key: cord-0809813-qtp390lm authors: Li, Lu; Wang, Xiaojuan; Wang, Rongrong; Hu, Yunzhen; Jiang, Saiping; Lu, Xiaoyang title: Antiviral Agent Therapy Optimization in Special Populations of COVID-19 Patients date: 2020-07-28 journal: Drug Des Devel Ther DOI: 10.2147/dddt.s259058 sha: 28d8c4f47fb368408c0c40f21354be4583c21178 doc_id: 809813 cord_uid: qtp390lm Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a global outbreak of disease. The antiviral treatment acts as one of the most important means of SARS-CoV-2 infection. Alteration of physiological characteristics in special populations may lead to the change in drug pharmacokinetics, which may result in treatment failure or increased adverse drug reactions. Some potential drugs have shown antiviral effects on SARS-CoV-2 infections, such as chloroquine, hydroxychloroquine, favipiravir, lopinavir/ritonavir, arbidol, interferon alpha, and remedsivir. Here, we reviewed the literature on clinical effects in COVID-19 patients of these antiviral agents and provided the potential antiviral agent options for pregnant women, elderly patients, liver or renal dysfunction patients, and severe or critically ill patients receiving renal replacement therapy or ECMO after SARS-CoV-2 infection. A novel coronavirus named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China from December 2019, and quickly spread across the world. As of 20 April 2020, more than 2,246,200 coronavirus disease-19 (COVID- 19) cases have been reported to WHO, and more than 152,700 patients have lost their lives. 1 COVID-19 has been found in over 210 countries, areas or territories, and is a global health crisis. Medication treatment, oxygen therapy, support techniques such as extracorporeal membrane oxygenation (ECMO), are the main therapeutic means of SARS-CoV-2 infection. Antivirals are a class of small molecules that function as inhibitors of one or more stages of a virus life cycle. 2 Antiviral drug therapy is one of the most important parts of medical treatment. At the early transmission period of COVID-19, no antiviral agents for SARS-CoV2 infection have been proven to be effective. With the deepening of researches and accumulation of clinical experiences, several kinds of antiviral agents are regarded as potentially effective drugs for SARS-CoV2 infection. According to the information from the Centers for Disease Control and Prevention, 3 the elderly are at higher risk for severe illness of COVID-19. Pregnant women experience immunologic and physiologic changes which might make them more susceptible to COVID-19. Both the elderly and pregnant women have special physiological characteristics and are at higher risks of medication treatment, especially the 19 patients weighing less than 50 kg, the recommended dose of chloroquine phosphate is 500 mg bid at the first 2 days, and 500 mg qd from day 3 to day 7; For COVID-19 patients weighing more than 50 kg, the recommended dose of chloroquine phosphate is 500 mg bid for 7 days. 11 A randomized clinical trial found that COVID-19 patients who receiving a high-dosage chloroquine (600 mg twice daily for 10 days) had a higher lethality and more instance of QTc interval than those who received a low-dosage chloroquine (450 mg twice daily on day 1 and once daily for 4 days). 12 Therefore, higher chloroquine dosage should not be recommended for critically ill patients with More clinical data about the effectiveness and safety of chloroquine are required for chloroquine dose optimization. Hydroxychloroquine is an analog of chloroquine and exhibits an antiviral effect similar to that of chloroquine. 13 A recent study demonstrated that hydroxychloroquine (EC50=0.72 μM) was found to be more potent than chloroquine in vitro. 14 The studies on the antiviral effects of hydroxychloroquine against SARS-CoV2 are controversial. An open-label non-randomized clinical trial showed that hydroxychloroquine (200 mg tid) combined azithromycin seems to be an alternative therapeutic strategy for SARS-CoV-2 elimination, 15 but the study had serious methodological flaws. A small, randomized clinical trial found that hydroxychloroquine (200 mg twice daily from day 1 to day 5) could shorten the time to clinical recovery and promote the absorption of pneumonia. 16 However, another small, randomized study in COVID-19 patients also found no difference in recovery rates between hydroxychloroquine treatment (400 mg daily) and other antivirals such as arbidol or lopinavir/ritonavir. 