MIMS, AYPG virtual forum on safety of SARS-CoV-2 treatment pulls in the crowd

With the movement control order (MCO) in full gear, most conferences and meetings are being postponed or cancelled. Some have taken to having conferences and meetings in a virtual setting, such as the recently ended American College of Cardiology/World Congress of Cardiology (ACC.20/WCC) conference. MIMS and the Asian Young Pharmacist Group (AYPG) took this opportunity to engage with pharmacists in the form of a Zoom meeting.

Aptly named the AYPG-MIMS Online Forum, the virtual event, held on 8 April, saw participation from five member nations and close to 300 members from 17 countries. The forum saw the presentation of a talk titled ‘Navigating Medication Safety during COVID-19’ by Nikki Ng, Managing Editor of MIMS Healthcare Data-Clinical Decision Support Division. It was followed by experience sharing session with representatives from each of the participating nations—Japan, Taiwan, Indonesia, Hong Kong, and Malaysia.

Navigating the COVID-19 storm  
Ng’s talk covered the drugs currently being used in treatment of COVID-19 and their safety profiles., as follows:

1.         Ibuprofen

2.         Glucocorticoids

3.         Remdesivir (GS-5734)

4.         Favipiravir (T-705)

5.         Lopinavir/Ritonavir

6.         Interferon

7.         Chloroquine

8.         Hydroxychloroquine

9.         Tocilizumab

10.       Umifenovir (Arbidol®)

11.       Azithromycin

12.       Other drugs

 

For the purpose of her presentation, Ng focused on remdesivir, lopinavir/ritonavir, interferon, chloroquine and hydroxychloroquine. In terms of medicine safety, Ng also covered the rationale of use, dose, risks, and potential drug interactions.  

For the time being, the cornerstone of treatment remains symptomatic treatment, said Ng. Common symptoms and typical complications are listed in Table 1.

• Common symptoms • Fever • Sore throat, cough, hemoptysis, sputum • Diarrhoea • Headache • Myalgia, fatigue, loss of smelling or tasting sensation • Complications • Acute respiratory distress syndrome (ARDS) • Acute kidney injury (AKI) • Septic shock • Secondary infections, ventilator-associated pneumonia

Table 1. Common COVID-19 symptoms and complications.

Ng made special mention of ibuprofen, the much-maligned drug in the early days of COVID-19 outbreak. More recent evidence has come to show that ibuprofen does not increase the inflammatory risk, and thus aggravating the condition of a COVID-19 patient, as initially reported. However, some sources still prefer to err on the side of caution and paracetamol remains the preferred option. Should ibuprofen be given, the usual precautions pertaining to non-steroidal anti-inflammatory drugs (NSAIDs) use eg, gastritis, renal impairment and hypertension, should be observed.

Generally, all NSAIDs are not contraindicated to use in COVID-19, as per US FDA and EMA. It’s just that paracetamol has a more favourable safety profile and efficacy for fever, hence, is preferred.

Glucocorticoids
Glucocorticoids are potent anti-inflammatory agents and immunosuppressants. It is thought that they can inhibit the release of various cytokines. Glucocorticoids were used during the SARS and MERS-CoV outbreaks as a means of suppressing lung inflammation. Ng noted that systemic glucocorticoids are widely used to treat septic shock despite uncertainty over their efficacy. However, shock in severe hypoxaemic respiratory failure is often a consequence of increased intrathoracic pressure (during invasive ventilation) impeding cardiac filling, and not vasoplegia.

The recommended dose should not exceed the equivalent of methylprednisolone 1-2 mg/kg/day for 3 to 5 days. [NHC China Diagnosis and Treatment protocol for Covid-19 ver. 7] In COVID-19 patients with refractory shock, there is weak evidence from the Surviving Sepsis campaign for IV hydrocortisone of 200 mg per day either as an infusion or in intermittent doses.

In SARS and MERS-CoV, there are reported risks of increased mortality, delayed viral RNA clearance, psychosis, diabetes, osteoporosis, and avascular necrosis. General risks of glucocorticoid use include increased susceptibility to infections, hypothalamic-pituitary-adrenal (HPA) axis suppression (in longer than 7 days use), Cushingoid appearance, skin atrophy, and, the withdrawal effect.

Remdesivir (GS-5734)
Remdesivir is an adenosine triphosphate nucleotide analogue, which works as an incorporation competitor with adenosine triphosphate, thereby confusing viral RNA-dependent RNA polymerase. Additionally, it acts as a delayed RNA chain terminator, causing the RNA to evade proofreading by viral exoribonuclease, leading to a decrease in viral RNA production.

It is a broad spectrum antiviral, which is thought to work against filoviruses (eg, Ebola and Marburg), coronaviruses (SARS-CoV, MERS-CoV), and paramyxoviruses (eg, respiratory syncytial virus or RSV, Nipah virus, and Hendra virus).

