Posaconazole serum level on day 2 predicts steady state posaconazole serum level.

To the Editor: Posaconazole has demonstrated superiority versus alternate antifungal agents in patients with acute myelogenous leukemia or myelodysplastic syndrome receiving intensive remission induction chemotherapy. Significant interpatient and intrapatient variations in serum level suggest benefit to therapeutic drug monitoring (TDM). Posaconazole TDM is controversial due, in part, to length of time to reach steady state and protracted time to process posaconazole serum samples. Data derived from computer simulations indicate that steady state posaconazole serum level may be predicted by the serum level obtained 3–5 hours after posaconazole administration on day 2. This simulation found that steady state posaconazole serum levels were double the day 2 serum level. Predicting the steady state serum level by extrapolating day 2 posaconazole serum level has not been investigated in humans. After obtaining institutional review board approval, 16 patients were included from December 2009 through June 2011. This cohort included 14 patients with acute myelogenous leukemia, 1 patient with acute leukemic transformation of chronic myelomonocytic leukemia, and 1 patient with acute lymphoblastic leukemia. The median age was 59 years (range, 19–81 years) with 9 male and 7 female patients. All patients received intensive remission induction chemotherapy for acute leukemia in combination with posaconazole prophylaxis. After completion of anthracycline administration, posaconazole 200 mg per os 3 times daily was administered in combination with adjuvant modalities to optimize absorption, as previously described. Day 2 posaconazole serum levels were obtained 3–5 hours after administration of fourth consecutive dose, and day 7 levels were obtained as a trough before morning dose. Serum posaconazole levels were assayed by solid-phase extraction highperformance liquid chromatography at the Fungus Testing Laboratory (San Antonio, TX). The precision of this assay is adjusted per curve by using high, medium, and low controls against each sample to derive a coefficient of determination. The lower limit of detection for this assay is 0.125 mg/mL, and the upper limit is 5 mg/mL. All 16 patients were evaluable. The median day 2 posaconazole serum level was 0.41 mg/mL (range, 0.23–0.81 mg/mL), and median day 7 posaconazole serum level was 0.99 mg/mL (range, 0.32– 2.26 mg/mL) (Table 1). The median increase in serum level from days 2 to 7 is 195% (range, 110%–398%). Median adherence to posaconazole bundle was 90% (range, 80%–100%). No patients (0%) experienced a decrease in serum posaconazole levels from days 2 to 7. Twelve patients (75%) experienced $170% increase in serum posaconazole level from days 2 to 7. Nine patients (56%) obtained a day 7 posaconazole serum level >0.7 mg/mL. No patients (0%) discontinued therapy due to intolerance of posaconazole or adjuvant modalities, and all patients (100%) demonstrated complete adherence to posaconazole and adjuvant modalities. Five calendar days (median; range, 5–8 days) passed between drawing the serum level and obtaining the result for each posaconazole serum level, irrespective of which day level drawn. Day 2 posaconazole serum level results were available on day 7 (median; range, 7–9 days) of posaconazole dosing, which is 5 days sooner than results of day 7 serum level. The median time from study entry (day of first dose of posaconazole) to obtaining results of day 7 serum posaconazole level was 12 days (range, 11–14 days). All 9 patients (100%) who obtained a posaconazole serum level >0.7 mg/mL on day 7 remained free of fungal infections throughout duration of neutropenia and the first 100 days after start of posaconazole. By contrast, of the 7 patients who did not obtain a posaconazole serum level >0.7 mg/mL on day 7, 1 patient (6%) was radiographically diagnosed with fungal pneumonia on day 78 after start of posaconazole. Currently only available as an oral suspension, posaconazole is an important member of the antifungal armamentarium, possessing broad spectrum of antifungal activity. Despite data demonstrating improved clinical outcomes, including overall survival, versus