17 An open-label, randomized controlled trial enrolled 150 mild to moderate COVID-19 patients showed that hydroxychloroquine administrated at a loading dose of 1200 mg daily for 3 days followed by a maintenance dose of 800 mg daily did not result in a significantly higher probability of negative conversion than the standard of care alone in patients. 18 An observational study indicated that hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death. 19 The effect of hydroxychloroquine remains uncertain. Hydroxychloroquine is one of the treatment options in "Solidarity" clinical trial of COVID-19 treatments, which is launched by the WHO and partners. On May 23, the WHO decided to implement a temporary pause of the hydroxychloroquine arm of the trial, because of concerns raised about the safety of the drug. On 3 June 2020, WHO announced that on the basis of the available mortality data, there are no reasons to modify the trial protocol, including hydroxychloroquine. 20 A recent study also demonstrated that although hydroxychloroquine did not prevent illness compatible with COVID-19 when used as postexposure prophylaxis, no serious adverse reactions were reported after hydroxychloroquine administration (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). 21 Randomized, controlled trials with larger sample numbers of COVID-19 patients to evaluate the efficiency and safety of hydroxychloroquine are needed. Favipiravir is a nucleotide analog that approved for a novel or re-emerging influenza in Japan and has been demonstrated as a broad-spectrum inhibitor of RNA virus. Favipiravir phosphoribosylated by cellular enzymes to favipiravir-ribofuranosyl-5ʹ-triphosphate, which then mistakenly recognized by viral RNA polymerase as a purine nucleotide. 22 A high concentration of favipiravir (EC 50 = 61.88 μM, CC 50 > 400 μM, SI > 6.46) was required to reduce the SARS-CoV-2 infection in vitro. 6 Recently, an open-label control study was conducted to evaluate the clinical effects of favipiravir in COVID-19 patients, and the dose regimen of favipiravir in this study was 1600 mg twice daily at the first day, and then 600 mg twice daily from day 2 to day 14. 23 The study indicated that favipiravir was independently associated with faster viral clearance and presented better treatment effects on COVID-19 patients. A randomized clinical trial showed that compared to arbidol, favipiravir did not significantly improve the clinical recovery rate at Day 7, but significantly improved the latency to relief for pyrexia and cough. 24 Favipiravir is a relatively safe potential antiviral agent for COVID-19, but the antiviral effects need to be further validated. Additionally, in some regions, it is not easy to mobilize against COVID- 19. Of note, previous studies demonstrated that the plasma concentration of favipiravir in USA patients was 50% of that in Japanese patients, which suggested a possible regional difference in the pharmacokinetics of favipiravir.-25 Therefore, the dose regimen for COVID-19 patients should be carefully considered. Lopinavir is a human immunodeficiency virus 1 (HIV-1) protease inhibitor and ritonavir is combined to increase the half-life time of lopinavir. Lopinavir/ritonavir showed inhibitory effects on SARS-CoV through inhibiting 3CLpro protease activity. 26 Some researchers have reported the treatment effects of lopinavir/ritonavir on COVID-19. A case report showed that SARS-CoV-2 loads significantly decreased after one-day treatment of lopinavir/ritonavir (400 mg/100 mg, twice daily), and no or little coronavirus titers have been observed since then. 27 A randomized, controlled, open-label trial was conducted to evaluate the clinical effects of lopinavir/ritonavir in severe COVID-19 patients, and they were orally administrated at a dose of 400 mg/100 mg twice daily for 14 days in this study. 28 The result showed that treatment with lopinavir/ritonavir was not associated with a difference from standard care in the time to clinical improvement. However, the 28-day mortality was numerically lower and patients had a shorter stay in the intensive care unit (ICU) in the lopinavir/ritonavir group than those in the standard care group. The author has indicated that after the exclusion of three patients who died within 24 hours after randomization and did not receive lopinavir/ritonavir, the time to clinical improvement in the lopinavir/ritonavir group was 1 day shorter than that in the control group using the modified intention-to-treat analysis. 