313: Tacrolimus Dosing in Allogeneic Hematopoietic Stem-Cell Transplantation Recipients Receiving Voriconazole

Tacrolimus (TAC) is primarily metabolized by the CYP450 3A4 isoenzyme. Voriconazole, often used to prevent fungal infections after allogeneic HSCT, is metabolized by the CYP450 3A4, 2C9 and 2C19 isosenzymes. Clinical trials in healthy volunteers have shown significant drug interactions between the two requiring TAC dose reduction. Ordinarily, TAC is started at the dose of 0.03 mg/kg IV daily on day -1. After starting it at this dose and having to reduce the dose substantially within 2–3 days in all patients receiving concomitant voriconazole 200 mg twice daily orally from day 0, we implemented a simple, preemptive TAC dose reduction strategy to maintain steady-state levels between 5 and 15 ng/mL. As a first step, IV TAC was initiated at the reduced dose of 0.022 mg/kg/day. As a second step, dose was reduced by 30–40% if the steady-state level 48 h after initiation of TAC (day +1) was between 7 and 10 ng/mL, and by 40–50% if the level was between 10 and 15 ng/mL. No change was made if the level was <7 ng/mL. Subsequently, levels were monitored 2–3 times a week and the dose adjusted as needed. Here, we evaluate the pharmacokinetic effects of concomitant voriconazole administration on blood TAC levels in 27 consecutive allogeneic HSCT recipients (28–64 y; median 55) in whom pre-emptive dose-modification was used during the first 2 weeks. A total of 170 levels (3–12 per patient; median 5) were checked between day +1 and day +16. None of the levels was subtherapeutic (<5 ng/mL), and 34 (20%) were >15 ng/mL. 24 of 27 patients required dose-reduction from day 0 to day +1 based on levels. Each patient required dose-reduction at least twice. An increase in the dose was needed in only 2 patients after initial dose-reduction. TAC doses (median, range) on days 0, 7 and 14 were 1.6 (1–2), 0.6 (0.13–1.4), and 0.4 (0.13–1.1) respectively indicating that the median absolute TAC dose, the median TAC mg/kg dose, and the median per cent TAC dose (100% being the baseline) declined substantially. However, the median TAC level over the first 2 weeks remained between 10 and 14.5. It is clear that lack of pre-emptive dose-reduction would have resulted in TAC levels climbing steadily. Based on this, we recommend starting TAC at 0.02–0.022 mg/kg rather than at 0.03 mg/kg if patients are on concomitant voriconazole, checking levels regularly, and reducing the dose by 30–40% if the 48-h level is 7–10 and by 40–50% if it is 10–15. Tacrolimus (TAC) is primarily metabolized by the CYP450 3A4 isoenzyme. Voriconazole, often used to prevent fungal infections after allogeneic HSCT, is metabolized by the CYP450 3A4, 2C9 and 2C19 isosenzymes. Clinical trials in healthy volunteers have shown significant drug interactions between the two requiring TAC dose reduction. Ordinarily, TAC is started at the dose of 0.03 mg/kg IV daily on day -1. After starting it at this dose and having to reduce the dose substantially within 2–3 days in all patients receiving concomitant voriconazole 200 mg twice daily orally from day 0, we implemented a simple, preemptive TAC dose reduction strategy to maintain steady-state levels between 5 and 15 ng/mL. As a first step, IV TAC was initiated at the reduced dose of 0.022 mg/kg/day. As a second step, dose was reduced by 30–40% if the steady-state level 48 h after initiation of TAC (day +1) was between 7 and 10 ng/mL, and by 40–50% if the level was between 10 and 15 ng/mL. No change was made if the level was <7 ng/mL. Subsequently, levels were monitored 2–3 times a week and the dose adjusted as needed. Here, we evaluate the pharmacokinetic effects of concomitant voriconazole administration on blood TAC levels in 27 consecutive allogeneic HSCT recipients (28–64 y; median 55) in whom pre-emptive dose-modification was used during the first 2 weeks. A total of 170 levels (3–12 per patient; median 5) were checked between day +1 and day +16. None of the levels was subtherapeutic (<5 ng/mL), and 34 (20%) were >15 ng/mL. 24 of 27 patients required dose-reduction from day 0 to day +1 based on levels. Each patient required dose-reduction at least twice. An increase in the dose was needed in only 2 patients after initial dose-reduction. TAC doses (median, range) on days 0, 7 and 14 were 1.6 (1–2), 0.6 (0.13–1.4), and 0.4 (0.13–1.1) respectively indicating that the median absolute TAC dose, the median TAC mg/kg dose, and the median per cent TAC dose (100% being the baseline) declined substantially. However, the median TAC level over the first 2 weeks remained between 10 and 14.5. It is clear that lack of pre-emptive dose-reduction would have resulted in TAC levels climbing steadily. Based on this, we recommend starting TAC at 0.02–0.022 mg/kg rather than at 0.03 mg/kg if patients are on concomitant voriconazole, checking levels regularly, and reducing the dose by 30–40% if the 48-h level is 7–10 and by 40–50% if it is 10–15.