Abstract
Purpose
Posaconazole is a triazole antifungal widely used for prophylaxis of invasive fungal disease (IFI). Posaconazole tablets allow reaching higher plasma levels than the oral suspension, but safety data with this formulation in real life are scarce. This study aimed at evaluating the safety profile, the pharmacokinetic variability, and the concentration–toxicity relationship of posaconazole tablets in patients with haematological malignancies.
Methods
Sixty neutropenic patients treated with posaconazole tablets for prophylaxis of IFI were prospectively included in the study. Adverse drug reactions (ADR) were recorded and analyzed by the Regional Pharmacovigilance Centre to assess posaconazole implication. Blood samples were drawn once a week and plasma trough concentrations (C min) were assayed by LC–MS/MS. The rates of ADR by quartile of C min were compared.
Results
Eighteen patients (30%) experienced at least one ADR attributed to posaconazole. Liver function test (LFT) abnormalities were encountered in 20% of patients and resulted in four (6.7%) treatment discontinuations. Posaconazole median (range) C min was 1.36 (< 0.1–3.44) µg/mL (inter-patient CV = 43.9%). During follow-up, 28.6% of patients had at least one concentration < 0.7 µg/mL, and 35.7% had at least one concentration > 2 µg/mL. Rates of ADR by quartile of C min were not different.
Conclusions
Posaconazole was well tolerated; however, LFT abnormalities were frequent. ADR occurrence was not linked to posaconazole exposure. Because posaconazole concentrations were highly variable, TDM can be helpful to avoid underexposure to the drug and increase its efficacy in preventing IFI. Conversely, a large proportion of patients was overexposed and might have benefited of a dose reduction.
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Acknowledgements
The authors wish to thank the medical team of the Department of Clinical Haematology, as well as the patients and their families.
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CBK and AP designed the study. SN was in charge of clinical care of the patients. CBK was involved with data acquisition. JPG provided the data regarding efficacy of the prophylaxis. AP conducted the pharmacokinetic and statistical analysis. SP conducted the safety data analysis. CBK, AP, and SP interpreted the data. AP, CBK, CT, SL, FL, and MCV participated to therapeutic drug monitoring of posaconazole. CBK, AP, and FL wrote the manuscript. MCV and EB gave final approval to the manuscript in its submitted form. All authors revised the manuscript for important intellectual content and approved the manuscript in its submitted form.
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The authors declare that they have no conflict of interest.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments.
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Boglione-Kerrien, C., Picard, S., Tron, C. et al. Safety study and therapeutic drug monitoring of the oral tablet formulation of posaconazole in patients with haematological malignancies. J Cancer Res Clin Oncol 144, 127–134 (2018). https://doi.org/10.1007/s00432-017-2523-2
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DOI: https://doi.org/10.1007/s00432-017-2523-2