Evaluation of a Protocol Managing the Cyclosporine and Nirmatrelvir/Ritonavir Interaction in Kidney Transplant Recipients.

Background: Nirmatrelvir/ritonavir has emerged as a crucial treatment for managing COVID-19 infections but interacts with calcineurin inhibitors. This study aims to assess the application of a standardized protocol managing this drug-drug interaction, specifically with cyclosporine, since current evidence is limited.

Methods: This retrospective study included recipients on cyclosporine undergoing therapy with nirmatrelvir/ritonavir between April 2022 and December 2023. As per protocol, cyclosporine doses were reduced by 80% and levels were measured two days after course completion. For subtherapeutic or therapeutic levels, cyclosporine dose was reinstated at 100%, with cyclosporine levels reassessed one week later. For supratherapeutic levels, the reduced dosage was maintained for an additional two days before being reinitiated at 100% of the baseline nirmatrelvir/ritonavir dose. Protocol adherence and clinical parameters such as cyclosporine levels, acute kidney injury episodes, hospitalization, and mortality were monitored up to 30-days after completion of nirmatrelvir/ritonavir therapy.

Results: Thirty-five kidney transplant recipients met eligibility criteria. At baseline, 83% of recipients had therapeutic cyclosporine levels. At the first follow-up two days after completion of nirmatrelvir/ritonavir there was a greater proportion of recipients with subtherapeutic and supratherapeutic levels compared to baseline (20% vs 9% and 31% vs 9%), which had improved by the second follow-up at nine days after completion of nirmatrelvir/ritonavir (14% and 14%). Three recipients experienced acute kidney injury for reasons unrelated to COVID-19 treatment. There were 4 hospitalizations; none related to COVID-19 treatment. There was no graft rejection or death 30 days after completion of nirmatrelvir/ritonavir.

Conclusions: Though cyclosporine levels outside therapeutic range were common immediately after completion of nirmatrelvir/ritonavir treatment, levels were restored rapidly. No clinically relevant safety events occurred within the 30-days. Adherence to the protocol is crucial when using nirmatrelvir/ritonavir in kidney transplant recipients.