The recommended IV dose is 200 mg loading on day 1, followed by 100 mg over an hour daily from day 2 to day 10. The IV dose for paediatric patients is 5 mg/kg/dose loading on day 1, followed by 2.5 mg/kg/dose daily from day 2 to day 10. It is also available as a solution and a lyophilized formulation. The preparations are compatible in normal saline or dextrose 5%, but should either solution be used, infusion should be done over 30 minutes to 2 hours. 

Interaction wise, remdesivir is converted into the intermediate metabolite GS-704277 and the nucleoside metabolite GS-441524. Inside cells, GS-441524 monophosphate converts to the active analog of adenosine triphosphate (GS-443902). In vitro wise, remdesivir is a substrate for CYP2C8, CYP2D6, and CP3A4; OATP1B1 and P-gp transporters but these are likely not impacted as remdesivir is administered by IV. Its drug interaction risks may be low but currently there is insufficient information about its metabolites.

Remdesivir is excreted mainly through the renal and biliary routes while its metabolism is predominantly mediated by hydrolase. It is contraindicated in patients with severe hepatic impairment due to lack of data. In those with renal impairment, no dose adjustment is necessary for mild-to-moderate impairment but is contraindicated in those with severe impairment. There are no effects on reproductive functions in males or on embryo-foetal and peri-postnatal development but its toxicity profile in reproductive/developmental functions are still lacking.

Favipiravir (T-705)
Favipiravir is a guanine analogue with a broad-spectrum activity towards RNA viruses, including the likes of influenza, rhinovirus, and RSV but not against DNA viruses. It inhibits the RNA-dependent RNA polymerase thereby terminating chain elongation at the site where it is incorporated.

It is currently approved in Japan for patients infected with novel or re-emerging influenza viruses and has a high barrier for resistance. Although it is currently not commercially available, Japan is looking to mass produce and give it free to as many as 30 countries.

In influenza, it is taken orally 1600 mg twice daily on day 1, then 600 mg twice daily on days 2 to 5. Alternatively, it can be started at 1800 mg twice a day on day 1 and then 800 mg twice daily on days 2 to 5. The oral dose for Ebola treatment and post exposure prophylaxis is 6000 mg (2400 mg, 1200 mg, 1200 mg 8 hours apart) on day 1, and subsequently 1200 mg twice daily on days 2 to 10. As the drug is so new, the optimal dose is yet to be determined.

Favipiravir is phosphoribosylated intracellularly to be an active form, favipiravir-RTP. It has complex nonlinear pharmacokinetics, probably due to saturation and/or auto-inhibition of the main enzymatic pathway, as favipiravir was shown to inhibit aldehyde oxidase in vitro. It is contraindicated in pregnant women as teratogenicity and embryotoxic effects were observed in animal studies. It inhibits paracetamol sulphate formation thereby increasing paracetamol levels by 20%.  However, this may not be clinically significant as it minimally affects the systemic pharmacokinetics of acetaminophen.

Lopinavir/ritonavir
Both molecules are HIV protease inhibitors and function by competitively inhibiting HIV protease, an enzyme involved in the replication of HIV. It is postulated that the combination would work on SARS-CoV-2 by targeting its main protease M^pro. There have been mixed results regarding its efficacy as case studies showed some improvement in reducing viral load and clinical outcomes, but larger trials have yet to confirm the findings with a control arm.

The lopinavir/ritonavir combination is dosed orally at 400 mg/100 mg twice daily for 5 or up to 21 days. Paediatric dose titration is based on the ratio of weight to body surface area.

Unfortunately, common side effects include diarrhoea, nausea, vomiting, hypokalaemia, elevated bilirubin levels, rash, and QT prolongation.

Drug interaction risk is also high as both lopinavir and ritonavir are potent CYP3A4 inhibitors. Therefore, patients need to be monitored for increased toxicities of CYP3A4 substrates. Both molecules have no evidence of human teratogenicity.

There is increased clearance during pregnancy, with some experts suggesting dose increase in pregnant patients but once-daily dosing is not recommended.

Interferon
Interferons are cytokines derived from leucocytes, lymphoblasts or fibroblasts, or produced via recombinant DNA technology. It is active against viruses, malignant neoplasms and have an immunomodulating effect. Interferon serves as a key component of host antiviral defense, and some suggest it suppresses the early phase of viral replication.

Interferon-alpha and beta both demonstrate anti SARS-CoV-1 and anti MERS-CoV activity in vitro. There is no optimal dose information for interferon use. It is contraindicated in those with hypersensitivity to interferon and those with severe decompensated liver. Additionally, Ng mentioned the risks in long-term use such as during Hepatitis B treatment of bone marrow suppression, depression, psychosis, suicide, thyroid imbalance, and elevated transaminases.

Chloroquine
This molecule is famous due to frequent mention by US President Donald Trump. It is a 4-aminoquinoline anti-protozoal for malaria prophylaxis and treatment. It is an existing product and comes at a low cost.

The molecule is postulated to block virus infection by increasing endosomal pH required for virus to cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. It also reduces expression of phosphatidylinositol binding clathrin assembly protein (PICALM), which prevents endocytosis-mediated uptake of SARS-CoV-2.

