Pharmacokinetic Impact of Posaconazole Discontinuation on Tacrolimus Levels in Heart Transplant Recipients

Abstract

<h3>Purpose</h3> Azole antifungals are CYP3A4 inhibitors known to significantly impact tacrolimus levels. Required tacrolimus dose reduction with azole initiation is well known; however, little is reported on empiric tacrolimus dose adjustments with azole discontinuation (d/c). We describe our experience with tacrolimus adjustment after d/c of posaconazole. <h3>Methods</h3> This is a retrospective single center review of heart transplant recipients who received 3 months of posaconazole prophylaxis immediately post-transplant. Upon d/c, our protocol increased total tacrolimus dose by 2-3 fold with level monitoring twice weekly for at least two weeks until at target. We analyzed the first 7 tacrolimus troughs and total daily doses (TDD) after d/c. Stable target levels post d/c were defined as first trough at goal with the TDD equivalent to doses at 3 months post d/c. Intrapatient tacrolimus level variability (IPV) was calculated using mean absolute deviation of dose corrected tacrolimus levels, with paired t test and descriptive statistics. <h3>Results</h3> Among 28 patients who received posaconazole from January 2020 to May 2021, average age was 55.5 years, 75% were male and 82% white. Tacrolimus TDD was significantly lower on posaconazole compared to 3 months post-d/c (0.02 vs 0.09 mg/kg/day, p = 0.0001). Analysis of target trough achievement is shown in Figure 1. Significant difference in IPV was noted between early (first 3) and late (next 4) levels, p=0.0004 (Figure 2). Median time to stable target levels was 21.5 (11-48) days. Four patients (14%) had 2R rejection within one month of d/c at which time median lowest tacrolimus level was 4.2 ng/mL (3.4-8.2 ng/mL). <h3>Conclusion</h3> Discontinuation of posaconazole leads to significant tacrolimus variability that can persist for weeks. A more conservative tacrolimus dose adjustment at time of d/c, with close monitoring throughout the first 3 weeks may be needed. Additional data is necessary to develop defined empiric dose adjustments for tacrolimus during this high-risk time.