A Prospective Study of Voriconazole Therapeutic Drug Monitoring (TDM) in Patients with Acute Leukemia.

Voriconazole (VOR) is an expanded spectrum azole that is often used to treat suspected or proven invasive aspergillosis (IA). VOR plasma drug levels are not routinely monitored and their correlation with clinical response and toxicity is unclear. We sought to clarify the kinetics of levels in patients started on VOR and their relationship with CYP2C19 genotype and clinical outcomes.

We prospectively enrolled inpatients undergoing induction or consolidation chemotherapy for AML who were able to take oral medications and started on VOR for suspected invasive aspergillosis (IA). All patients received an initial intravenous loading dose of 6mg/kg bid for two doses, then 200mg bid. VOR dose could be increased at the physician's discretion. Trough VOR levels (μg/mL) were monitored at days 0,2,4,6 and performed using HPLC. Patients also underwent genotyping for CYP2C19. Clinical and radiologic responses were graded independently by two physicians. Hepatotoxicity was correlated to peak VOR levels.

We enrolled 33 patients of which 60.6% were male and 39.4% female. Mean age was 60.2±15.4 yrs. The distribution of peak VOR levels was as follows: <2 μg/mL (n=6); 2-6 μg/mL (n=22); >6 μg/mL (n=5). Mild hepatotoxicity (liver enzymes greater than 2x baseline) was seen in 6/22 (27.2%) of patients with levels between 2-6 μg/mL and 1/5 (20%) of patients with levels >6 μg/mL. No hepatotoxicity was noted in those with peak VOR <2 μg/mL. No significant correlation was seen in mg/kg dose of VOR and levels. Of the 33 patients, 19 (57.6%) met the EORTC/MSG criteria for possible, probable, or proven invasive fungal disease. Of these 9 (47.4%) patients had a response to therapy. Mean peak VOR levels in responders vs. nonresponders was 3.78 vs. 3.12 (p=0.63). Response to therapy was 2/2 (100%) if levels were <2 μg/mL, 6/14 (42.9%) if levels were 2-6 μg/mL, and 1/3 (33%) if levels were >6 μg/mL. Breakthrough infections occurred in 5/33 (15.2%) patients given VOR, all of whom had peak levels between 2-6 μg/mL. Genotyping was performed on 11/33 (33.3%) patients and included slow metabolizers (n=5; median peak VOR 3.0), rapid metabolizers (n=5; median peak VOR 3.0) and undetermined (n=1). Genotype did not correlate with clinical outcomes.

The majority of patients attained voriconazole levels > 2 μg/mL by day 6 of treatment. Voriconazole levels do not appear to predict response to therapy or breakthrough infection although mild hepatotoxicity can occur if levels are >2 μg/mL.

Seki:Astellas: Honoraria; Pfizer: Honoraria; Merck: Consultancy, Honoraria, Research Funding. Kumar:Merck: Honoraria; Pfizer: Honoraria.