29 The lopinavir/ritonavir combination is relatively safe and could be easily mobilized against COVID-19. Additional clinical trials with a larger sample size involving patients with milder disease, earlier drug administration, and an extended treatment course may be helpful in further evaluating the effectiveness of lopinavir/ritonavir against COVID-19. On the other hand, some studies indicated that COVID-19 patients may get benefit from lopinavir/ritonavir combined arbidol treatment, see section "Arbidol". Arbidol is a small indole-derivative molecule and involves inhibition of virus-mediated fusion with the target membrane and a resulting block of virus entry into target cells. 30 A retrospective study including 69 adults revealed that arbidol showed a tendency to the discharging rate and reduce mortality. 31 Combination of arbidol and lopinavir/ritonavir has applied as the basic regimen for antiviral treatment in some hospitals and showed antiviral effects in COVID-19. 32 A single-center retrospective cohort study revealed that oral arbidol and lopinavir/ritonavir in the combination group was associated with a significant elevated negative conversion rate of coronavirus' test in 7-day and 14-day, in comparison with lopinavir/ritonavir only in the monotherapy group. Furthermore, combination therapy is associated with a significantly improved the chest CT scans in 7-day. 33 A retrospective study found that COVID-19 patients treated with arbidol had a shorter duration of positive RNA test compared to those treated with lopinavir/ritonavir. 34 A recent study found that arbidol post-exposure prophylaxis was a protective factor against the development of COVID-19, 35 arbidol might reduce the infection risk of the COVID-19 in hospital and family settings. Arbidol is a relatively safe potential antiviral agent for COVID-19, but in some regions, it is not easy to obtain. Previous in vitro studies found that IFN-α and IFN-β showed antiviral effect against SARS-CoV. 36 Both IFN-α and IFN-β were applied during MERS-CoV infection. 37 A nonrandomized single-arm intervention study found that IFN-α2b combined with ribavirin showed lower crude 14day mortality rate than supportive care. 38 A retrospective cohort study found that IFN-α was not associated with crude mortality rate, while an increase in crude mortality rate was observed in MERS-CoV infection patients who treated with IFN-β. 39 Another nonrandomized single-arm intervention study showed that no difference was observed in the unadjusted mortality rate between IFN-α2a and IFNβ1a, where all MERS-CoV patients were co-treated with ribavirin. 40 Due to the lacking of evidence in the early period of COVID-19 outbreak, only IFN-α nebulization is recommended as a potential antiviral treatment method for SARS-CoV-2 infection by the Chinese National Health Committee. 11 IFN-α is always used as one of the combination therapy drugs during COVID-19 treatment. In clinical trials, IFN-α often combined with other antivirals, such as favipiravir, 23 lopinavir/ritonavir. 41 There are no clinical trials about the effects of IFN-α monotherapy on SATS-CoV-2 infection. The recommended dose is 5 million units twice daily by aerosol inhalation. IFN-α nebulization should be performed in negative-pressure wards rather than general wards due to the possibility of aerosol transmission. 32 The denaturation of IFN-α would be related to the heating of nebulizer solution; therefore, ultrasonic nebulization should be avoided. 42 Remdesivir, an adenosine analog, is a monophosphoramidate prodrug and metabolized into its active form, which can obscure viral RNA polymerase and evade proofreading by viral exonuclease, thereby causing a decrease in viral RNA production. 43 A model for SARS-CoV-2 RdRp was constructed and the results suggested that remdesivir was a potent drug against the newly emerged COVID-19 disease. 44 In vitro study showed that remdesivir (EC50= 0.77 μM; CC50>100 μM; SI > 129.87) potently blocked SARS-CoV-2 infection at low concentration and showed the high SI. 6 Compassionate use was reported on a deteriorating case with good recovery. 45 Currently, a randomized, controlled, double-blind trial (https://clinicaltrials.gov/ct2/show/ NCT04252664) involving hospitalized adult patients with mild and moderate COVID-19 disease in China has been suspended. A newly published study demonstrated that clinical improvement was observed in 68% severe COVID-19 patients who were treated with compassionate-use remdesivir. 