Serum Concentrations of Posaconazole (PCZ) with Delayed-Release Tablets (DRT) in High-risk Patients

Background: Posaconazole is a broad-spectrum triazole antifungal agent FDA approved for the prophylaxis of invasive fungal infections (IFIs). PCZ DRT delivers more consistent serum concentrations compared to the oral suspension and has become the preferred agent at many centers. Consensus guidelines recommend concentrations ≥700 mcg/L for prophylaxis and ≥1,000 mcg/L for treatment of IFIs to maximize efficacy, though clinical variables influencing drug levels remain poorly defined. We sought to determine the percentage of our patients receiving PCZ DRT for prophylaxis or treatment of IFIs who achieved a therapeutic level.

Methods: A retrospective single-center study was conducted on high-risk inpatients where PCZ serum concentrations were obtained during treatment or prophylaxis. Patients receiving <6 days of treatment with 300mg PCZ DRT daily were excluded. High-risk was defined as patients undergoing chemotherapy for a primary hematologic malignancy and those undergoing hematopoietic cell (HCT) or solid organ transplantation. Standard National Cancer Institute definitions were used to characterize diarrhea and mucositis.

Results: The most frequent underlying medical condition was hematological malignancy (42/53, 79%), of which 45% had undergone a HCT as part of their treatment; 26/53 (49%) received PCZ for prophylaxis. A total of 37/53 (70%) had PCZ serum levels ≥700 mcg/L regardless of indication, including 22/26 (85%) that received PCZ for prophylaxis. Of the patients that received PCZ for treatment, only 12/27 (44%) had PCZ serum levels ≥1,000 mcg/L. PCZ serum levels were not statistically different in patients with a weight ≥90kg, diarrhea grade ≥2, mucositis grade ≥2, or poor dietary intake. However, lower mean PCZ levels were found in patients with graft-versus-host disease (GVHD) compared to those without GVHD (853 vs. 1325 mcg/L, respectively; p<0.05). Four patients (15%) developed breakthrough invasive fungal infections, one of which had a subtherapeutic level.

Conclusion: The PCZ DRT provides adequate concentrations in only 70% of our patient population and even lower in patients treated for IFIs. Lower concentrations noted among patients with GVHD suggests a need for prospective studies evaluating therapeutic drug monitoring and/or dose adjustments among these patients.