Immunosuppressants/lopinavir/ritonavir interaction
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Various toxicities: case report A 69-year-old woman developed vomiting, tremor, diarrhoea and increased tacrolimus and everolimus levels following concomitant administration of off-label lopinavir/ritonavir for COVID-19 infection along with everolimus and tacrolimus as immunosuppressive therapy. The woman, who had hypothyroidism and pulmonary lymphangioleiomyomatosis complicated by pulmonary hypertension, had undergone right lung transplantation in August 2008. Her immunosuppressive therapy included everolimus 1.25mg two times a day and prolonged release (PR) tacrolimus 1 mg/day [routes not stated] along with prednisone and various other co-medications. The tacrolimus target trough concentration was 2–4 µg/L, and everolimus target trough concentration was 5–8 µg/L. On 16 March 2020, she developed headaches and myalgia. Five days prior, she came in contact with SARS-CoV-2 carrier. Subsequently, her SARSCoV-2 nasal PCR test was positive, confirming COVID-19 infection. Thereafter, she was admitted to the ICU as she required oxygen therapy for febrile dyspnoea. A major alveolar syndrome was noted in chest X-ray in the transplanted right lung. On day 11, she started receiving off-label lopinavir/ritonavir 200/50mg daily. The tacrolimus therapy was switched to 0.5 mg/day (immediate release), and everolimus dosage was reduced to 0.1mg two times a day. On the same day, her serum creatinine was 123 µmol/L, indicating abnormal renal function (day 11). On day 12, lopinavir/ritonavir 200/50mg frequency was changed to twice daily. On day 13, she developed severe vomiting, followed by tremor and diarrhoea on day 14. These symptoms were considered secondary to the pharmacokinetic interaction of lopinavir/ritonavir with everolimus and tacrolimus. The symptoms were related to the elevated levels of tacrolimus and everolimus, which were seven times greater than the target trough concentrations under antiviral treatment. Her serum creatinine was 136 µmol/L on day 13. On day 15, her symptoms worsened, and the chest X-ray showed increased opacities in the transplanted right lung. The woman’s treatment with lopinavir/ritonavir was reduced to once daily, and then was stopped after a total of eight doses. The dose of immediate release tacrolimus was reduced to 0.2 mg/day and everolimus to 1 mg/day on day 15. On day 16, her everolimus and tacrolimus treatment was stopped. Subsequently, her symptoms resolved on day 17. She was rehydrated and her renal function recovered. During the hospital stay, her liver function remained stable. The woman was re-initiated on PR tacrolimus 1 mg/day, and everolimus 1.25mg two times a day. On day 18, she was discharged with continued monitoring of renal and liver function, and the concentrations of immunosuppressive drugs. Raeth J, et al. Immunosuppression in a lung transplant recipient with COVID-19? Lessons from an early case. Respiratory Medicine and Research 78: 100782, Nov 2020. 803500164 Available from: URL: http://doi.org/10.1016/j.resmer.2020.100782
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