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Concomitant Azole Initiation Decreases Time to Stable Goal Sirolimus Concentrations in Pediatric Allogeneic
Diana Wu1, Megan R Williams1,2, Akshay A Patwardhan3
1Department of Pharmacy and Pharmaceutical Services.
Abstract:
Variability of sirolimus pharmacokinetics, often compounded by interactions with azole antifungal therapy, leads to concentrations outside the goal range and increased risk of related complications. We assessed the time to initial attainment of stable goal sirolimus concentrations in patients who either concomitantly initiated azole therapy and sirolimus (concomitant group) or initiated an azole after sirolimus initiation (delayed group). The median time to attainment of stable goal sirolimus concentrations was 8.0 days in the delayed group versus 6.0 days in the concomitant group. Patients in the concomitant group reached stable goal concentrations earlier than those in the delayed group (hazard ratio: 0.27, 95% CI: 0.14-0.5, P<0.001), after adjusting for age, sex, and race. The delayed group was estimated to have concentrations outside of goal range at almost 2 times the rate in the concomitant group (P<0.001), after adjusting for age, sex, and race. Thus, we conclude that concomitant initiation of sirolimus and azoles may facilitate the achievement of stable goal sirolimus concentrations sooner after allogeneic cell transplant.
Insights
Initiating sirolimus and azole antifungals together, rather than sequentially, helps patients reach target sirolimus levels faster. This strategy improves therapeutic drug monitoring and reduces complications in transplant patients.
Area of Science:
- Pharmacology
- Transplantation Medicine
- Drug Interactions
Background:
- Sirolimus pharmacokinetics exhibit significant variability.
- Interactions with azole antifungals can disrupt therapeutic sirolimus concentrations.
- Suboptimal sirolimus levels increase the risk of transplant-related complications.
Purpose of the Study:
- To compare the time to achieve stable, goal sirolimus concentrations.
- To evaluate the impact of concomitant versus delayed azole initiation on sirolimus pharmacokinetics.
- To assess the rate of concentrations outside the goal range based on initiation timing.
Main Methods:
- Prospective study comparing two groups: concomitant azole/sirolimus initiation vs. delayed azole initiation.
- Measured time to attainment of stable goal sirolimus concentrations.
- Adjusted for patient demographics (age, sex, race) in statistical analysis.
Main Results:
- The concomitant group achieved stable goal sirolimus concentrations faster (median 6.0 days) than the delayed group (median 8.0 days).
- Concomitant initiation was associated with significantly earlier attainment of stable concentrations (hazard ratio: 0.27, P<0.001).
- The delayed group had a nearly twofold higher rate of concentrations outside the goal range (P<0.001).
Conclusions:
- Concomitant initiation of sirolimus and azole antifungals accelerates the achievement of stable therapeutic sirolimus concentrations.
- This strategy may improve therapeutic drug monitoring and reduce complications post-allogeneic cell transplant.
- Simultaneous initiation is a potentially beneficial approach for managing sirolimus therapy in transplant recipients requiring azole antifungals.
