Abstract

Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2. (SARS-CoV-2) SARS-CoV-2 first emerged in Wuhan China in December 2019 and rapidly spread worldwide. Infections have risen to 4 million with the outbreak being classified as a pandemic. Unfortunately, there is no established cure for the disease necessitating compassionate use of available therapies which show promise.

Research on related coronaviruses such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) over the past decade have brought to light scientific evidence of probable benefit of some drugs with limited clinical evidence of efficacy. It’s hoped that use in COVID-19 may give the much hoped for results while at the same time the world is struggling with the lack of a therapy which presents these agents as our most immediate source of hope.

Drugs currently being used include Remdesivir, Lopinavir/ritonavir, hydroxychloroquine among others.

In this article we evaluate and compare evidence from different sources on the efficacy of remdesivir and lopinavir/ritonavir to COVID-19 infection. This is to establish a clear correlation in use which would potentially open up for future studies while at the same time guide practitioners in care for COVID-19 patients. According to World Health Organization (WHO), clinical trials are focusing on these drugs because they are believed to directly block SARS-CoV-2 from replicating inside lung tissues. Unfortunately, these trials require long periods of time to establish reliable evidence.

Keyword: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Coronavirus disease 2019 (COVID-19), Remdesivir, Lopinavir/ritonavir, Clinical trials

Background

A recent outbreak of coronavirus disease 2019 (COVID-19) caused by the novel coronavirus designated as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) started in Wuhan, China, at the end of 2019. The clinical characteristics of COVID-19 include fever, dry cough, myalgia, sputum production, sore throat, headache, dyspnea, pneumonia, acute respiratory syndrome leading to respiratory or multiorgan failure, and death. Thus far, there are no specific therapeutic agents for coronavirus infections. The SARS-CoV-2 is 80% homologous with the Severe Acute Respiratory s Syndrome-associated coronavirus (SARS-CoV), which started in China in 2002, and some enzymes are even more than 90% homologous. Consequently, scientists are expecting to find drugs for the treatment of COVID-19 from experiences with of SARS-CoV and Middle East Respiratory Syndrome (MERS-CoV).

Considering SARS-CoV-2 is a new virus strain, scientists have acted with agility to isolate the virus and perform gene sequencing enabling development of probable therapies. Even so, it is time consuming to develop new drugs and vaccines as well as to explore biotherapeutic options which can be used clinically. On the backdrop of this, therapies that shown promise in previous outbreaks have been tried on compassionate use especially in critically ill patients. There agents include lopinavir/ritonavir, ribavirin, remdesivir, interferon and corticosteroids.

This review is aimed at establishing the rationale for and value of use in COVID-19 patients drawing from pharmacological properties and evidence from clinical case use of remdesivir and lopinavir/ritonavir.

Remdesivir pharmacology and its use in clinical cases and trials

Remdesivir (also GS-5734) is a monophosphoramidate prodrug of an adenosine (nucleoside) analogue that was developed by Gilead Sciences in 2017 for antiviral potential in particular for anti-Ebola, anti-Marburg virus activity. Remdesivir has broad-spectrum activity against other RNA viruses, including paramyxoviruses, pneumoviruses, the SARS and MERS coronaviruses (CoVs) and endemic circulating human CoVs, and possibly against newly emerging CoVs such as SARS-CoV-2. It has been used on the basis of individual compassionate use over the past several months in patients with COVID-19 in some countries The first patient to test positive for SARS-CoV-2 in the US was treated with IV remdesivir (using compassionate use of an investigational therapy prescribing) and his clinical condition improved significantly within the next 24h with no detectable adverse effects.

Pharmacokinetic and dosage

Pharmacokinetic experiments in cynomolgus monkeys showed the first-pass effect of oral remdesivir resulted in a low bioavailability of the drug. Intramuscular injection of 3 mg/kg had a 50% survival rate compared with the control group. Administering intravenously at a dose of 10 mg/kg, remdesivir rapidly decomposed into the original drug (nucleoside phosphate) in rhesus monkeys. Within 2hrs, remdesivir quickly distributed in peripheral blood mononuclear cells (PBMCs), and soon afterwards activated to nucleoside triphosphate to reach a peak, with a survival rate of 100%, that’s why scientist prefer to use IV as its dosage form and not oral dosage form. Remdesivir can be used at any time after onset of symptoms in hospitalized patients.

