Strategies to Mitigate the Drug-Drug Interaction between Nirmatrelvir/Ritonavir and Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplant Recipients on Azole Antifungals: Results of a Case Series.

Introduction: Nirmatrelvir/ritonavir (NIM/r) inhibits tacrolimus metabolism resulting in a profound drug-drug interaction that is further complicated by the use of azole antifungals.

Case Presentations: We describe three strategies, in 4 patient cases, for the initiation of NIM/r in allogeneic hematopoietic stem cell transplant (alloHSCT) recipients on tacrolimus at the time of diagnosis. Patients 1 and 2 (strategy 1) experienced prolonged, elevated tacrolimus concentrations after an empiric 33% reduction in tacrolimus dose and adjustment of azole antifungal at NIM/r initiation (strategy 1) and with complete discontinuation of tacrolimus and azole antifungal at NIM/r initiation (strategy 2). Patients 3 and 4 (strategy 3) did not experience elevated tacrolimus concentrations on NIM/r treatment with complete discontinuation of tacrolimus and azole antifungal and a 12-24-h delay in NIM/r initiation. Reinitiation of tacrolimus after NIM/r completion resulted in variable tacrolimus concentrations.

Conclusion: NIM/r-tacrolimus is a serious drug-drug interaction which can be mitigated by early discontinuation of tacrolimus and azole antifungals, close monitoring, and reinitiation of tacrolimus and antifungal 48-72 h after completion of therapy.