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<p class="title-left"><span class="bold">Remdesivir and Potential Interactions With Psychotropic Medications:</span></p>
<p class="subtitle">A COVID-19 Perspective</p>
<p class="byline-regular">Zeeshan Mansuri, MD, MPH<span class="superscript">a,</span><span class="asterisk">*</span>; Bhumika Shah, MD<span class="superscript">b</span>; Muhammad Khalid Zafar, MD<span class="superscript">a</span>; Taranjeet Jolly, MD<span class="superscript">c,‡</span>; and Shailesh Jain, MD, MPH, ABDA<span class="superscript">a,‡</span></p>
<p class="drop-cap-with-body-text"><span class="bold-14pt-for-cap"><span class="bold">T</span></span>he US Food and Drug Administration (FDA) has approved remdesivir for severe coronavirus disease 2019 (COVID-19) in children and adults.<span class="htm-cite"><a href="#ref1">1</a></span> Remdesivir is a prodrug of a nucleotide analog that inhibits viral RNA-dependant RNA polymerase.<span class="htm-cite"><a href="#ref2">2</a>,<a href="#ref3">3</a></span> Initially studied in vitro for Ebola, remdesivir has shown efficacy against severe acute respiratory syndrome coronavirus 2.<span class="htm-cite"><a href="#ref2">2</a>,<a href="#ref3">3</a></span> Remdesivir is metabolized into a triphosphate metabolite.<span class="htm-cite"><a href="#ref4">4</a></span> Not much is known about remdesivir’s drug interactions with psychotropics. We searched PubMed, Embase, Scopus, SciELO, PsycINFO, and Web of Science and looked at multiple guidelines including Medscape and Liverpool. Given the limited information available, the objective of this commentary is to review the potential interactions of remdesivir with psychotropic medications and summarize the current evidence.</p>
<p class="subheads-subhead-2">Potential Pharmacodynamic Interactions</p>
<p class="body-text">Remdesivir has a low propensity for pharmacodynamic interactions given its mechanism of action.<span class="htm-cite"><a href="#ref1">1</a>,<a href="#ref5">5</a></span></p>
<p class="subheads-subhead-3-with-body-text"><span class="bold-italic">QTc prolongation.</span> There are no published reports of prolonged QTc, torsades de pointes, or arrhythmias in any database, including the World Health Organization’s VigiBase or FDA Adverse Event Reporting System.<span class="htm-cite"><a href="#ref1">1</a></span> There is 1 study<span class="htm-cite"><a href="#ref6">6</a></span> on favipiravir, which is a similar medication. The small study<span class="htm-cite"><a href="#ref6">6</a></span> of 56 patients did not lead to QTc prolongation. Other options for COVID-19 treatment include chloroquine/hydroxychloroquine and ritonavir/lopinavir, which have a propensity to prolong the QT interval.<span class="htm-cite"><a href="#ref1">1</a>,<a href="#ref5">5</a></span> Since the moderate-to-severe COVID-19 patients also likely have ≥<span class="thinspace"> </span>1 medical conditions that can prolong the QT interval, the absence of QT prolongation with remdesivir is crucial when making treatment decisions.<span class="htm-cite"><a href="#ref1">1</a>,<a href="#ref5">5</a></span></p>
<p class="subheads-subhead-2">Potential Pharmacokinetic Interactions</p>
<p class="body-text">There is limited information about the absorption, distribution, metabolism, and elimination of remdesivir.<span class="htm-cite"><a href="#ref1">1</a></span>In vitro, remdesivir is a substrate for cytochrome P450 (CYP) 2C8, 2D6, and 3A4, along with p-glycoprotein and organic anion transporting polypeptides 1B1 (OATP1B1). It is also an inhibitor of CYP3A4, OATP1B1, OATP1B3, bile salt export pump, multidrug resistance-associated protein MRP4, and sodium/taurocholate cotransporting polypeptide. These in vitro studies<span class="htm-cite"><a href="#ref7">7</a></span> have not been followed up by studies assessing its clinical importance.<span class="htm-cite"><a href="#ref1">1</a></span> The clinical application of these in vitro studies is unknown at this point.<span class="htm-cite"><a href="#ref1">1</a></span></p>
<p class="body-text">There were some initial concerns about remdesivir and possible CYP3A4–based interactions. However, since it is primarily metabolized by hydrolase and initial results suggest that it is sensitive to esterases, no clinically relevant interactions are expected.<span class="htm-cite"><a href="#ref1">1</a></span></p>
<p class="body-text">When coadministered with carbamazepine, there is a potential decrease in remdesivir concentration. This combination should not be coadministered.<span class="htm-cite"><a href="#ref5">5</a></span> A similar interaction is described when coadministered with phenobarbital, phenytoin, and primidone, and so they should not be coadministered with remdesivir.<span class="htm-cite"><a href="#ref5">5</a></span> Remdesivir, when coadministered with eslicarbazepine or oxcarbazepine, needs close monitoring or dose adjustment, as it has the potential to decrease the concentration of remdesivir.<span class="htm-cite"><a href="#ref5">5</a></span></p>
<p class="body-text">St John’s wort can decrease remdesivir levels.<span class="htm-cite"><a href="#ref5">5</a></span> At this time, antidepressants, in general, are not known to interact with remdesivir.<span class="htm-cite"><a href="#ref5">5</a></span></p>
