Tacrolimus and Lopinavir/Ritonavir Interaction in Liver Transplantation

OBJECTIVE: To report an interaction between tacrolimus and the protease inhibitor combination lopinavir/ritonavir in a liver transplant patient. CASE SUMMARY: A 48-year-old white male liver transplant recipient receiving tacrolimus 5 mg twice daily for immunosuppression started highly active antiretroviral therapy for his HIV-positive status. Three days after initiation of lopinavir/ritonavir, the tacrolimus concentration rose sharply to toxic levels. Subsequent tacrolimus doses were withheld until tacrolimus concentrations normalized over 15 days. The tacrolimus dose was reestablished at a much lower dose, 0.5 mg once weekly. An objective causality assessment revealed that the adverse event was highly probable. DISCUSSION: Tacrolimus is metabolized in the liver via CYP3A4. Protease inhibitors are known to inhibit CYP3A4 and have been documented to increase tacrolimus concentrations, putting the patient at risk of developing nephrotoxic and/or neurotoxic symptoms. In this case, concomitant use of lopinavir/ritonavir caused tacrolimus concentrations to rise more dramatically than had been previously reported in the literature for other protease inhibitors. CONCLUSIONS: Extreme caution must be used when administering tacrolimus concomitantly with lopinavir/ritonavir. Therapeutic concentrations of tacrolimus can be maintained with tacrolimus doses that are far below standard dosages.