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Population pharmacokinetics, safety and dosing optimization of voriconazole in patients with liver dysfunction: a prospective study
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  • Dan Tang,
  • Miao Yan,
  • Bai Song,
  • Yi-chang Zhao,
  • Yi Xiao,
  • Feng Wang,
  • Wu Liang,
  • Bi-kui Zhang,
  • Xi Chen,
  • Jian Zou,
  • Yi Tian,
  • Wen-long Wang,
  • Yong-fang Jiang,
  • guozhong gong,
  • Min Zhang,
  • Da-xiong Xiang
Dan Tang
the Second Xiangya Hospital of Central South University
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Miao Yan
the Second Xiangya Hospital of Central South University
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Bai Song
China Pharmaceutical University
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Yi-chang Zhao
The Second Xiangya Hospital of Central South University
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Yi Xiao
the Second Xiangya Hospital, Central South University
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Feng Wang
the Second Xiangya Hospital, Central South University
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Wu Liang
Changsha VALS Technology Co., Ltd
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Bi-kui Zhang
The Second Xiangya Hospital of Central South University
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Xi Chen
China Pharmaceutical University
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Jian Zou
Nanjing First Hospital, Nanjing Medical University
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Yi Tian
The Second Xiangya Hospital of Central South University
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Wen-long Wang
The Second Xiangya Hospital of Central South University
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Yong-fang Jiang
The Second Xiangya Hospital of Central South University
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guozhong gong
Second Xiangya Hospital
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Min Zhang
the Second Xiangya Hospital, Central South University
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Da-xiong Xiang
The Second Xiangya Hospital of Central South University
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Abstract

Aims This study aimed to explore the relationship between voriconazole trough concentration (Ctrough) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised dosing regimen for patients with liver dysfunction. Methods The study prospectively enrolled 51 patients with 272 voriconazole concentrations. Receiver operating characteristic (ROC) curves were used to explore the relationship between voriconazole Ctrough and toxicity. The pharmacokinetic data was analysed with nonlinear mixed-effects method. Dosing simulations stratified by TBIL (TBIL-1: TBIL < 51 μmol/L; TBIL-2: 51 μmol/L ≤ TBIL < 171 μmol/L; TBIL-3: TBIL ≥ 171 μmol/L) were performed. Results ROC curve analysis revealed that voriconazole Ctrough of ≤ 5.1 mg/L were associated with significantly lower the incidence of adverse events. A one-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. Population pharmacokinetic parameters of clearance (CL), the volume of distribution (V) and oral bioavailability (F) were 0.88 L/h, 148.8 L and 88.4%, respectively. Voriconazole CL was significantly associated with total bilirubin (TBIL) and platelet count. The V increased with weight. Patients with TBIL-1 could be treated with loading dose of 400 mg every 12 hours (q12h) for first day and maintenance dose of 100 mg q12h intravenously or orally. TBIL-2 and TBIL-3 patients could be treated with loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or 100 mg once daily (qd) and 50 mg qd orally or intravenously, respectively. Conclusions TBIL-based dosing regimens provide a practical strategy for voriconazole maximizing treatment outcomes.

Peer review status:ACCEPTED

02 May 2020Submitted to British Journal of Clinical Pharmacology
04 May 2020Submission Checks Completed
04 May 2020Assigned to Editor
07 May 2020Reviewer(s) Assigned
08 Jun 2020Review(s) Completed, Editorial Evaluation Pending
29 Jun 2020Editorial Decision: Revise Major
24 Aug 20201st Revision Received
27 Aug 2020Submission Checks Completed
27 Aug 2020Assigned to Editor
27 Aug 2020Review(s) Completed, Editorial Evaluation Pending
27 Aug 2020Editorial Decision: Revise Minor
05 Sep 20202nd Revision Received
07 Sep 2020Submission Checks Completed
07 Sep 2020Assigned to Editor
07 Sep 2020Review(s) Completed, Editorial Evaluation Pending
08 Sep 2020Editorial Decision: Accept