On December 22, 2021, the Food and Drug Administration issued an emergency use authorization for use of two oral anti-viral medications Paxlovid (nirmatrelvir/
In response, the American Society of Transplantation (ATS) issued a statement to provide a framework for use of the antivirals for organ transplant recipients. The ATS noted that Paxlovid is challenging to use in many transplant patients due to significant drug interactions and difficulty with therapeutic drug monitoring in outpatients with active COVID-19 infection. The potential for drug interactions with immunosuppression is based on the mechanism of action of ritonavir, a common medication used as part of the treatment regimen for HIV. Ritonavir is a potent inhibitor of CYP3A and will increase levels of sirolimus, everolimus, tacrolimus, and cyclosporine. Multiple other interactions are also possible, including with antifungals and anticoagulants.
In the absence of published, peer-reviewed data on the management of this complex drug-drug interaction, a panel of experts in gastroenterology and hepatology, renal and pancreatic transplantation, infectious disease, and pharmacology at NewYork-Presbyterian/
The authors noted that their prior experience using ritonavir in solid organ transplant recipients confirmed the need to drastically reduce CNI dosing and to carefully monitor drug levels to avoid supra-therapeutic CNI exposure. An earlier study in which researchers in the Center for Liver Disease and Transplantation at NewYork-Presbyterian/
Weill Cornell Medicine and Columbia researchers recently published a retrospective study of the use of nirmatrelvir/
ritonavir in solid organ transplant recipients with mild COVID-19. Their findings show that the clinically significant interaction between nirmatrelvir/ ritonavir and immunosuppressive agents can be reasonably managed with a standardized dosing protocol.
“Upon discontinuation of ritonavir, CNI and mTORi metabolism is expected to slowly return to baseline over a period of several days to weeks due to the irreversible inhibition of CYP3A activity caused by ritonavir,” wrote the authors. “In a pharmacokinetic analysis investigating the effect of ritonavir (300 mg BID) on CYP-mediated metabolism of midazolam (a CYP3A substrate), recovery of CYP3A activity reached only 27 percent of baseline after 3 days of ritonavir withdrawal. This was notably slower than CYP3A activity recovery after withdrawal of voriconazole (a reversible CYP3A enzyme inhibitor).”
Another pharmacokinetic model evaluating ritonavir inhibition on CYP3A likewise identified that full enzyme recovery takes up to 7 days, although 70 percent to 90 percent enzyme recovery may be expected after 2 to 5 days depending on the age of the patient.
The authors offer the following recommendations for clinicians managing solid organ transplant recipients who commence treatment with nirmatrelvir/
- Cautiously approach CNI and mTORi dose adjustments and drug level monitoring
- Due to the differing degree of ritonavir’s impact on CYP-mediated metabolism of tacrolimus versus cyclosporine, empiric dose-reduction strategies must be stratified
- For tacrolimus, immediately hold all future doses while patients complete a 5-day course of nirmatrelvir/
ritonavir; for cyclosporine, the team advises an empiric dose reduction - If possible, measure a tacrolimus level on day 3 to assess the need for a one-time tacrolimus dose during nirmatrelvir/
ritonavir treatment; the CNI level should be evaluated as soon as possible upon completing nirmatrelvir/ ritonavir treatment - Resume tacrolimus or dose increases of cyclosporine once drug levels approach the therapeutic target, and frequently reassess for at least 2 weeks given the variable time course of CYP3A enzyme recovery
“If bi-weekly laboratory monitoring cannot be performed to titrate CNI dosing, care should be individualized to account for pre-ritonavir CNI levels, risk for CNI toxicity, and allograft rejection risk,” the authors noted.
In summary, the Weill Cornell Medicine and Columbia researchers offer these recommendations as a starting point for managing this complex drug-drug interaction. Individual patient variations and other associated medications, such as azole antifungals, vitamin K antagonists, and direct oral anticoagulants, may necessitate a more individualized approach for use or avoidance of nirmatrelvir/
Related research by Weill Cornell Medicine and Columbia faculty evaluated outcomes among solid organ transplant recipients with mild COVID-19 and described the drug-drug interaction of nirmatrelvir/