The dosage form and strength in adults and pediatrics, for injection; lyophilized powder for reconstitution is 100mg/vial and for injection; solution is 100mg/20ml (5mg/ml). The FDA granted emergency use authorization for remdesivir to treat hospitalized adults and children with suspected SARS-CoV-2 infection to be dosed to patients weighing 40kg or more as below;

• Patients requiring mechanical ventilation and/or ECMO (extracorporeal membrane oxygenation): Day 1 loading dose of 200 mg IV infused over 30-120 min, THEN days 2-10 maintenance dose: 100 mg IV qDay
• Patients who don’t require mechanical ventilation and/or ECMO: Day 1 loading dose: 200 mg IV infused over 30-120 min, THEN Days 2-5 maintenance dose: 100 mg IV qDay. If clinical improvement is not demonstrated, treatment may be extended for up to 5 additional days (i.e. up to 10 days total)

The active drug is remdesivir triphosphate which is generated from metabolism by CYP2C8, 2D6 and 3A4. However, the most current understanding is that in vivo remdesivir metabolism is dominated by hydrolase activity, which would suggest that the range of possible drug-drug interactions with clinically relevant CYP2C8/2D6/3A4 inhibitors and inducers is unlikely to occur. Its excretion is via Urine (~74%; 49% as metabolite); feces (18%).

Remdesivir triphosphate acts as an inhibitor of RNA-dependent RNA polymerases. Remdesivir-TP competes with adenosine triphosphate for incorporation into nascent viral RNA chains. Once incorporated into the viral RNA results in delayed chain termination during replication of the viral RNA. Because the drug doesn’t cause immediate chain termination, the drug appears to evade proofreading by viral exo-ribonuclease (an enzyme thought to excise nucleotide analog inhibitors) Remdesivir-TP is a weak inhibitor of mammalian DNA and RNA polymerases with low potential for mitochondrial toxicity thus selective in activity.

The most common adverse effects in studies of remdesivir for COVID‑19 include respiratory failure and organ impairment, including hypoalbuminemia, hypokalemia, anemia, thrombocytopenia, and jaundice. Other reported side effects include gastrointestinal distress, elevated transaminase levels, hypotension, nausea, vomiting, diaphoresis, and shivering. If these symptoms occur, the drug should be discontinued immediately and implement appropriate treatment. Pharmacokinetic data in patients with renal, hepatic, pregnant or lactating mothers have not been established.

Remdesivir use in clinical cases and clinical trials

The drug was found not to be effective in Ebola, but in lab studies, it has proven effective at inhibiting the growth of similar viruses, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). In a petri dish, remdesivir can prevent human cells from becoming infected with SARS-CoV-2, according to a letter published in the journal Nature in February. The Food and Drug Administration (FDA) have approved remdesivir for compassionate use in patients with severe COVID-19 disease. In other countries, requirements to receive remdesivir may be less stringent. STAT medical news site reported that five clinical trials in China and the U.S. are currently evaluating whether remdesivir can reduce complications or shorten the disease course in COVID-19 patients.

George Thompson, an infectious disease specialist at UC Davis Medical Center who treated an early, severe case of COVID-19, told Science magazine that their patient got better after getting the drug, about 36 hours after diagnosis[1]. The doctors initially thought the patient would die. The patient once visited Wuhan but was neither directly exposed to Wuhan Seafood Market nor had direct contact with the diagnosed patients, the patient was treated with IV remdesivir and his clinical condition improved significantly within the next 24h without observation of adverse effects.

