627. Too Much of a Good Thing? The Clinical Effects of Very High Serum Posaconazole Levels


 
 
 Posaconazole therapeutic drug monitoring (TDM) is widely utilized to assess therapeutic efficacy and safety (i.e., hepatotoxicity, QTc prolongation); however, little is known about clinical effects of very high serum posaconazole serum levels (i.e., ≥ 5000 mg/mL). Reported incidence rate of adverse drug reactions (ADRs) with posaconazole per most recent clinical trial was ∼30%. The primary objective was to compare the ADR incidence in patients with serum posaconazole levels of 3000-4999 ng/mL to ≥5000 ng/mL.
 
 
 
 This retrospective cohort study included adult patients with a posaconazole serum level ≥3000 ng/mL from 1/1/2019 to 04/30/2021. The primary outcome was symptomatic ADR at time of first serum level ≥3000 ng/mL. Secondary outcomes were laboratory defined hepatoxicity, electrolyte and adrenal laboratory abnormalities, QTc changes, and dose changes in response to TDM. Patient outcomes were censored after the first serum level and were compared between groups using Fisher’s exact tests.
 
 
 
 Ninety patients met inclusion criteria, 80 with a level of 3000-4999 ng/mL and 10 with a level of ≥ 5000 ng/mL occurring at a median of 91 days (26-443) and 27 days (12-45) from posaconazole initiation, respectively. Majority of patients were immunocompromised (55.6% transplant recipients, 28.9% active malignancy, 5.6% other) with a split of treatment (50%) and prophylaxis (42.2%) indication. Symptomatic ADRs were very common in patients with posaconazole levels of ≥5000 ng/mL and 3000-4999 ng/mL (80% vs. 58.8%; p=0.31), primarily neurologic (49.1% overall) followed by gastrointestinal (32.7% overall). Hepatotoxicity was also common (≥5000 ng/mL 40% vs 3000-4999 ng/mL 23.4%, p=0.26). Fifty percent of patients had the posaconazole dose continued without change. Electrolytes and QTc results were similar between groups, but median overall QTc was borderline high (456 [IQR 435, 479]).
 
 
 
 There are safety concerns for patients with serum posaconazole levels ≥3000 ng/mL. Posaconazole levels should be monitored and, importantly, dose adjusted according to serum level and patient symptoms for both treatment and prophylaxis indications.
 
 
 
 Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria.
