Abstract | STUDY OBJECTIVES: DESIGN: Prospective pharmacokinetics study. SETTING: The intensive care unit in a tertiary-care medical center. PATIENTS: METHODS: Model-based simulations with therapeutic range of 2-6 mg/L as the plasma trough concentration (Cmin ) target and the free area under the concentration-time curve from 0 to 24 h (ƒAUC24 ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC24 /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child-Pugh class A and B (CP-A/B) and Child-Pugh class C (CP-C) patients. RESULTS: A two-compartment model with first-order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child-Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP-A/B and CP-C patients to attain the Cmin target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP-A/B patients and 50 mg q12h or 100 mg q24h for CP-C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP-A/B and CP-C patients at an MIC of 1 mg/L, with plasma Cmin monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available. CONCLUSIONS: For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP-A/B and CP-C patients.
|
Authors | Xiao-Bin Lin, Ka Yin Lui, Peng-Hao Guo, Xiao-Man Liu, Tao Liang, Xiao-Guang Hu, Li Tong, Jing-Jing Wu, Yan-Zhe Xia, Pan Chen, Guo-Ping Zhong, Xiao Chen, Chang-Jie Cai |
Journal | Pharmacotherapy
(Pharmacotherapy)
Vol. 42
Issue 1
Pg. 23-33
(01 2022)
ISSN: 1875-9114 [Electronic] United States |
PMID | 34655497
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | © 2021 Pharmacotherapy Publications, Inc. |
Chemical References |
- Antifungal Agents
- Voriconazole
|
Topics |
- Administration, Intravenous
- Antifungal Agents
(administration & dosage, pharmacokinetics)
- Critical Illness
- Dose-Response Relationship, Drug
- Humans
- Liver Diseases
(drug therapy)
- Microbial Sensitivity Tests
- Prospective Studies
- Voriconazole
(administration & dosage, pharmacokinetics)
|