NEW ORLEANS, LA—Both the tablet and intravenous (IV) formulations of posaconazole appeared to be safe and effective for primary prophylaxis against invasive fungal infections in patients with hematologic malignancies, according to results of a retrospective cohort study presented at IDWeek 2016.
Compared to the suspension formulation of posaconazole, the tablet and IV formulations achieve higher serum concentrations, leading some to believe toxicity may be more common. Samuel L. Aitken, PharmD, from The University of Texas MD Anderson Cancer Center, Houston, TX, and colleagues evaluated the pharmacokinetics (PK) and toxicity associated with new posaconazole formulations in patients with hematologic malignancies.
Invasive fungal infections are a common complication in this population, including in those who have undergone hematopoietic stem cell transplantation.
Of the 1321 episodes of inpatient posaconazole use between January 2014 and January 2016, 558 were for primary antifungal prophylaxis. From this group, 343 unique patients were assessed for safety and effectiveness, with a subgroup of 76 patients assessed for PK.
The patients had received >3 days of either the tablet or IV formulation; clinical and toxicity data were obtained and correlated with serum posaconazole if available. Rate of invasive fungal infection were assessed following the EORTC/MSG criteria. Researchers also evaluated hepatotoxicity using standard NCI grading scales, with grade 3/4 hepatotoxicity considered to be significant. For patients with more than one admission, only their first inpatient primary prophylaxis episode was considered.
A total of 11 patients (3%) received IV posaconazole and 97%, 300mg posaconazole daily. Mean age was 80 years and 57% were male; 62% had acute myeloid leukemia, 20% had received prior hematopoietic stem cell transplantation, and 79% had active malignancy.
Of the 76 patients assessed for PK, 22% had a posaconazole serum level obtained with a median value of 1,380ng/mL (interquartile range [IQR] 864-1860); levels >2,000ng/mL were observed in 13 patients (17%).
Significant elevations in ALT, alkaline phosphatase, or total bilirubin were uncommon during prophylaxis, occurring in 5% of patients. Any grade 3/4 hepatotoxicity occurred in 5.38% of patients; alanine aminotransferase in 1.59%, and total bilirubin in 4.8%. There was no reported occurrences of grade 3/4 alkaline phosphatase.
A mean increase in the QTc interval of 14±35msec (range -88 to 105) was seen in 79 patients (23%) who underwent electrocardiograms prior to and during posaconazole prophylaxis.
Dr. Aitken reported that proven/probable invasive fungal infection occurred in 5 patients (1%), 4 of whom died. “All invasive fungal infections occurred in patients with levels >700ng/mL,” he added.
“Posaconazole serum levels do not appear to correlate with safety or effectiveness in this cohort,” he concluded. “Cost benefit analyses of therapeutic drug monitoring with new posaconazole formulations are warranted.”
Finally, since 17% of patients had posaconazole drug levels <700ng/mL, additional studies are needed to identify patients who may benefit from therapeutic drug monitoring.