Multicenter study of posaconazole therapeutic drug monitoring: exposure-response relationship and factors affecting concentration

Abstract

Posaconazole has an important role in the prophylaxis and salvage treatment of invasive fungal infections (IFIs), although poor and variable bioavailability remains an important clinical concern. Therapeutic drug monitoring of posaconazole concentrations has remained contentious, with the use of relatively small patient cohorts in previous studies hindering the assessment of exposure-response relationships. This multicenter retrospective study aimed to investigate relationships between posaconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect posaconazole concentrations. Medical records were reviewed for patients who received posaconazole and had ≥1 concentration measured at six hospitals in Australia. Data from 86 patients with 541 posaconazole concentrations were included in the study. Among 72 patients taking posaconazole for prophylaxis against IFIs, 12 patients (17%) developed a breakthrough fungal infection; median posaconazole concentrations were significantly lower than in those who did not develop fungal infection (median [range], 289 [50 to 471] ng/ml versus 485 [0 to 2,035] ng/ml; P < 0.01). The median posaconazole concentration was a significant predictor of breakthrough fungal infection via binary logistic regression (P < 0.05). A multiple linear regression analysis identified a number of significant drug interactions associated with reduced posaconazole exposure, including coadministration with proton pump inhibitors, metoclopramide, phenytoin or rifampin, and the H(2) antagonist ranitidine (P < 0.01). Clinical factors such as mucositis, diarrhea, and the early posttransplant period in hematopoietic stem cell transplant recipients were also associated with reduced posaconazole exposure (P < 0.01). Low posaconazole concentrations are common and are associated with breakthrough fungal infection, supporting the utility of monitoring posaconazole concentrations to ensure optimal systemic exposure.

Fig 1

Posaconazole concentration by daily dose (24 h). The black lines and corresponding concentrations represent the medians.

Fig 2

Predicted probability of breakthrough fungal infection determined from the logistic regression analysis. Open circles represent one patient's median posaconazole concentration and outcome of therapy (failure, breakthrough fungal infection; success, no breakthrough infection); logit function = −0.005χ + 0.421, where χ = median posaconazole concentration (ng/ml). Predicted probabilities were calculated from the natural antilog of the logit.

Fig 3

Box plots displaying the effect of a concomitant proton pump inhibitor (A), mucositis (B), or diarrhea (C) on the day of sampling on posaconazole concentration.

Fig 4

Median posaconazole concentrations measured in 16 patients within 5 days before hematopoietic stem cell transplant (pre-HSCT) and in the early posttransplant period (within 5 days) (post-HSCT).