Drug Repurposing and Pharmacogenomics on the Onslaught of the COVID-19 Pandemic

by John Nicolas Olitin (Isochore)

More than a year into the COVID-19 pandemic, vaccines of different types from different producers have started to roll out in various parts of the world and countries have rushed to secure vaccine supplies and distribute it to their citizens. Despite this, a lot of people have resorted to the use of off-label drugs for the prevention and treatment of COVID-19.

Drug repurposing involves the use of drugs that have no established safety and efficacy data as medication for COVID-19, citing off-label or compassionate use as reasons. While there are alternative therapeutic resources that have the potential to be repurposed for treating symptoms in COVID-19 patients, at a reduced cost and time required for treatment than vaccines, these also have the disadvantages of having low success rates and possible side effects.

Several drugs have been studied and clinically tested at the start of the pandemic for repurposing, and some of them have been USA FDA approved or have shown to be safe in levels and can potentially be used for COVID-19. These include astemizole, clofazimine, and remdesivir, among others, although it should be noted that each of these do not by themselves cure COVID-19 and may come with different side effects.

In the Philippines, there is a current issue regarding the use of ivermectin for the treatment of COVID-19. Ivermectin is an anthelmintic, antiparasitic drug that has the potential to prevent viral replication of a broad spectrum of viruses. However, the Philippine FDA and Merck & Co., Inc., the pharmaceutical company responsible for its production and distribution has already issued a warning statement against the use of the drug as treatment for COVID-19 or as replacement for the COVID vaccine. It is not registered for human treatment in the Philippines since the only approved Ivermectin drug in the country is for animal and veterinary use. Despite this, several heads of different organizations and associations have filed for an appeal for the emergency use of ivermectin as a “drug to prevent and treat COVID-19.”

Another perspective that needs to be considered when repurposing drugs involves the field of pharmacogenetics and pharmacogenomics. Pharmacogenetics deals with the response of different individuals to drugs and medications based on their genetic makeup. On the other hand, pharmacogenomics focuses on the analysis of whole genomes for genes related to drug metabolizing enzymes, transporters, and other genetic elements that affect therapeutic safety and efficacy.

Over the past years, there have been significant improvements and advances in the field of pharmacogenomics, including the formation of guidelines for the use of genomic medicine which is slowly being utilized for treatment or maintenance for patients with certain diseases like some types of cancers.

On the application of pharmacogenomics in drug repurposing for COVID-19, there have been identified mechanisms by which genetic determinants may affect the therapeutic efficacy of these drugs for COVID-19. 

For example, ivermectin has shown inhibition against SARS-CoV-2 in vitro through inhibition of Importin α/β1 (IMPα/β1)-mediated nuclear import of viral proteins. Ivermectin is metabolized by CYP3A4 and is both a substrate and a potent inducer of the P-gp, which can increase ivermectin plasma levels. Despite this, it is still not recommended for the treatment of COVID-19 in patients. Recent studies report that the chance of a successful clinical trial using the approved dose of ivermectin is low since ivermectin cannot enable the lungs to reach 50% inhibition of the virus.

As for remdesivir, the preliminary clinical trials have already shown results supporting its effectivity as a repurposed drug for COVID-19. Remdesivir is primarily metabolized by hydrolase in vivo, and it generally has a low risk for significant pharmacokinetics (PKs) interactions. Other studies suggest that it is a substrate for drug metabolizing enzymes CYP2C8, CYP2D6, and CYP3A4, as well as a substrate for OATP1B1 and P-gp transporters, therefore known variants of these genes could theoretically affect the PKs of remdesivir. According to current knowledge, no guideline recommends pharmacogenetic testing before remdesivir administration.

More pharmacogenomic studies need to be performed to determine the involved interactions and risks at the genetic level of repurposed drugs for COVID-19. Moving forward, it is also important to continue the study of pharmacogenomics for it to become a more useful and reliable resource for even more diseases.