Tacrolimus Dose Adjustment for SCT Recipients Receiving Concommitant Isavuconazole

Abstract

Similar to other triazoles, isavuconazole (ISAV) is an inhibitor of many CYP3A4 metabolized drugs including tacrolimus. TAC requires significant dose reduction when given with voriconazole and posaconazole, yet the degree of inhibition with ISAV use is unknown. A retrospective study was conducted to characterize the interaction between TAC and ISAV. Patients received concomitant TAC intravenous (iv) (0.02mgkg start day -1) and oral ISAV (372mg start day 0-no loading dose). TAC levels were drawn peripherally and proportionally adjusted to a target range 8-12mcg/ml. 49 patients were included. Most (75%) were treated for AML with busulfan/fludarabine. Table1 shows large interpatient variability in TAC levels over 2 weeks of iv treatment. More than 50% of first iv levels (day+1) were above target range (>12ng/ml) and > 30% potentially toxic (> 15ng/ml). Likely as a result of ISAV's long half-life, TAC needed to be continually dose reduced to maintain target levels. At the end of iv treatment, overall TAC dose reduction was 45%. To eliminate the large number of elevated 1st dose TAC level, a modest reduction in 1st TAC dose (0.017mg/kg) was implemented. Results in 12 patients showed median TAC=11, with one TAC level 15ng/ml. When changed to oral therapy, TAC levels showed large interpatient variability (median=7.4; range 3.3-14). Most of the first TAC levels after switch to oral therapy were below target range (56% When given with ISAV, TAC levels exhibit large interpatient variability and significant accumulation over time. Lowering initial TAC dose to 0.017mg/kg reduces the risk for elevated 1st dose TAC levels. Using an oral-to-iv conversion ratio of at least 3:1 may minimize the risk for early oral TAC levels falling below target range.