Determination of posaconazole concentration with LC-MS/MS in adult patients with hematologic malignancy

Abstract

Background: Posaconazole has an important role in the prophylaxis of invasive fungal infections (IFIs), however oral suspension formulation is associated with variable bioavailability. The relationship between posaconazole concentrations achieved with the oral suspension and the IFI occurrence were analyzed along with demographic and clinical covariates (mucositis, diarrhea, liver enzymes, co-medications, and food intake).

Methods: One hundred twenty-two adult patients with AML/MDS undergoing remission induction chemotherapy were enrolled. They received posaconazole as prophylaxis and 557 posaconazole measurements were performed with a validated LC-MS/MS method.

Results: The median (range) posaconazole concentration (ng/ml) on days 2, 3, 7, 14, and 21 was 271 (43-493), 564 (101-1461), 713 (85-2186), 663 (85-1994), and 497 (43-1872), respectively. Thirteen patients (11%) developed proven (1/13), probable (2/13), and possible IFIs (10/13). A significant relationship existed between lower steady-state posaconazole concentrations and a higher breakthrough IFI incidence by binary logistic regression (P=0.0108). Posaconazole value of ≥ 338 ng/ml on day 3 predicted the achievement of ≥ 500 ng/ml at day 7 (sensitivity: 78.5%, specificity: 66.7%, AUC: 0.747). Food intake (P=0.0014) and proton pump inhibitor (P=0.0063) were significantly associated with higher and lower posaconazole concentrations, respectively.

Conclusions: TDM of posaconazole oral suspension formulation is recommended based on the exposure-response relationship of the present study.

Keywords: Invasive fungal infections; Mass spectrometry; Posaconazole; Prophylaxis; Therapeutic drug monitoring.