Management of Drug Interaction between Posaconazole and Sirolimus in Allogeneic Hematopoietic Stem Cell Transplantation Recipients

Purpose: Posaconazole (PSZ) is contraindicated when used concomitantly with sirolimus (SRL) because of a substantial increase in SRL plasma concentration. However, PSZ is clinically used for prophylaxis and treatment of fungal infections in HSCT recipients receiving SRL. Currently, there are no published evaluations of the clinical management of PSZ and SRL interactions. The objective of this study is to determine safe drug management strategies of SRL with PSZ in patients undergoing HSCT.

Methods: The medical records of 75 allogeneic HSCT recipients at City of Hope who received tacrolimus (TCL), SRL and PSZ concomitantly were reviewed retrospectively. Records spanned from January 1, 2008 to December 31, 2011. Data including baseline demographics, SRL levels, and SRL and PSZ doses were recorded for each patient for 28 days. Subgroup analysis was conducted of patients whose initial SRL dose was reduced by greater than 50% (Group 1, n=38) and those whose initial SRL dose was reduced by less than 50% (Group 2, n=37).

Results: Concomitant administration of PSZ and SRL resulted in an increased SRL steady state Concentration/Dose [(ng/mL)/(mg/day)] ratio by a factor of 2.6, which occurred on a mean of 18 days after initiation of PSZ. SRL C/D ratio increased a maximum 3.82 fold (range: 1.75-5.9) during coadministration of PSZ and SRL. Mean maximum SRL trough level was 11 ng/mL in Group 2 and 9.15 ng/mL in Group 1 (p=0.013). No patients in Group 1 had SRL levels exceeding 15 ng/mL, while nine patients (24%) in Group 2 had SRL levels that exceeded 15 ng/mL (p=0.004).

Conclusion: Additional PSZ increases SRL C/D ratio by a factor of 2.6 in HSCT recipients. Also, Initial SRL dose reduction above 50% seems to be appropriate for safe drug management in patients receiving concomitant PSZ.