A Multi-Center Study of Posaconazole Therapeutic Drug Monitoring: Exposure-Response and Factors Affecting Concentration

A Multi-Center Study of Posaconazole Therapeutic Drug Monitoring: Exposure-Response and Factors Affecting Concentration

  1. Michael J. Dolton1,
  2. John E. Ray2,
  3. Sharon C-A. Chen3,
  4. Kingsley Ng4,
  5. Lisa Pont1 and
  6. Andrew J. McLachlan1,5,#

+Author Affiliations


  1. 1Faculty of Pharmacy, University of Sydney, Sydney, Australia

  2. 2Clinical Pharmacology & Toxicology, SydPath, St Vincent’s Hospital, Sydney, Australia

  3. 3Centre for Infectious Diseases & Microbiology and the University of Sydney, Westmead Hospital, Westmead, Australia

  4. 4Department of Pharmacy, Westmead Hospital, Westmead, Australia

  5. 5Centre For Education and Research on Ageing, Concord Repatriation General Hospital, Sydney, Australia

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 relatively small patient cohorts in previous studies hindering the assessment of exposure-response relationships. This multi-center retrospective study aimed to investigate relationships between posaconazole concentration and clinical outcomes and adverse events, and 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 compared to those who did not develop fungal infection (median (range); 289(50–471) ng/mL vs. 485(0–2035) ng/mL, p<0.01). 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 co-administration with proton pump inhibitors, metoclopramide, phenytoin or rifampicin, and the H2 antagonist ranitidine (p<0.01). Clinical factors such as mucositis, diarrhea, and the early post-transplant 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.

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