Navigating Muddy Waters of COVID-19 Drug-Drug Interactions

Volume 13, Issue 3

With the remission of the first Omicron wave, many states and companies are paring down mask and vaccine mandates, and many Americans are taking a break from thinking about COVID-19. While some time away from this topic does sound appealing, the virus is not taking a break, and new subvariants of Omicron are starting to emerge.

In this week’s issue of Talking Therapeutics, we look at a particular new variant and what its emergence means for currently available COVID-19 therapeutics. 

Point 1: We Can’t Punt Paxlovid Despite Problems 

The emergence of the original Omicron variant shrunk our pharmacologic armamentarium. Many then-popular antibody preparations like Regeneron’s casirivimab/imdevimab and Lilly’s bamlanivimab/etesevimab were neutralized by the variant’s spike protein mutations.

Sotrovimab, which was specifically designed to resist future SARS-CoV-2 mutations, initially retained activity against the original Omicron variant. However, a new subvariant of Omicron named BA.2 is starting to spread with greater frequency, and initial data published in the New England Journal of Medicine this week suggests that this subvariant can resist even sotrovimab.

With sotrovimab off the table, infected patients will have to turn to the oral options for COVID-19 infection—molnupiravir and ritonavir-boosted nirmatrelvir (Paxlovid). Unfortunately, the former is limited by its modest efficacy, and the latter is limited by significant drug-drug interactions owing to the ritonavir component. Which brings me to my next point… 

Point 2: Doing the Drug-Drug Interaction Dance

Ritonavir is a very potent inhibitor of CYP3A4, which leads to interactions with commonly prescribed medications like statins and blood thinners. For certain patient populations on chronic immunosuppression agents, like those with solid-organ transplants or malignancy, these interactions could be very dangerous if not managed properly.

This past week, my colleagues at New York-Presbyterian Hospital and I published our experience managing these interactions in a cohort of solid-organ transplant patients. Our experience shows that use of a standardized dosing protocol for medications like tacrolimus and cyclosporine can safely manage the ritonavir interaction without exposing patients to the risk of drug toxicity.

Given that immunosuppressed patients carry a higher risk for adverse outcomes with COVID-19 infection, it is very enticing to use a drug like Paxlovid that has been shown to reduce the risk of hospitalization and death. And with sotrovimab potentially sunsetting due to the BA.2 variant, interest in using Paxlovid will only increase. Fortunately, the results of our research show these potentially dangerous drug-drug interactions can be safely managed.