<p class="body-text">Antipsychotics like thioridazine can potentially decrease remdesivir levels and require close monitoring or dose adjustment.<span class="htm-cite"><a href="#ref5">5</a></span> At this time, other typical and atypical antipsychotics, in general, are not known to interact with remdesivir.<span class="htm-cite"><a href="#ref5">5</a></span></p>
<p class="body-text">In summary, since there is a paucity of clinical experience with remdesivir, we urge psychiatrists to check updated drug interactions when coadministering any psychotropic medications.</p>
<p class="end-matter"><span class="bold-italic">Received:</span> May 9, 2020.</p>
<p class="end-matter"><span class="bold-italic">Published online:</span> May 28, 2020.</p>
<p class="end-matter"><span class="bold-italic">Potential conflicts of interest:</span> None. </p>
<p class="end-matter"><span class="bold-italic">Funding/support:</span> None.</p>
<p class="references_references-heading"><span class="bold">REFERENCES</span></p>
<p class="references-references-text-1-9"><a name="ref1"></a><span class="htm-ref"> 1. </span>Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Remdesivir (GS-5734). FDA website. <a href="https://www.fda.gov/media/137566/download" target="_blank"><span class="hyperlink">https://www.fda.gov/media/137566/download</span></a>. Accessed May 16, 2020.</p>
<p class="references-references-text-1-9"><a name="ref2"></a><span class="htm-ref"> 2. </span>Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial [published online ahead of print April 29, 2020]. <span class="italic">Lancet. </span>2020;395(10236):1569–1579. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190303/" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref3"></a><span class="htm-ref"> 3. </span>Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe COVID-19 [published online ahead of print April 10, 2020]. <span class="italic">N Engl J Med</span>. 2020;NEJMoa2007016. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=32275812&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.1056/NEJMoa2007016" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref4"></a><span class="htm-ref"> 4. </span>Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. <span class="italic">Nature</span>. 2016;531(7594):381–385. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=26934220&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.1038/nature17180" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref5"></a><span class="htm-ref"> 5. </span>COVID-19 Drug Interactions. <a href="https://www.covid19-druginteractions.org/" target="_blank"><span class="hyperlink">https://www.covid19-druginteractions.org/</span></a>. Accessed May 16, 2020. </p>
<p class="references-references-text-1-9"><a name="ref6"></a><span class="htm-ref"> 6. </span>Kumagai Y, Murakawa Y, Hasunuma T, et al. Lack of effect of favipiravir, a novel antiviral agent, on QT interval in healthy Japanese adults. <span class="italic">Int J Clin Pharmacol Ther.</span> 2015;53(10):866–874. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=26308176&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.5414/CP202388" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref7"></a><span class="htm-ref"> 7. </span>Coronavirus disease 2019 treatment: a review of early and emerging options. <a href="https://academic.oup.com/ofid/article/7/4/ofaa105/5811022" target="_blank"><span class="hyperlink">https://academic.oup.com/ofid/article/7/4/ofaa105/5811022</span></a>. Accessed May 16, 2020.</p><div id="affilDiv"></div>
<p class="front-matter-rule"><span class="superscript">a</span>Department of Psychiatry, Texas Tech University Health Science Center at Odessa/Permian Basin, Odessa, Texas</p>
<p class="front-matter"><span class="superscript">b</span>De Sousa Research Foundation, Mumbai, India</p>
<p class="front-matter"><span class="superscript">c</span>Department of Psychiatry, Penn State College of Medicine, Harrisburg, Pennsylvania</p>
<p class="front-matter">‡Drs Jolly and Jain share equal credits for senior authorship.</p>
<p class="front-matter"><span class="asterisk">*</span><span class="italic">Corresponding author:</span> Zeeshan Mansuri, MD, MPH, Texas Tech University Health Science Center at Odessa/Permian Basin, 2301 W Michigan Ave, Midland, Texas 79701 <span class="hyperlink">(<a href="mailto:zeeshanmansuri@gmail.com">zeeshanmansuri@gmail.com</a>)</span>.</p>
<p class="front-matter"><span class="italic">Prim Care Companion CNS Disord 2020;22(3):20com02664</span></p>
<p class="front-matter-rule"><span class="bold-italic">To cite:</span> Mansuri Z, Shah B, Zafar MK, et al. Remdesivir and potential interactions with psychotropic medications: a COVID-19 perspective. <span class="italic">Prim Care Companion CNS Disord</span>. 2020;22(3):20com02664.</p>
<p class="doi-line"><span class="bold-italic">To share:</span> https://doi.org/<span class="doi">10.4088/PCC.20com02664</span></p>
<p class="front-matter"><span class="italic">© Copyright 2020 Physicians Postgraduate Press, Inc.</span></p>
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