key: cord-0782404-wm4rzofl authors: Eugene, A. R. title: Fluoxetine pharmacokinetics and tissue distribution suggest a possible role in reducing SARS-CoV-2 titers date: 2020-12-19 journal: nan DOI: 10.1101/2020.12.17.20248442 sha: 4fc6cfde7285e834097064bb5315901d14ca889a doc_id: 782404 cord_uid: wm4rzofl Background. Recent in vitro studies have shown fluoxetine inhibits the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) pathogen and one clinical study reported fluoxetine exposure at a median dose of 20mg in patients with the SARS-Cov-2 coronavirus disease 2019 (COVID-19) had a significantly lower risk of intubation and death. The aim of this study is to conduct in silico population dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 90% inhibition (EC90) of SARS-Cov-2 as reported in Calu-3 human lung cells. Methods. Population pharmacokinetic parameter estimates for a structural one-compartment model with first-order absorption was used to simulate fluoxetine concentration-time data. A population of 1,000 individuals were simulated at standard fluoxetine doses (20mg/day, 40mg/day, and 60mg/day) to estimate the percentage of the patients achieving a trough level for the EC90 SARS-Cov-2 inhibitory concentration at each day throughout a 10-day treatment period. All analyses were conducted via statistical programming in R. Results. Standard fluoxetine antidepressant doses resulted in a range of 79% to 97% of the patient population achieving a trough target plasma concentration of 25.1 ng/ml which translates to lung-tissue distribution coefficient of 60-times higher (EC90 of 4.02 M). At a dose of 40mg per day, at least 85% of patients will reach the trough target EC90 concentration within 3-days. The findings of this pharmacokinetic dosing study corroborate both in vitro and observational clinical study findings showing fluoxetine inhibits the SARS-Cov-2 pathogen at commonly treated doses in the practice of psychiatry. (COVID-19) had a significantly lower risk of intubation and death. The aim of this study is to 23 conduct in silico population dosing simulations to quantify the percentage of patients achieving a 24 trough level for the effective concentration resulting in 90% inhibition (EC90) of SARS-Cov-2 25 as reported in Calu-3 human lung cells. Methods. Population pharmacokinetic parameter estimates for a structural one-compartment 27 model with first-order absorption was used to simulate fluoxetine concentration-time data. A 28 population of 1,000 individuals were simulated at standard fluoxetine doses (20mg/day, 29 40mg/day, and 60mg/day) to estimate the percentage of the patients achieving a trough level for 30 the EC90 SARS-Cov-2 inhibitory concentration at each day throughout a 10-day treatment 31 period. All analyses were conducted via statistical programming in R. Results. Standard fluoxetine antidepressant doses resulted in a range of 79% to 97% of the 33 patient population achieving a trough target plasma concentration of 25.1 ng/ml which translates 34 to lung-tissue distribution coefficient of 60-times higher (EC90 of 4.02 μM). At a dose of 40mg 35 per day, at least 85% of patients will reach the trough target EC90 concentration within 3-days. 36 The findings of this pharmacokinetic dosing study corroborate both in vitro and observational 37 clinical study findings showing fluoxetine inhibits the SARS-Cov-2 pathogen at commonly 38 treated doses in the practice of psychiatry. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 Introduction 46 The selective serotonin reuptake inhibitor (SSRI) fluoxetine is a racemic mixture of two 47 stereoisomers, (R)-fluoxetine and (S)-fluoxetine, and maintains regulatory approvals for a wide- (Schloer et al., 2020) . Taken together, these in vitro studies 59 prove in a dose-dependent manner, the SSRI fluoxetine inhibits the SARS-CoV-2 pathogen 60 known to cause the worldwide pandemic, the novel coronavirus disease 2019 . Considering the well-established clinical symptoms of COVID-19 affecting the lungs, fluoxetine 63 lung concentrations would be an important factor to consider when interpreting any study results. Johnson et al. reported human-tissue concentrations, in airline pilots, of fluoxetine in whole-65 blood ranged from 0.021-1.4 μg/ml and lung concentrations ranged from 1.56 μg/ml to 51.9 66 μg/ml, leading to a fluoxetine distribution coefficient of 60 (Johnson, Lewis & Angier, 2007) . Clinically, the fluoxetine SARS-Cov-2 in vitro findings were corroborated by Hoertel et al. who 68 showed in a multicenter observational retrospective cohort study of patients who were treated 69 with fluoxetine and diagnosed with COVID-19, experienced a lower risk of intubation and death 70 (hazard ratio=0.32; 95% confidence interval, 0.14-0.73, p=0.007) at a median fluoxetine dose of 71 20mg (standard deviation [SD]=4.82) (Hoertel et al., 2020) . In this context, the aim of this study 72 is to conduct in silico population pharmacokinetic dosing simulations to quantify the percentage 73 of patients expected to achieve the trough effective concentration resulting in 90% inhibition of 74 SARS-Cov-2. