Kim Vanstraelen1, Juergen Prattes2, Johan Maertens3, Katrien Lagrou4, Hélène Schoemans3, Nele Peersman4, Pieter Vermeersch4,5, Koen Theunissen6, Raf Mols7, Patrick Augustijns7, Pieter Annaert7, Martin Hoenigl8,9,10, Isabel Spriet11. 1. Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, University Hospitals Leuven, Leuven, Belgium. Kim_vanstraelen@hotmail.com. 2. Department of Internal Medicine, Section of Infectious Diseases and Tropical Medicine, Medical University of Graz, Graz, Austria. Juergen.prattes@medunigraz.at. 3. Department of Hematology, Acute Leukemia and Stem Cell Transplantation Unit, University Hospitals Leuven, Leuven, Belgium. 4. Department of Microbiology and Immunology, Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium. 5. Department of Cardiovascular Sciences, University Hospitals Leuven, Leuven, Belgium. 6. Department of Hematology, Jessa Hospital Hasselt, Hasselt, Belgium. 7. Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, University Leuven, Leuven, Belgium. 8. Department of Internal Medicine, Section of Infectious Diseases and Tropical Medicine, Medical University of Graz, Graz, Austria. 9. Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. 10. Division of Infectious Diseases, Department of Medicine, University of California, San Diego, USA. 11. Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, University Hospitals Leuven, Leuven, Belgium.
Abstract
PURPOSE: Low posaconazole plasma concentrations (PPCs) are frequently encountered in allogeneic hematopoietic stem cell transplant (HSCT) patients, due to variable gastrointestinal absorption. In this study, the impact of intestinal mucositis on posaconazole exposure is investigated. PATIENTS AND METHODS: A prospective pharmacokinetic study was performed including allogeneic HSCT patients receiving posaconazole prophylaxis with the oral suspension or tablets. Steady state PPCs were determined using high-performance liquid chromatography-fluorescence detection at the day of transplantation (=day 0), day +7, and +14. Citrulline was measured using liquid chromatography-tandem mass spectrometry to evaluate severity of mucositis, at baseline (day -7 or -6), and at day 0, +7 and +14. Additionally, citrulline plasma concentrations and steady state trough PPCs were determined in hematological patients without HSCT or mucositis. RESULTS: Thirty-four HSCT patients received posaconazole oral suspension together with 25 cL of Coca Cola, 6 HSCT patients received posaconazole tablets and 33 hematological patients not receiving HSCT received posaconazole oral suspension. The median (interquartile range) average PPC was 0.26 mg/L (0.17-0.43), 0.67 mg/L (0.27-1.38), and 1.08 mg/L (0.96-1.38), with suspension in HSCT patients, suspension in hematological patients and tablets in HSCT patients, respectively. A higher trough PPC was encountered with the oral suspension when citrulline plasma concentrations were above 10 μmol/L compared to values below 10 μmol/L (p < 0.001), whereas for tablets, average PPCs remained high with citrulline plasma concentrations below or above 10 μmol/L (p = 0.64). CONCLUSION: Posaconazole tablets should be preferred to suspension in HSCT patients immediately after transplantation to prevent insufficient plasma exposure due to intestinal mucositis.
PURPOSE: Low posaconazole plasma concentrations (PPCs) are frequently encountered in allogeneic hematopoietic stem cell transplant (HSCT) patients, due to variable gastrointestinal absorption. In this study, the impact of intestinal mucositis on posaconazole exposure is investigated. PATIENTS AND METHODS: A prospective pharmacokinetic study was performed including allogeneic HSCT patients receiving posaconazole prophylaxis with the oral suspension or tablets. Steady state PPCs were determined using high-performance liquid chromatography-fluorescence detection at the day of transplantation (=day 0), day +7, and +14. Citrulline was measured using liquid chromatography-tandem mass spectrometry to evaluate severity of mucositis, at baseline (day -7 or -6), and at day 0, +7 and +14. Additionally, citrulline plasma concentrations and steady state trough PPCs were determined in hematological patients without HSCT or mucositis. RESULTS: Thirty-four HSCT patients received posaconazole oral suspension together with 25 cL of Coca Cola, 6 HSCT patients received posaconazole tablets and 33 hematological patients not receiving HSCT received posaconazole oral suspension. The median (interquartile range) average PPC was 0.26 mg/L (0.17-0.43), 0.67 mg/L (0.27-1.38), and 1.08 mg/L (0.96-1.38), with suspension in HSCT patients, suspension in hematological patients and tablets in HSCT patients, respectively. A higher trough PPC was encountered with the oral suspension when citrulline plasma concentrations were above 10 μmol/L compared to values below 10 μmol/L (p < 0.001), whereas for tablets, average PPCs remained high with citrulline plasma concentrations below or above 10 μmol/L (p = 0.64). CONCLUSION:Posaconazole tablets should be preferred to suspension in HSCT patients immediately after transplantation to prevent insufficient plasma exposure due to intestinal mucositis.
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