Rifampin as Rescue Therapy for Paxlovid-Associated Calcineurin Inhibitor Toxicity

Introduction: Ritonavir-nirmatrelvir (Paxlovid) is effective in treating COVID-19 but is a strong CYP inhibitor that can provoke life threatening calcineurin inhibitor toxicity (CNI). We present a novel case of treating severe CNI intoxication 2/2 to Paxlovid using rifampin as rescue therapy in a heart transplant recipient. Case Description: The patient was a 40YO male with history of heart transplant in 2003 on tacrolimus and rapamycin, hypertension, and type II diabetes. He contracted covid-19 and was prescribed Paxlovid. Patient presented 3 days later with severe headache, tremors, tachycardia, and hypertension. Found to have acute kidney injury (AKI) with creatinine (Cr) 3.15 from baseline Cr 1.0. Tacrolimus level 53 and rapamycin 23. Tacrolimus and rapamycin held with no improvement. Treated with CYP inducer rifampin 300mg BID for 1 day and IV hydration for 3 days. Patient’s symptom resolved. AKI improved with Cr near baseline. Subsequent troughs improved until no longer supratherapeutic. Restarted on rapamycin and tacrolimus day 4 of hospitalization. Discussion: Paxlovid is a strong inhibitor of cytochrome P450 activity which when used with CNIs can provoke supra-therapeutic levels. Toxicity is associated with AKI, neurotoxicity, and HTN. The use of rifampin for CYP induction therapy resulted in resolution of symptoms, rapid reduction of CNI trough concentrations, and full renal recovery. As Paxlovid becomes more widely used for covid-19 treatment, we can expect more incidence of CNI toxicity. Rifampin is a potent CYP inducer and can be an effective rescue therapy for severe CNI toxicity. More studies are needed to understand drug-drug interactions and treatment of CNI toxicity.