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 Pharmacokinetic Model 82 Pharmacometric model estimates for differential equation parameters and respective variances 83 for a structural one-compartment pharmacokinetic model with first-order absorption were used to 84 simulate fluoxetine concentration-time data. Model estimates were derived from drug plasma 85 concentrations in 25 females taking a mean dose of 29.4 mg (7.5-80 mg/day) when fluoxetine 86 plasma levels were at steady-state due to being collected for analysis at a minimum median time To estimate the percentage of patients from a population of one thousand simulated patients who 108 would achieve the trough target EC90 concentration, pharmacokinetic dosing of fluoxetine will 109 consist of three dosing trials of fluoxetine: 20mg/day, 40mg/day, and lastly 60mg per day. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101/2020.12.17.20248442 doi: medRxiv preprint The fraction of fluoxetine unbound in human plasma is 94%, which requires a 6% increase in 122 plasma levels to achieve whole-blood concentrations to subsequently approximate the blood:lung the Cmax is 132 ng/mL (CV=68%), Tmax of 220-hours (range, 49-220), AUC 0 Last is 20,500 141 ng•hour/ml, and population t ½ is 81.4 (SD=113), which is interpreted as 55% of the population 142 achieving the EC90 trough target at day-1 and 95% by day-10. Moreover, Figure 3 shows in a 143 patient population treated with fluoxetine at 60mg daily, results in a Cmax of 191 ng/mL 144 (CV=71%), 220-hours (range, 49-232), AUC 0 Last 29,700 ng•hour/ml, and t ½ of 85.4 (SD=209) 145 allowing 72% of the population reaching the target trough concentration threshold on day-1 and 146 97% by day-10 of fluoxetine treatment. Table 1 provides an overview of the pharmacokinetics 147 and pharmacodynamics with blood levels (ng/ml and μM) in plasma as well as calculated organ 148 concentrations (whole-blood, lung, brain, heart, liver, spleen, and kidney) as well as, the percent 149 of the population achieving trough EC90 target during a treatment period of 10-days. concentrations, standard fluoxetine doses achieve the concentrations in the lungs, brain, and 235 heart, except for the rhinovirus EC50 for the heart tissue but which will be reached in the brain 236 and lungs, as shown in Table 1. 237 238 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 A limitation of this study is associated with the previously validated fluoxetine pharmacometric 239 model being in women and did not include men (Tanoshima et al., 2014) . However, as shown Intermediate Metabolizers should be closely monitored for potential fluoxetine side-effects, but 252 may also have a higher rate of achieving the target trough EC90 concentration at a 20mg daily 253 fluoxetine dose relative to CYP2D6 Normal (Extensive) Metabolizers. Conclusions 257 Investigating fluoxetine pharmacokinetics, this study confirmed that previously published 258 median effective concentrations and specifically the EC90 fluoxetine value inhibiting SARS-259 Cov-2 in Calu-3 human lung cells is achievable using standard fluoxetine doses (20mg/day, 260 40mg/day, and 60mg/day) and also corroborates findings from a retrospective clinical study 261 showing fluoxetine exposure associated with reduced risk of intubation and death. Due to the 262 high fluoxetine brain (15-times higher) and lung (60-times higher) tissue distributions, relative to 263 whole-blood and plasma concentrations (6% lower than whole blood), treatment with fluoxetine 264 may serve as pragmatic therapeutic option in patients with lingering post-COVID-19 syndrome 265 neurocognitive effects or in primary management of COVID-19. Overall, assuming patients are 266 not treated with medications that result in drug interactions with fluoxetine -that is are sensitive 267 or moderate CYP2D6 metabolic substrates -a dose of 40mg per day of fluoxetine will likely be 268 most effective with inhibiting SARS-Cov-2 titers. That 40mg daily fluoxetine dose will lead to 269 55% of the population achieving the trough EC90 target at day-1, 93% by day-7, and 95% of 270 patients achieving the trough target EC90 concentration within 10-days of fluoxetine. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10. 1101 /2020 Tables 372 373 Table 1 : Fluoxetine pharmacokinetics and pharmacodynamics showing blood levels (ng/ml and 374 μM) and percent of population achieving plasma trough concentration of 25.1 ng/ml leading to a 375 lung-EC90 target of 4.02 μM during a treatment period of 10-days. The dashed horizontal line depicts the effective concentration resulting in 90% inhibition (EC90) 389 of SARS-Cov-2 that will result in 60-times higher level in the lungs. The dashed horizontal line depicts the effective concentration resulting in 90% inhibition (EC90) 396 of SARS-Cov-2 that will result in 60-times higher level in the lungs . 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint Schloer et al., 2020) . Maximum plasma concentration (Cmax) are expressed as geometric mean (geometric coefficient of variation, CV%). Fluoxetine tissue distribution coefficients (60 for lung, 20 for spleen, 15 for brain, 10 for heart, and 9 for kidneys) were scaled from whole-blood, then plasma, and then to organs as reported (Johnson, Lewis & Angier, 2007) . 419 420 421 422 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 Table 1: Fluoxetine pharmacokinetics and pharmacodynamics showing blood levels (ng/ml and μM) and percent of population achieving plasma trough concentration of 25.1 ng/ml leading to a lung-EC90