Clinical considerations for coadministration of the novel antifungal Isavuconazole with immunosuppressive agents

Townsend R., Desai A., Howieson C., Kowalski D., Pearlman H., Yamazaki T., Mujais S.

Abstract: 

Background:

Isavuconazole (ISA) is a novel, broad-spectrum, triazole undergoing Phase III clinical development for the treatment of invasive fungal infections (IFIs). Patients undergoing organ transplantation are at increased risk of IFIs, raising the likelihood of co-administration of ISA with immunosuppressive drugs. Therefore, the pharmacokinetics and safety of ISA and the transplant drugs cyclosporine, mycophenolate mofetil, prednisone, sirolimus, and tacrolimus were investigated.
 

Methods:

Five Phase I, open-label, drug-interaction studies were conducted in healthy subjects. Pharmacokinetics and safety of single doses of cyclosporine, mycophenolate mofetil, prednisone, sirolimus, and tacrolimus were assessed in the presence and absence of multiple doses of oral ISA.
 

Results:

Co-administration with ISA increased the area under the whole blood/plasma concentration-time curves of tacrolimus (+125%), sirolimus (+100%), mycophenolic acid (+35%), cyclosporine (+29%), and prednisolone (+8%). Pharmacokinetics of ISA were mostly unaffected; however, maximum plasma concentration of ISA was higher during co-administration with cyclosporine (+30%) and tacrolimus (+26%). No major safety concerns were reported in any of the studies.
 

Conclusions:

Attention to systemic drug levels and possible dose adjustments are required following administration or discontinuation of ISA in subjects receiving immunosuppressive drugs, in particular cyclosporine, sirolimus, and tacrolimus.