46 A recent double-blind, randomized, placebocontrolled trial of intravenous remdesivir in adults hospitalized with Covid-19 showed that Remdesivir was superior to placebo in shortening the time to recovery. 47 FDA issued an emergency use authorization for the investigational antiviral drug remdesivir for the treatment of suspected or laboratoryconfirmed COVID-19 in adults and children hospitalized with severe disease. 48 Remdesivir seems to be one of the most promising antivirals against SARS-CoV-2 infection, but it is still an investigated drug with unknown adverse effects and is relatively hard to obtain. Evaluation of remdesivir efficacy still requires ongoing randomized, placebocontrolled trials of remdesivir therapy. An animal study indicated that chloroquine could pass across the placenta and accumulated in melanin structures of the fetal eyes. 49 Moreover, a pharmacokinetic study of chloroquine based on a population pharmacokinetic modeling showed that pregnancy significantly reduced exposure to chloroquine. 50 Pregnancy may lead to the failure of chloroquine treatment. Nevertheless, chloroquine has been a choice for malaria prevention and treatment in pregnant women. 51, 52 A study revealed that chloroquine can be safe in pregnant women after a dosage of 500 mg/day. 53 We suggested that a daily dosage of chloroquine higher than 500 mg should be avoided in pregnant women. Hydroxychloroquine treatment could improve the pregnancy outcome in women with antiphospholipid antibodies. 54 However, the dose of hydroxychloroquine (200 mg bid) was lower than that recommended in COVID-19 (200 mg bid to tid). Hydroxychloroquine could be detected in the cord blood, and the concentrations were similar to those in the maternal serum. 55 Higher concentrations of hydroxychloroquine may result in drug accumulation in the fetus. Considering the lower adverse drug reactions of hydroxychloroquine, 13 we suggest that the advantages and disadvantages should be carefully evaluated before using hydroxychloroquine in pregnant women with COVID-19. Favipiravir is prohibited for pregnant women. Animal experiments showed that early embryonic lethality (rat) and teratogenicity (monkey, mouse, rat and rabbit) were observed at doses similar to or lower than clinical exposure. 56 The use of the lopinavir/ritonavir by pregnant women did not increase the rate of preterm birth and low birth weight. 57 Lopinavir/ritonavir oral solution contains 42.4% (volume/volume) alcohol and 15.3% (weight/volume) propylene glycol. Therefore, the oral solution is not recommended for use during pregnancy. It was reported that a reduction in lopinavir plasma concentrations during pregnancy of around 30% compared with those in non-pregnant adults. 58 Increasing the dose of lopinavir/ritonavir during pregnancy to 600 mg/150 mg resulted in lopinavir plasma concentrations equivalent to those in non-pregnant adults receiving standard doses (400 mg/100 mg). Based on these data, the US Department of Health and Human Services guidelines recommends increasing lopinavir/ritonavir dose to 600 mg/150 mg twice daily in the third trimester. 59 However, FDA recommends taking lopinavir/ ritonavir 400/100 mg twice daily in pregnant women with no documented lopinavir-associated resistance substitutions, and no dose adjustment of lopinavir/ritonavir is required for patients during the postpartum period. 60 We suggest that lopinavir/ritonavir tablets could be used during pregnancy, and if lopinavir/ritonavir were used with standard doses during pregnancy, SARS-CoV-2 loads and drug concentration of lopinavir should be monitored. IFN-α is assumed to have abortifacient potential. IFN-α is used by aerosol inhalation for COVID-19 treatment, which may indicate less systemic distribution. However, the previous study showed that adverse reactions and blood concentration were related to inhaled dosage. 61 Three million units daily administered by aerosol induced a significant biological activity of IFN-α. 62 Considering the recommended dose (5 million twice daily) is higher, we suggest that IFN-α aerosol inhalation therapy is to be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Currently, there is no related research on the application of arbidol in pregnant women. Therefore, we suggest that arbidol is not recommended in COVID-19 patients during pregnancy. According to the fact sheet of remdesivir for health care providers, remdesivir should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus. 63 Elderly patients are more likely to have decreased renal function, thereby may lead to chloroquine accumulation. The Chinese National Health Committee did not recommend elderly COVID-19 patients to receive chloroquine treatment. 