Pharmacotherapy Modifications Due to Drug Interactions with Concomitant Fungal Prophylaxis and Nontuberculous Mycobacteria Treatment after Transplant

Abstract

Introduction Patients undergoing orthotopic heart transplant (OHT) have a 0.2 to 2.8% rate of infection with nontuberculous mycobacteria (NTM) in the year after transplant. Rifamycins, particularly rifampin, remain the backbone of NTM therapy; rifampin therapy can be especially challenging in solid organ transplant (SOT) due to potent CYP3A4 induction. Rifabutin, an alternative rifamycin, though less studied, is commonly substituted for rifampin in SOT due to less drug-drug interactions (DDI). Rifabutin is also a CYP3A4 substrate which can be impacted by concomitant CYP3A4 inhibitors. We report a case of an OHT recipient requiring systemic fungal prophylaxis while on rifabutin for pulmonary NTM. Case Report He is a 44-year old Caucasian male on 12 months of NTM treatment with rifabutin, azithromycin, and ethambutol who presented for OHT in his final month of treatment for pulmonary Mycobacterium kansasii. After OHT, he was started on high-dose steroids and triple-drug immunosuppression (IS). His NTM regimen was extended for another month. In addition to his IS regimen, isavuconazole was initiated for fungal prophylaxis rather than standard protocol posaconazole, for less CYP3A4 inhibition of rifabutin. Due to DDI, he required close therapeutic drug monitoring (TDM) to attain tacrolimus levels of 10-12ng/mL, requiring 10-15 mg/day (0.11-0.16 mg/kg/day) on the CYP3A4 inhibitor/inducer regimen. Rifabutin also remained therapeutic (0.3mcg/ml) on 300mg daily despite isavuconazole inhibition. After completion of rifabutin, tacrolimus requirements reduced to 6mg/day (0.06 mg/kg/day) with isavuconazole CYP3A4 inhibition alone. No breakthrough fungal infections occurred during isavuconazole prophylaxis despite the potential for rifabutin CYP3A4 induction. Summary Use of moderate CYP3A4 inhibitor isavuconazole with rifabutin did not result in rifabutin toxicity, particularly the shared ocular effects of ethambutol, and permitted effective systemic fungal prophylaxis. The degree of reduced exposure of isavuconazole inhibition due to a concomitant CYP3A4 induction of rifabutin remains unknown and requires monitoring for breakthrough infections. Close TDM may permit concomitant administration of significantly interacting CYP3A4 inhibitors, inducers, and substrates in complicated SOT patients.