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-hour delay in NIM/r initiation. Re-initiation 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 re-initiation of tacrolimus and antifungal 48-72 hours after completion of therapy.