepressant doses (20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, and 60 mg/day) to estimate the percentage of the patients achieving a trough plasma level for the EC50 and EC90 SARS-CoV-2 inhibition. All analyses and graphing were conducted in the R. Results. By day-10 at 20 mg/day 93.2% and 47% of the population will achieve the trough target plasma EC50 and EC90 concentrations, respectively, which translates to a lung tissue distribution coefficient of 60-times higher EC50 (283.6 ng/ml [0.82 mM]) and EC90 (1390.1 ng/ml [4.02 mM]). Further, by day-10 at an ideal dose of 40 mg/day, 99% and 93% of patients will reach the trough EC50 and EC90 concentrations, respectfully. Lastly, only a dose of 60 mg/day will reach the SARS-CoV-2 EC90 inhibitory concentration in the brain. Conclusion. Overall, with a minimum treatment period of 10-days and a minimum dose of 20 mg/day, this study corroborates in vitro studies reporting fluoxetine inhibiting SARS-CoV-2 titers and also multiple observational clinical studies showing therapeutic benefit of fluoxetine in COVID-19 patients.

Antidepressant Use and Its Association with 28-Day Mortality in Inpatients with SARS-CoV-2: Support for the FIASMA Model against COVID-19

“…Inhibition of the ASM catalyzing the formation of ceramides [ 50 , 65 ] by FIASMA antidepressants may result in two effects: antiviral—through the reduced formation of ceramide-enriched membrane domains that facilitate SARS-CoV-2 entry in cells, and anti-inflammatory—through the inhibition of ASM in endothelial cells and the immune system [ 7 , 12 ]. Based on these results, fluoxetine, which is on the World Health Organization’s Model List of Essential Medicines, has the greatest in vitro inhibitory effect on the ASM-ceramide system [ 50 ], a favorable pharmacokinetic profile [ 66 ], and is one of the best in tolerability [ 8 , 9 ] among SSRIs, should be considered a promising molecule to prioritize for randomized clinical trials in COVID-19 [ 7 , 11 ].…”

Association Between Selective Serotonin Reuptake Inhibitors Prevalent Use and COVID-19–Related Mortality

“…Third, the present study lacks an SSRI dose range report. This represents a limitation because prior work suggests that the effect on acid-sphingomyelinase activity of a drug is likely to depend on the prescribed dose 44 . Nevertheless, most patients in this cohort were treated for mood disorders, and a common dose range prescription for SSRI was expected under these diagnoses.…”

The effect of antidepressants on the severity of COVID-19 in hospitalized patients: A systematic review and meta-analysis

“…For example, effective results of Fluoxetine in the treatment of Covid-19 have clinically relevant to pharmacogenomics concerns, and a minimum dose of 20 mg/day for at least 10-days inhibits SARS-CoV-2 infectivity due to efficient lung distribution at a 60-times higher concentration. However, this matter may not be achievable for other medications [ 65 ]. As we mentioned before, According to Nemeth et al [ 24 ] study Fluoxetine use was associated with a about 70% decrease in mortality and threefold survival in the Fluoxetine group;.…”