11 We suggest taking care of dose selection and closely monitor renal function as well as other adverse effects such as cardiac disorders and ocular disorders. Hydroxychloroquine has a lower level of tissue accumulation than chloroquine, thereby, has few adverse reactions. 13 Hydroxychloroquine could be used in elder COVID-19 patients, and adverse drug reactions such as cardiac disorders, ocular disorders and renal function should be monitored. Considering the declined physiological function, older adults should be closely monitored after taking favipiravir. Lopinavir/ritonavir clinical trials did not include a sufficient number of subjects age ≥65 years. 60 Considering the declined physiological function, the adverse effects and the drug interactions should be closely monitored after older adults taking lopinavir/ritonavir. It was reported that the use of arbidol in patients over 65 years old reduced the incidence of nosocomial pneumonia, and adverse reactions associated with the arbidol were not identified in the study. 64 We suggest that elderly COVID-19 patients could use arbidol. Besides, arbidol is metabolized by CYP3A4, and ritonavir is a CYP3A inhibitor; therefore, a combination of ritonavir and arbidol may increase the arbidol serum concentration. Adverse effects such as elevation of serum transaminase in elderly COVID-19 patients who receiving combination treatment of arbidol and lopinavir/ritonavir. IFN-α could be used in elderly patients. However, adverse reactions such as fever, influenza-like symptoms, nausea, flush, and headache were observed in patients receiving IFN-α inhalation. 61 Adverse reactions may be more severe in the elderly patients, and caution should be exercised in the use of IFN-α. The pharmacokinetics of remdesivir have not been evaluated in patients >65 years of age. In general, appropriate caution should be exercised in the administration of remdesivir and monitoring of elderly patients. 63 Chloroquine could deposit in liver tissues in considerable amounts. It should be used with caution in patients with liver dysfunction. 65 Hydroxychloroquine is metabolized by the liver. Although there are no dosage adjustments provided in the manufacturer's labeling, hydroxychloroquine should be used with caution in patients with liver dysfunction. 66 Favipiravir is mainly metabolized to the hydroxylated form by aldehyde oxidase and partly by xanthine oxidase. 67 Patients with severe liver dysfunction (Child-Pugh C) showed an increase in AUC (6.3 fold) and C max (2.1 fold). 56 We suggested that COVID-19 patients with severe liver function impairment should reduce favipiravir dosage. Lopinavir is principally metabolized by CYP3A and ritonavir is an inhibitor of CYP3A. 68 Mild to moderate liver function impairment led to a 30% increase in AUC of lopinavir, but no clear correlation between the increase and clinical treatment was observed. 69 Lopinavir/ritonavir has not been studied in patients with severe hepatic impairment. 69 Based on the fact that lopinavir/ritonavir can lead to elevated liver enzymes and bilirubin, lopinavir/ritonavir may worsen liver dysfunction. Therefore, we suggest that caution should be exercised when administering lopinavir/ritonavir in COVID-19 patients with hepatic impairment. Presently, arbidol has not been studied in patients with liver function impairment, and there is no relevant recommendation in the manufacturer's labeling either. Considering that arbidol is mainly metabolized by CYP3A4 and UGT1A9, 70 we suggest that COVID-19 patients with liver function impairment should use arbidol with clinical caution. IFN-α is contraindicated in patients with autoimmune hepatitis or decompensated liver disease. Although it is administrated by aerosol inhalation, we suggested that it should not be used in COVID-19 with autoimmune hepatitis or decompensated liver disease. The pharmacokinetics (PK) of remdesivir in humans is not clear. According to the PK study in rhesus monkeys, remdesivir exhibits a short plasma half-life with faster systemic elimination and rapidly distributed in peripheral blood mononuclear cells. In vitro study indicated low cytotoxicity of remdesivir in human primary hepatocytes. 