A study was done, which was investigator-initiated, individually randomized, placebo-controlled, double-blind trial to assess the effectiveness and safety of intravenous remdesivir in adults (aged ≥18 years) admitted to hospital with severe COVID-19. The trial was done at ten hospitals in Wuhan, Hubei, China). Patients received either intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or the same volume of placebo infusions for a total of 10 days (both provided by Gilead Sciences, Foster City, CA, USA). Although not statistically significant, in patients receiving remdesivir or placebo within 10 days of symptom onset in the intention-to-treat (ITT) population, those receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo. Among patients who were treated within 10 days of symptom onset, remdesivir was not a significant factor but was associated with a numerical reduction of 5 days in median time to clinical improvement. Ongoing controlled clinical trials are expected to confirm or refute this finding.

Lopinavir/ritonavir pharmacology and its use in clinical cases and trials

Lopinavir/ ritonavir is a combination of the HIV protease inhibitors; Lopinavir, which acts against the viral 3CL protease, ritonavir was found to boost half-life of lopinavir by inhibiting cytochrome p450(CYP3A4). Lopinavir/ritonavir-based antiretroviral therapy (ART) is generally well tolerated and has shown durable virologic efficacy in clinical trials in ART-naive and -experienced patients with virologic failure. Lopinavir/r is one of the preferred PIs (protease inhibitors for first-line treatment of HIV infection in adults, adolescents and children, according to US and British guidelines Lopinavir/ritonavir is considered second-line therapy in the WHO guidelines and alternative therapy in industrialized world guidelines due to toxicity. It has modest antiviral activity against SARS-CoV-2. Together with ritonavir, which increases drug bioavailability. What makes lopinavir–ritonavir particularly attractive is that it is widely available and manufacturable to scale and that it could be prescribed immediately. In fact, there are several case reports and case series where this agent is being used against COVID-19.

Absorption and distribution

Peak plasma concentrations of lopinavir occur 4 hours after dosing and steady-state concentrations occur within 10–16 days. At steady state, 98% of lopinavir is bound to plasma proteins. Administration of lopinavir/ritonavir 400/100 mg twice-daily yields mean steady-state lopinavir plasma concentrations 15- to 20-fold higher than those of lopinavir monotherapy in HIV-infected patients.

The absorption of lopinavir–ritonavir in capsule or liquid form is favorably affected by the presence of food, particularly if high in fat. The CNS penetration is good. It has a semen: plasma ratio of 0.07. It is distributed into breast milk.

Metabolism

Lopinavir is extensively metabolized by oxidative hepatic metabolism,CYP3A4 system, but this is inhibited by ritonavir. Decreased clearance is not expected with renal insufficiency, and some increase in lopinavir/r exposure occurs with worsening hepatic dysfunction. Significant CYP3A4 inhibition occurs, and a patient’s medications should be thoroughly reviewed before lopinavir/r therapy.

Excretion

Over an 8-day period after single dosing with the combined formulation, around 10% and 83% of the administered dose is recovered in urine and feces, respectively. Less than 3% of the dose is recovered as unchanged drug in urine and 20% in feces. In mild to moderate hepatic impairment, an increase in exposure of approximately 30% is observed, but is probably not clinically relevant. It should be avoided in severe hepatic impairment.

Route of administration and Dosage

Lopinavir/ritonavir is available in three dosage forms: lopinavir 200 mg/ritonavir 50 mg co-formulated heat stable tablets; lopinavir 100 mg/ritonavir 25 mg co-formulated heat stable tablets; and lopinavir 400 mg/ritonavir 100 mg per 10 mL oral solution. Lopinavir/ritonavir tablets may be taken with or without food; the oral solution must be taken with food. Adult dosage is lopinavir/ritonavir 400 mg/100 mg twice daily or lopinavir/ritonavir 800 mg/200 mg once daily. Twice-daily lopinavir/ritonavir dosing should be used with three or more baseline lopinavir-associated drug resistance substitutions or when used with efavirenz, nevirapine, nelfinavir, carbamazepine, phenobarbital, or phenytoin. Pediatric dosing is weight based.

