Tacrolimus dose modification in patients receiving concomitant isavuconazole after hematopoietic stem cell transplantation.

INTRODUCTION: Isavuconazole is increasingly being used for antifungal prophylaxis during stem cell transplantation. Isavuconazole is a moderate inhibitor of Cytochrome P4503A4, and tacrolimus levels are anticipated to be elevated when given concomitantly with isavuconazole. We developed and validated a dose-modified tacrolimus regimen to better achieve and maintain target tacrolimus levels.Methods: Allogeneic stem cell transplantation recipients who received concomitant tacrolimus and isavuconazole from September 2017 to September 2018 were included. Tacrolimus was adjusted to achieve a target range 8-12 ng/ml. Intravenous tacrolimus was first initiated at 0.02 mg/kg/day on day 1, and transitioned to oral therapy using a 2:1 conversion ratio (n = 48). Clinical observations showed high interpatient variability. The intravenous dose was then reduced to 0.017 mg/kg/day, and oral:intravenous conversion changed to 3.1:1 (n = 24). RESULTS: Interpatient variability was high (lower in the 0.017 mg/kg/day group; P < 0.0217). Patients in the 0.017 mg/kg/day group required fewer dose changes (P < 0.023) and had fewer levels >15 ng/ml (P < 0.021). Median tacrolimus dose declined over time; 0.016, 0.012 and 0.011 on days 1, 7 and 10 for patients receiving 0.02 mg/kg/day and 0.017, 0.014 and 0.013 in the 0.017 mg/kg group. Day 10 tacrolimus accumulation factor was 1.42 Rac(Cmax) in the 0.02 mg/kg/day cohort compared to 1.23 Rac(Cmax) in the 0.017 mg/kg/day cohort (P < 0.015). When transitioned to oral therapy, a oral:intravenous conversion ratio >3.1:1 was shown to improve chances for achieving target levels (P > 0.0744). CONCLUSION: We recommend initiating intravenous tacrolimus dose at 0.017 mg/kg/day and using a 3.1:1 oral:intravenous conversion to reduce interpatient variability, drug accumulation and the number of suboptimal tacrolimus levels. Tacrolimus requires frequent drug level monitoring.

Revisiting Infectious Complications Following Total Parenteral Nutrition Use During Hematopoietic Stem Cell Transplantation.

BACKGROUND: Total parenteral nutrition (TPN) is frequently used to manage caloric needs during hematopoietic stem cell transplantation (HSCT). Previous studies in transplant patients who received TPN have reported widely discordant results with regard to infection and mortality, and risk factors for TPN-related infection remain unclear. METHOD: We conducted a retrospective study of all HSCT recipients treated with TPN between 2005 to 2014 at Northwestern Memorial Hospital to determine the incidence and epidemiology of infections. Electronic records were used to identify patients treated with TPN for at least 2 days who developed infection. RESULTS: Among 198 patients treated with TPN, 30% developed documented infection. Total parenteral nutrition treatment duration (13 vs. 7 days; p < .0001) and the timing of TPN initiation (> day 9 post HSCT; p < .0001) were significantly higher in patients who received TPN and developed infection. Receipt of an allogeneic transplant was associated with increased risk for infection (p < .0138), and day 60 mortality was significantly higher in TPN-treated patients with infection (p < .0001). CONCLUSION: Stem cell recipients who receive TPN, especially from an allogeneic donor, have high rates of infection and mortality. Minimizing TPN exposure may reduce the chance for infection.