A Retrospective Analysis of the Effect of Isavuconazole on Immunosuppressant Serum Blood Levels and Intravenous to Oral Dose Adjustments

Abstract

Introduction Triazole anti-fungal drugs have been important in preventing fungal infections in immunosuppressed pts who have received an allogeneic hematopoietic cell transplant (allo-HSCT). These agents inhibit fungal cytochrome P450 (CYP) enzymes, preventing ergosterol formation that is essential for fungal wall synthesis. However they also inhibit human CYP enzymes which are responsible for metabolism of certain drugs, notably immunosuppressants (IS) commonly used in allo-HSCT. This study is a retrospective analysis of the effect of the new triazole anti-fungal, isavuconazonium sulfate (ISV), on the serum blood levels of tacrolimus (Tac), cyclosporine (CsA), and Sirolimus (Siro) in pts who have received allo-HSCT. Patients and Methods This retrospective analysis included 78 pts who received a conventional, double-umbilical cord, or haplo-identical allogeneic stem cell transplant who received Tac, CsA, or Siro and were initiated on ISV for fungal prophylaxis. The pre-ISV serum blood level of IS was compared to the serum level 48 hrs after the start of the ISV loading dose. We also examined how IS were converted from IV to oral by comparing the IS level on the day of IV to PO conversion to the IS level 48 hrs after PO was initiated while pts received ISV. Results There were 85 instances of ISV initiation in 78 pts on IS. Of the 85 instances of ISV initiation 23 (27%) received CsA, 55 (65%) received Tac, and 7 (8%) received Siro. The median age was 56 (range 21-75) and 25 (32%) of the pts were female. Pts receiving IV CsA (n = 23) had a median percent dose change (%DC) of -10% on initiation of ISV and the median 48hr percent level change (%LC) was -5.7%, with a median net difference (%ND) of +6%. For the pts who were converted from IV CsA to PO CsA (n = 20) the empiric %DC from IV to PO was +25% with a %LC of +1.71% with a %ND of -18.51%. This corresponds to an IV:PO of 1:1.2. For pts receiving IV Tac (n = 55) the median %DC was -16.7% and the %LC was -3.4% with a %ND of +12.4 %. The pts who were converted from IV Tac to PO (n = 41) had a median empiric %DC of +200% with a corresponding %LC of -30.26, with a %ND of +228.49%. This corresponds to a IV:PO of 1:2.3. For the pts receiving Siro (n = 7) the median %DC was 0% and the median %LC of +17.8% with a %ND of +23.8%. Conclusion Initiation of ISV did result in serum level elevations in patients receiving CsA, Tac, and Siro. For CsA the increase in level was minimal, however for Tac and Siro the level increased 12.4% and 23.8% respectively which may be clinically important and dose reductions should be considered in select patients. This study also showed how ISV affects the IV to PO conversion of Tac and CsA with IV:PO ratios of 1:2.3 and 1:1.2 respectively. This demonstrates that ISV affects first-pass metabolism of Tac and CsA and this should be taken into consideration when making IV to PO conversions.