43 It is not known if dosage adjustment is needed in patients with hepatic impairment and remdesivir should only be used in patients with hepatic impairment if the potential benefit outweighs the potential risk. 63 One of the main adverse reactions of remdesivir is the increased liver transaminases; therefore, remdesivir should not be initiated in patients with ALT ≥ 5 times the upper limit of normal at baseline. 63 Further study is needed for the safety of remdesivir in patients with liver dysfunction. Chloroquine and its metabolites excreted from urine. Slightly more than half of the urinary drug products can be accounted for as unchanged chloroquine. When the glomerular filtration rate (GFR) is less than 10 mL/min, the dose of chloroquine should reduce by half. 71 Hydroxychloroquine is excreted by urine as metabolites and unchanged drug (up to 60%). Dosage should be adjusted according to GFR: when GFR ranges from 20 to 50 mL/min, the maximum daily dose of hydroxychloroquine should be 75 mg, when GFR ranges from 10 to 20 mL/min, the maximum daily dose of hydroxychloroquine should be 50 mg; when GFR is less than 10 mL/min, the hydroxychloroquine is contraindicated. 72 Favipiravir is mainly excreted in the urine as the hydroxylated form, little is excreted as unchanged drug. We suggested that COVID-19 patients with renal function impairment should not adjust the dose regimen. Lopinavir PK has not been studied in patients with renal impairment; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment. We suggest that COVID-19 patients with renal function impairment should not adjust the dose regimen. Arbidol has not been studied in patients with renal function impairment. It was reported that in human urine, glucuronide and sulfate conjugates of arbidol were detected as the major metabolites, accounting for 6.3% of the dose excreted within 0 to 96 h after drug administration. The fecal specimens mainly contained the unchanged arbidol, accounting for 32.4% of the dose. 70 Therefore, we speculate that COVID-19 patients with mild to moderate renal function impairment should not adjust the dose regimen, and the manufacturer's labeling 73 suggested that patients with severe renal function impairment should use arbidol with clinical caution. Since IFN-α is administrated by aerosol inhalation, we suggest that dose adjustment is not needed in patients with renal dysfunction. The elimination of remdesivir in humans is not clear. In vitro study showed low cytotoxicity of remdesivir in renal proximal tubular epithelial cells. 43 Patients with eGFR greater than or equal to 30 mL/min have received remdesivir for treatment of COVID-19 with no dose adjustment of remdesivir, and remdesivir is not recommended in adult patients with eGFR less than 30 mL/min unless the potential benefit outweighs the potential risk. 63 Renal replacement therapy (RRT), especially the continuous renal replacement therapy (CRRT), could keep a stable mean arterial pressure and effective renal perfusion, maintain the fluid, electrolyte, and acid-alkaline balance in efficient and smooth manners, and is often required in critically ill patients. (10.3389/fphar.2020.00786) According to the recent report, about 17% of the critically ill COVID-19 patients received RRT. 74 Pharmacokinetics of drugs could be altered during RRT. 75 For patients receiving hemodialysis or peritoneal dialysis, the dosage of chloroquine should be as same as patients with GFR< 10 mL/min, namely, administer 50% of the original dose. For patients receiving CRRT, no dosage adjustment is necessary. 71 A case report investigated the effects of continuous venovenous haemofiltration (CVVH) on patients taking favipiravir and showed that CVVH had no clinically relevant contribution to total clearance of favipiravir. 76 Reducing the dose regimen of favipiravir during CVVH may be not appropriate. Pharmacokinetics of hydroxychloroquine, lopinavir/ ritonavir, and arbidol have not been studied in patients with renal replacement therapy. Lopinavir and ritonavir are 98-99% bound to the blood plasma protein albumin and alpha-1-acid-glycoprotein. 59 We speculate that renal replacement therapy would not affect the plasma concentration of lopinavir/ritonavir. Considering arbidol, lopinavir/ritonavir are mainly metabolized by liver and excreted by fecal, we speculate that adjusting the dose regimens of these two agents in COVID-19 patients with RRT is not needed. Hydroxychloroquine is eliminated by kidney. Considering its low molecular weight, we confer that it could be cleared by CRRT. Dose adjustment could be applied according to residual renal function. RRT has little effects on drug concentration in lung tissues; therefore, we speculated that no drug dosage adjustment is needed for IFN-α inhalation. ECMO is a life-support modality used in patients with refractory cardiac and/or respiratory failure. Recently study indicated that ECMO may have a role in the management of COVID-19 patients who have refractory hypoxemic respiratory failure. 