Resistance

Significant resistance to the antiretroviral efficacy of ritonavir-booted lopinavir occurs as a result of amino acid substitutions at positions 32, 47 and 82 in the protease region. Protease inhibitor resistance is uncommon in patients identified with early failure of combination therapy with ritonavir boosted-lopinavir and nucleotide reverse transcriptase inhibitors.

Adverse effects

Adverse effects seen with lopinavir/r are primarily gastrointestinal: diarrhea or loose stools, nausea, and, less commonly, vomiting and rash. Hypercholesterolemia and hypertriglyceridemia are reported in patients taking lopinavir/r. According to the data of the Antiretroviral Pregnancy Registry (2013) the malformation rate is 2.3% (26 of 1,125 births) after first trimester exposure, and thus not increased in comparison to the general US population. Studies with HIV-infected pregnant women indicate that the treatment with lopinavir/ritonavir is well tolerated. Pharmacokinetic investigations show lower plasma levels, primarily in the last trimester. It is unclear if pregnant women require a higher dose or just a continuation of the PI standard therapy. Administration of standard doses of PIs with rifampicin is contraindicated.

Lopinavir/ritonavir use in clinical cases and clinical trials

Lopinavir/r was compassionately used as treatment for SARS-CoV-1 in 2003-2004 and showed some promise. Effectiveness of the combination was limited in mice but appreciable in nonhuman primate models of MER-CoV. An urgent randomized clinical trial of the efficacy of lopinavir–ritonavir in patients with COVID-19 in Wuhan, China, the epicenter of the outbreak was performed. Unfortunately, the trial results were disappointing. No benefit was observed in the primary end point of time to clinical improvement, published March 18 in the New England Journal of Medicine.

A total of 199 people with low oxygen levels were randomized to either receive lopinavir/r or a placebo. While fewer people taking lopinavir/r died, the difference was not statistically significant, meaning it could have been due to random chance. And both groups had similar levels of virus in their blood over time. However, other studies are still ongoing, and there’s still a possibility this combination could show some benefit. As with other antivirals, this drug would likely work better if given earlier in the disease course. Results from a clinical trial comparing a lopinavir-ritonavir combination to the standard of care for COVID-19 suggest the therapy is promising. The findings will be considered as part of the upcoming Randomized Evaluation of COVID-19 therapy (RECOVERY) trial. The lopinavir-ritonavir trial started when there were only 500 COVID-19 cases worldwide. Researchers at the Jin Yin-Tan Hospital treated 199 COVID-19 patients with either the HIV antiviral combination of lopinavir-ritonavir or the standard of care. According to the team, the symptoms of patients treated with lopinavir-ritonavir improved faster than those given the standard of care alone. The researchers also cited acceptable safety levels throughout reported by European pharmaceutical review.

Conclusion

Both remdesivir and lopinavir/r have antiviral activity which possibly could be used to stop the SARS-CoV-2 replication in the human body cells, both have different areas of target in the virus (SARS-CoV) life cycle. An in vitro study against MERS-CoV which is known to be similar to SARS-CoV-2 showed that the antiviral activity of remdesivir plus interferon beta (IFNb) was superior to that of lopinavir/r. Prophylactic and therapeutic remdesivir improved pulmonary function and reduced lung viral loads and severe lung pathology in mice, whereas lopinavir/r-IFNb slightly reduced viral loads without affecting other disease parameters. Therapeutic lopinavir/r-IFNb improved pulmonary function but did not reduce virus replication or severe lung pathology. There is insufficient evidence to recommend the use of Lopinavir/r for COVID-19 outside of research studies. In order to determine the efficacy and safety of Lopinavir/r for COVID-19, more adequately powered randomized clinical trials of Lopinavir/r are required. Remdesivir is still under clinical trials, it has shown promising results and according to the most researchers it’s the best drug known to speed recovery in COVID-19 patients. Clinical trials for both remdesivir and lopinavir/r are underway. Until now there is no treatment for COVID-19.

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