Chloroquine may be delivered in phosphate, sulphate or hydrochloride form. Chloroquine phosphate is dosed at 500 mg twice daily for 5 to 20 days. Chloroquine is dosed at 600 mg at diagnosis, then 300 mg 12 hours later followed by 300 mg twice daily for 5 days. However, if chloroquine is given via IV, it should be by slow infusion, otherwise severe cardiotoxicity may develop. The optimal dose of chloroquine is also yet to be determined.

Chloroquine comes with QT prolonging risk, and thus may have potential drug interaction with other QT prolonging drugs (eg, azithromycin, lopinavir/ritonavir). It is contraindicated in patients with retinopathy, porphyria, epilepsy, pre-existing maculopathy, G6PD deficiency, recent myocardial infarction and QTc >500 msec. Acute toxicity may occur within 30 minutes of administration. This manifests as headache, drowsiness, visual disturbances, cardiovascular collapse shock syndrome, seizures and respiratory or cardiac arrest. However, it isn’t contraindicated in pregnancy.  

Hydroxychloroquine
This molecule is a 4-aminoquinoline antimalarial with actions similar to those of chloroquine. There are some data showing hydroxychloroquine’s effectiveness in inhibiting the entry, transport and the post-entry stages of SARS-CoV-2, similar to the chloroquine and one study found hydroxychloroquine to be a more potent agent than chloroquine in inhibiting SARS-CoV-2 in vitro.

Hydroxychloroquine is also thought to help mediate the cytokine storm via its immunomodulatory effects. Current evidence for its use is mainly based on two trials-a Chinese and a French study.

In the French study, hydroxychloroquine was dosed orally at 200 mg three times a day for 10 days. [Int J Antimicrob Agents. 2020 Mar 20:105949] While in the Chinese study, it is dosed orally at 200 mg twice daily for 5 days. However, physiologically based pharmacokinetic (PBPK) modeling suggests an oral dose of 400 mg twice daily as a loading, then 200 mg twice daily for 4 days. As hydroxychloroquine has a long half-life, it requires a loading dose. Its contraindications are all similar to chloroquine and it should be remembered that it may have interactions with QT prolonging drugs.

Other drugs currently in the limelight are tocilizumab, azithromycin and umifenovir. Tocilizumab is an interleukin-6 receptor inhibitor and is thought to reduce key inflammatory factors during the cytokine release syndrome faced by some COVID-19 patients. Umefenovir is a broad-spectrum antiviral agent for influenza prevention and treatment. It has been shown that umifenovir can impact early viral replication in SARS-CoV-2. Azithromycin, a macrolide antibacterial agent, is thought to have many immunomodulating effects to reduce inflammation and promote long-term healing and repair. It should be used as adjunctive therapy in COVID-19 patients. 

Before closing, Ng said the COVID-19 situation has made patient treatment a chaotic affair, but it does highlight the importance of pharmacists in ensuring medication safety. Pharmacists should always remember to check patients for pre-existing health conditions, allergies and medication. Then pharmacists should check to see if the medications prescribed are indicated plus look at potential medication safety. Finally, pharmacists can make clinical judgment based on the current known facts. Ng noted that there is a lot of emerging information on Covid-19, and pharmacists should evaluate carefully yet keeping an open mind to embrace new evidence

COVID-19 backgrounder
SARS-CoV-2 is the newest addition to human CoVs (HCoVs) that also include 229E, OC43, HKU1, NL63, severe acute respiratory syndrome (SARS)-CoV, and Middle East respiratory syndrome (MERS)-CoV. It falls in the genus of Betacoronavirus and is currently treated symptomatically only, with no approved or known drugs to treat the disease.

There are reports that more than 100 patients treated with chloroquine phosphate demonstrated superior inhibition of exacerbation of pneumonia, improvement in lung imaging findings, promotion of a virus negative conversion, and shorter disease course compared to regular standard of care, but details are sparse.

The WHO Solidarity trial is currently under way to test out four treatment regimens on top of the local standard of care. The four arms are—remdesivir; chloroquine or hydroxychloroquine; lopinavir plus ritonavir; and lopinavir with ritonavir plus interferon beta-1a. The trial will see participation from over 70 countries and will recruit adult (18 years and above) confirmed COVID-19 patients who are hospitalized, and in the view of the doctor, has no contraindication to any of the study regimens. [Available at https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments. Accessed on 9 April]


Reference:
Remdesivir
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2. EMA. Summary on Compassionate Use Remdesivir. https://www.ema.europa.eu/en/news/ema-provides-recommendations-compassionate-use-remdesivir-covid-19. Accessed on 5 April

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Favipiravir
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Lopinavir/Ritonavir
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Interferon
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Chloroquine
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8. Singh AK, Singh A, Shaikh A et al. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes Metab Syndr 2020 Mar 26;14(3):241-246.

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Hydroxychloroquine
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2. Singh AK, Singh A, Shaikh A et al. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes Metab Syndr 2020 Mar 26;14(3):241-246.

3. Gautret P, Lagier JC, Parola P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020 Mar 20:105949.

4. Yao X, Ye F, Zhang M et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020 Mar 9.

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