74, 77 Drug pharmacokinetics alterations during ECMO were demonstrated. 78 A case report investigated the effect of ECMO on patients taking ritonavir. Ritonavir has administrated 100 mg once daily before ECMO and 100 mg twice daily during ECMO. The result exhibited that the drug levels of ritonavir were lower than the expected concentrations for a typical individual in the population, suggesting that the PK of ritonavir changed during ECMO. 79 We suggest that COVID-19 patients with ECMO may need to increase the dose regimen of lopinavir/ritonavir and conduct therapeutic drug monitoring to achieve personalized treatment. Considering IFN-α is used as topical administration, we conferred that dosing adjustment is not required during ECMO. Little is known about the alteration of other antivirals during ECMO. It has been reported that significant absorption of drugs occurs in the ECMO circuit, which is correlated with increased lipophilicity of the drug. 80 Among these antivirals, lopinavir, ritonavir, and arbidol are hydrophobic; therefore, increased dose regimen may be needed during ECMO. According to the information about using remdesivir in treating COVID-19, the suggested dosages are the same in patients with or without ECMO. 63 On the other hand, COVID-19 patients who receiving ECMO are more likely to be accompanied by severe symptoms, therefore need a prolonged treatment course. 63 As a novel infection disease, the treatment of COVID-19 is continuously being explored and improved. Due to the alteration of physiological characteristics in special populations, individual antiviral treatment should be performed to achieve better clinical outcomes and avoid adverse drug reactions. Further studies of antiviral agents in special populations of COVID-19 patients are required. Publish your work in this journal Drug Design, Development and Therapy is an international, peerreviewed open-access journal that spans the spectrum of drug design and development through to clinical applications. Clinical outcomes, patient safety, and programs for the development and effective, safe, and sustained use of medicines are a feature of the journal, which has also been accepted for indexing on PubMed Central. The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit http://www. dovepress.com/testimonials.php to read real quotes from published authors. Submit your manuscript here: https://www.dovepress.com/drug-design-development-and-therapy-journal World Health Organization. Coronavirus disease (COVID-19) pandemic Immunology of COVID-19: current state of the science COVID-19) New insights into the antiviral effects of chloroquine Chloroquine is a potent inhibitor of SARS coronavirus infection and spread Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Chinese Clinical Trial Registry Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Coppock K FDA announces two drugs given 'compassionate use' status in treating COVID-19 Chinese National Health Committee Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label nonrandomized clinical trial Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial Zhejiang Da Xue Xue Bao Yi Xue Ban Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial Observational study of hydroxychloroquine in hospitalized patients with Covid-19 Solidarity" clinical trial for COVID-19 treatments A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19 Favipiravir (T-705), a novel viral RNA polymerase inhibitor Experimental treatment with favipiravir for COVID-19: an Open-Label Control Study. Engineering (Beijing). Epub Favipiravir versus Arbidol for COVID-19: a randomized clinical trial Favipiravir: pharmacokinetics and concerns about clinical trials for 2019-nCoV infection Molecular dynamic simulations analysis of ritonavir and lopinavir as SARS-CoV 3CL(pro) inhibitors Case of the index patient who caused tertiary transmission of COVID-19 infection in Korea: the application of lopinavir/ritonavir for the treatment of COVID-19 infected pneumonia monitored by quantitative RT-PCR A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19 A trial of lopinavir-ritonavir in Covid-19. Reply Arbidol as a broad-spectrum antiviral: an update Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China Zhejiang Da Xue Xue Bao Yi Xue Ban Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19 Potential of arbidol for postexposure prophylaxis of COVID-19 transmission-a preliminary report of a retrospective cohort study SARS: systematic review of treatment effects Pharmacologic treatments and supportive care for middle east respiratory syndrome Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study Treatment outcomes for patients with middle eastern respiratory syndrome coronavirus (MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia IFN-α2a or IFN-β1a in combination with ribavirin to treat middle east respiratory syndrome coronavirus pneumonia: a retrospective study Comparative effectiveness and safety of ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha, and ribavirin plus lopinavir/ritonavir plus interferonalpha in patients with mild to moderate novel coronavirus disease 2019: study protocol Stability of recombinant consensus interferon to air-jet and ultrasonic nebulization Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys Anti-HCV, nucleotide inhibitors, repurposing against COVID-19 First case of 2019 novel coronavirus in the United States Compassionate use of remdesivir for patients with severe Covid-19 Remdesivir for the treatment of Covid-19 -preliminary report COVID-19) update: FDA issues emergency use authorization for potential COVID-19 treatment Accumulation of chorioretinotoxic drugs in the foetal eye Optimal antimalarial dose regimens for chloroquine in pregnancy based on population pharmacokinetic modelling Chloroquine as weekly chemoprophylaxis or intermittent treatment to prevent malaria in pregnancy in Malawi: a randomised controlled trial UK malaria treatment guidelines 2016 Ocular toxicity and antenatal exposure to chloroquine or hydroxychloroquine for rheumatic diseases The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies Evidence of transplacental passage of hydroxychloroquine in humans Safety and efficacy of lopinavir/ritonavir during pregnancy: a systematic review Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States Protein binding of lopinavir and ritonavir during 4 phases of pregnancy: implications for treatment guidelines KALETRA ® (lopinavir and ritonavir) tablets and oral solution AbbVie Inc Pharmacokinetics of inhaled recombinant and natural alpha interferon Minimal dose of aerosolized interferon-alpha in human subjects: biological consequences and side-effects Fact sheet for health care providers: emergency use authorization (EUA) of remdesivir (GS-5734™) Pharmacoepidemiological study of the course of influenza and other acute respiratory viral infections in risk groups Ebola virus infection: review of the pharmacokinetic and pharmacodynamic properties of drugs considered for testing in human efficacy trials Effects of ritonavir-boosted lopinavir on the pharmacokinetics of quinine Pharmacokinetics of lopinavir/ritonavir in HIV/hepatitis C virus-coinfected subjects with hepatic impairment Pharmacokinetics, metabolism, and excretion of the antiviral drug arbidol in humans Chloroquine: drug information A case of severe hydroxychloroquine-induced retinal toxicity in a patient with recent onset of renal impairment: a review of the literature on the use of hydroxychloroquine in renal impairment Jiangsu Wuzhong Pharmaceutical group corporation Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a singlecentered, retrospective, observational study A guide to understanding antimicrobial drug dosing in critically Ill patients on renal replacement therapy Pharmacokinetics of favipiravir during continuous venovenous haemofiltration in a critically ill patient with influenza Preparing for the most critically Ill Patients with COVID-19: the potential role of extracorporeal membrane oxygenation Overcoming barriers to optimal drug dosing during ECMO in critically ill adult patients The effect of venovenous ECMO on the pharmacokinetics of ritonavir, darunavir, tenofovir and lamivudine Determinants of drug absorption in different ECMO circuits Arbidol: a potential antiviral drug for the treatment of SARS-CoV-2 by blocking trimerization of the spike glycoprotein All authors contributed toward conception and design, acquisition of data, drafting and critically revising the paper, gave final approval of the version to be published, and agree to be accountable for all aspects of the work. The authors report no conflicts of interest in this work.