Nirmatrelvir/ritonavir use: Managing clinically significant drug-drug interactions with transplant immunosuppressants

Solid organ transplant recipients (SOTRs) are at significant risk for morbidity and mortality due to SARS-CoV-2 infection.1 Nirmatrelvir, a novel orally bioavailable protease inhibitor, has demonstrated significant activity against SARS-CoV-2.2 In a recently completed phase 2/3 clinical trial in 2246 patients infected with SARS-CoV-2, nirmatrelvir (co-administered with ritonavir 100 mg twice daily) reduced the risk of hospitalization or death by 89% compared to placebo. Ritonavir is a potent cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp) inhibitor and poses significant challenges with drug-drug interactions, most notably with transplant immunosuppressive medications. In light of the FDA emergency use authorization of nirmatrelvir/ritonavir, we convened a group of multidisciplinary experts at our center to provide recommendations for managing SOTR on calcineurin inhibitors (CNIs) or mammalian target of rapamycin inhibitors (mTORi) who are to begin treatment with this new agent. It should be noted that nirmatrelvir/ritonavir requires renal dose adjustment and is not recommended in patients with eGFR <30 ml/min. Prior experience using ritonavir in SOTR has confirmed the need to drastically reduce CNI dosing and judiciously monitor drug levels to avoid supra-therapeutic CNI exposure. In a cohort of HCV-infected liver transplant recipients who started treatment with a ritonavir-boosted direct-acting antiviral (DAA) regimen, therapeutic levels were maintained when the cyclosporine dose was reduced to 20% of the original regimen, while patients receiving tacrolimus required a dose reduction to 0.5 mg once weekly.3 In a separate investigation, healthy volunteers co-administered a CNI with a ritonavir-boosted DAA regimen experienced a 57-fold increase in tacrolimus exposure and 5.8-fold increase in cyclosporine exposure.4 No data exist to guide mTORi dose adjustments, although ritonavir is expected to similarly inhibit mTORi metabolism. 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 CYP 3A activity caused by ritonavir. In a pharmacokinetic analysis investigating the effect of ritonavir (300 mg BID) on CYP-mediated metabolism of midazolam (a CYP 3A substrate), recovery of CYP 3A activity reached only 27% of baseline after 3 days of ritonavir withdrawal. This was notably slower than CYP 3A activity recovery after withdrawal of voriconazole (a reversible CYP 3A enzyme inhibitor).5 A separate pharmacokinetic model assessing ritonavir inhibition (100 mg BID) on CYP 3A similarly identified that full enzyme recovery takes upwards of 7 days, although 70%–90% enzyme recovery may be expected after 2–5 days depending on patient age.6 As such, we recommend that clinicians managing SOTR who begin treatment with nirmatrelvir/ritonavir must cautiously approach CNI and mTORi dose adjustments and drug level monitoring (Figure 1). Due to the differing magnitude of ritonavir's impact on CYP-mediated metabolism of tacrolimus versus cyclosporine, empiric dose-reduction strategies must be stratified. For tacrolimus, we recommend immediately holding all future doses while patients complete a 5-day course of nirmatrelvir/ritonavir; conversely, for cyclosporine, we recommend an empiric dose reduction. If feasible, it would be advisable to 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 assessed as soon as possible upon nirmatrelvir/ritonavir completion. Resumption of tacrolimus or dose increases of cyclosporine should begin once drug levels approach the therapeutic target, and frequent re-assessment should continue for a period of at least 2 weeks given the variable time course of CYP 3A 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. These recommendations serve as a suggested starting point for management of this complex drug-drug interaction in the absence of published, peer-reviewed data. Individual patient variability and other concomitant medications such as—azole antifungals, vitamin K antagonists, and direct oral anticoagulants, among others (which may also require empiric adjustment/discontinuation) may require a more individualized approach for use or altogether avoidance of nirmatrelvir/ritonavir. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.