Isavuconazonium Pharmacokinetic Interactions with Immunosuppression in Thoracic Transplant Recipients

Abstract

Purpose Isavuconazonium (ISA) treats and prevents invasive fungal infections. Advantages over other azoles include improved bioavailability and less CYP inhibition. Its effect on calcineurin inhibitor (CNI) and sirolimus (SRL) concentrations (concns.) has not been studied thus far relative to other azoles in thoracic transplant (TXP) patients (pts). Our aim is to study ISA's relative effect on CNI and SRL concns. Methods A retrospective chart review was conducted in thoracic TXP recipients on ISA. Tacrolimus (TAC) and SRL whole blood trough concns. were collected at baseline (BL), day 3, and weekly for 9 weeks after the start of ISA. Concentration to dose (C/D) ratios were calculated using TAC or SRL concns. and total daily doses. Median percent C/D change from BL was assessed at each time point. Results Fourteen pts were included (10 lung, 3 heart, and 1 heart/lung TXP). ISA was used to treat invasive fungal infections in 12 pts and as prophylaxis in 2 pts. ISA was started at a median of 477 days post-TXP. 6 TAC and 3 SRL pts transitioned from posaconazole (POSA), 1 TAC pt transitioned from voriconazole (VORI), and 1 TAC pt from fluconazole (FLUC) to ISA. Reasons for transition to ISA from other azoles included adverse effects (5/11) and ineffective therapy (6/11). 1 TAC and 2 SRL pts started ISA de novo. By day 28, the median TAC C/D decreased from BL by 75.5% and SRL C/D decreased by 68.5% in pts who transitioned from POSA to ISA (Figure 1). Pts on prior FLUC and VORI also demonstrated respective TAC C/D reductions of 63% and 57% by day 14. Pts starting ISA de novo showed a 73% median increase in SRL C/D and a 57% increase in TAC C/D by day 14. Conclusion Up to a 4-fold TAC and SRL dose increase may be expected when transitioning from other azole antifungals to ISA. The largest change in dose requirement occurred by week 2, and C/D did not stabilize until week 4. Given interpatient variability, clinicians should continue therapeutic drug monitoring of TAC and SRL levels to guide dose adjustments when transitioning between azoles.