Pharmacokinetics of isavuconazole at different target sites in healthy volunteers after single and multiple intravenous infusions.

Autor:	Bergmann F; Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.; Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria., Wölfl-Duchek M; Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.; Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria., Jorda A; Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria., Al Jalali V; Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria., Leutzendorff A; Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.; Department of Infectiology and Tropical Medicine, University Clinic of Internal Medicine I, Medical University Vienna, Vienna, Austria., Sanz-Codina M; Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria., Gompelmann D; Division of Pulmonology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria., Trimmel K; Department of Neurology, Medical University of Vienna, Vienna, Austria., Weber M; Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria., Eberl S; Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria., Van Os W; Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria., Minichmayr IK; Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria., Reiter B; Department of Laboratory Medicine, Medical University of Vienna, Waehringer Gürtel 18-20, Vienna, Austria., Stimpfl T; Department of Laboratory Medicine, Medical University of Vienna, Waehringer Gürtel 18-20, Vienna, Austria., Idzko M; Division of Pulmonology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria., Zeitlinger M; Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
Jazyk:	angličtina
Zdroj:	The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2024 May 02; Vol. 79 (5), pp. 1169-1175.
DOI:	10.1093/jac/dkae088
Abstrakt:	Background: Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited. Materials and Methods: We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus. Results: C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57 ± 1.68 mg/L (mean ± SD) and 106 ± 32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07 ± 0.03, 0.94 ± 0.46 and 27.1 ± 17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106 ± 32.1, 1.68 ± 0.72, 22.6 ± 11.0 and 650 ± 426 mg·h/L, respectively. Conclusion: Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICs ≤ 1 mg/L. (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)
Databáze:	MEDLINE
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