C Boglione-Kerrien1, S Picard2, C Tron2,3,4, S Nimubona5, J-P Gangneux6, S Lalanne2,3,4, F Lemaitre2,3,4, E Bellissant2,3,4, M-C Verdier2,3,4, A Petitcollin2,3,4. 1. Laboratory of Biological Pharmacology, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Centre, Rennes University Hospital, 2 rue Henri le Guilloux, 35033, Rennes, France. christelle.boglione-kerrien@chu-rennes.fr. 2. Laboratory of Biological Pharmacology, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Centre, Rennes University Hospital, 2 rue Henri le Guilloux, 35033, Rennes, France. 3. Laboratory of Experimental and Clinical Pharmacology, Faculty of Medicine, Rennes 1 University, Rennes, France. 4. CIC-P 1414 Clinical Investigation Centre, Inserm, Rennes, France. 5. Department of Clinical Haematology, Rennes University Hospital, Rennes, France. 6. Parasitology and Mycology Department, Rennes University Hospital, Rennes, France.
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.
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 neutropenicpatients 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.
Authors: Ioannis Kyriakidis; Athanasios Tragiannidis; Silke Munchen; Andreas H Groll Journal: Expert Opin Drug Saf Date: 2016-12-16 Impact factor: 4.250
Authors: Rafael F Duarte; Javier López-Jiménez; Oliver A Cornely; Michel Laverdiere; David Helfgott; Shariq Haider; Pranatharthi Chandrasekar; Amelia Langston; John Perfect; Lei Ma; Marlou L P S van Iersel; Nancy Connelly; Nicholas Kartsonis; Hetty Waskin Journal: Antimicrob Agents Chemother Date: 2014-07-21 Impact factor: 5.191
Authors: Aaron Cumpston; Ryan Caddell; Alexandra Shillingburg; Xiaoxiao Lu; Sijin Wen; Mehdi Hamadani; Michael Craig; Abraham S Kanate Journal: Antimicrob Agents Chemother Date: 2015-05-18 Impact factor: 5.191
Authors: Issam I Raad; Ray Y Hachem; Raoul Herbrecht; John R Graybill; Roberta Hare; Gavin Corcoran; Dimitrios P Kontoyiannis Journal: Clin Infect Dis Date: 2006-04-11 Impact factor: 9.079
Authors: Oliver A Cornely; Rafael F Duarte; Shariq Haider; Pranatharthi Chandrasekar; David Helfgott; Javier López Jiménez; Anna Candoni; Issam Raad; Michel Laverdiere; Amelia Langston; Nicholas Kartsonis; Marlou Van Iersel; Nancy Connelly; Hetty Waskin Journal: J Antimicrob Chemother Date: 2015-11-26 Impact factor: 5.790
Authors: H Ruth Ashbee; Rosemary A Barnes; Elizabeth M Johnson; Malcolm D Richardson; Rebecca Gorton; William W Hope Journal: J Antimicrob Chemother Date: 2013-12-29 Impact factor: 5.790
Authors: Sumit Bhatnagar; Dwaipayan Mukherjee; Ahmed Hamed Salem; Dale Miles; Rajeev M Menon; John P Gibbs Journal: Cancer Chemother Pharmacol Date: 2021-01-04 Impact factor: 3.333
Authors: Martin Hoenigl; Robert Krause; David Lenczuk; Wilma Zinke-Cerwenka; Hildegard Greinix; Albert Wölfler; Jürgen Prattes; Ines Zollner-Schwetz; Thomas Valentin; Timothy C Lin; Andreas Meinitzer Journal: Antimicrob Agents Chemother Date: 2018-05-25 Impact factor: 5.191
Authors: Russell E Lewis; Dimitrios P Kontoyiannis; Pierluigi Viale; Eric M Sarpong Journal: Antimicrob Agents Chemother Date: 2019-09-16 Impact factor: 5.191
Authors: Anne-Grete Märtson; Anette Veringa; Edwin R van den Heuvel; Martijn Bakker; Daan J Touw; Tjip S van der Werf; Lambert F R Span; Jan-Willem C Alffenaar Journal: Mycoses Date: 2019-06-18 Impact factor: 4.377
Authors: Thuluz Meza-Menchaca; Angel Ramos-Ligonio; Aracely López-Monteon; Abraham Vidal Limón; Leonid A Kaluzhskiy; Tatjana V Shkel; Natallia V Strushkevich; Luis Felipe Jiménez-García; Lourdes Teresa Agredano Moreno; Verónica Gallegos-García; Jorge Suárez-Medellín; Ángel Trigos Journal: Biomolecules Date: 2019-09-12