PMID- 33064889
OWN - NLM
STAT- MEDLINE
DCOM- 20220106
LR  - 20220106
IS  - 1875-9114 (Electronic)
IS  - 0277-0008 (Linking)
VI  - 41
IP  - 2
DP  - 2021 Feb
TI  - Using Child-Pugh Class to Optimize Voriconazole Dosage Regimens and Improve 
      Safety in Patients with Liver Cirrhosis: Insights from a Population 
      Pharmacokinetic Model-based Analysis.
PG  - 172-183
LID - 10.1002/phar.2474 [doi]
AB  - BACKGROUND: Cirrhotic patients are at a high risk of fungal infections. 
      Voriconazole is widely used as prophylaxis and in the treatment of invasive 
      fungal disease. However, the safety, pharmacokinetics, and optimal regimens of 
      voriconazole are currently not well defined in cirrhotic patients. DESIGN: 
      Retrospective pharmacokinetics study. SETTING: Two large, academic, tertiary-care 
      medical center. PATIENTS: Two hundred nineteen plasma trough concentrations 
      (C(min) ) from 120 cirrhotic patients and 83 plasma concentrations from 11 
      non-cirrhotic patients were included. METHODS: Data pertaining to voriconazole 
      were collected retrospectively. A population pharmacokinetics analysis was 
      performed and model-based simulation was used to optimize voriconazole dosage 
      regimens. RESULTS: Voriconazole-related adverse events (AEs) developed in 29 
      cirrhotic patients, and the threshold C(min) for AE was 5.12 mg/L. A 
      two-compartment model with first-order elimination adequately described the data. 
      The Child-Pugh class and body weight were the significant covariates in the final 
      model. Voriconazole clearance in non-cirrhotic, Child-Pugh class A and B 
      cirrhotic (CP-A/B) and Child-Pugh class C cirrhotic (CP-C) patients was 7.59, 
      1.86, and 0.93 L/hour, respectively. The central distribution volume and 
      peripheral distribution volume was 100.8 and 55.2 L, respectively. The oral 
      bioavailability was 91.6%. Model-based simulations showed that a loading dose 
      regimen of 200 mg/12 hours intravenously or orally led to 65.0-75.7% of 
      voriconazole C(min) in therapeutic range on day 1, and the appropriate 
      maintenance dosage regimens were 75 mg/12 hours and 150 mg/24 hours intravenously 
      or orally for CP-A/B patients, and 50 mg/12 hours and 100 mg/24 hours 
      intravenously or orally for CP-C patients. The predicted probability of achieving 
      the therapeutic target concentration for optimized regimens at steady-state was 
      66.8-72.3% for CP-A/B patients and 70.3-74.0% for CP-C patients. CONCLUSIONS: 
      These results recommended that the halved loading dose regimens should be used, 
      and voriconazole maintenance doses in cirrhotic patients should be reduced to 
      one-fourth for CP-C patients and to one-third for CP-A/B patients compared to 
      that for patients with normal liver function.
CI  - (c) 2020 Pharmacotherapy Publications, Inc.
FAU - Wang, Taotao
AU  - Wang T
AUID- ORCID: 0000-0002-6459-7139
AD  - Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China.
FAU - Yan, Miao
AU  - Yan M
AD  - Department of Pharmacy, The Second Xiangya Hospital, Central South University, 
      Changsha, China.
FAU - Tang, Dan
AU  - Tang D
AD  - School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 
      Nanjing, China.
FAU - Dong, Yuzhu
AU  - Dong Y
AD  - Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China.
AD  - Department of Pharmacy, the Third Affiliated Hospital of Chongqing Medical 
      University, Chongqing, 401120, China.
FAU - Zhu, Li
AU  - Zhu L
AD  - Department of Infectious Disease, the First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, 710061, China.
FAU - Du, Qian
AU  - Du Q
AD  - Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China.
FAU - Sun, Dan
AU  - Sun D
AD  - Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China.
FAU - Xing, Jianfeng
AU  - Xing J
AD  - School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.
FAU - Dong, Yalin
AU  - Dong Y
AUID- ORCID: 0000-0001-5619-0788
AD  - Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Pharmacotherapy
JT  - Pharmacotherapy
JID - 8111305
RN  - 0 (Antifungal Agents)
RN  - JFU09I87TR (Voriconazole)
SB  - IM
MH  - Antifungal Agents/administration & dosage/adverse effects/pharmacokinetics
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - *Liver Cirrhosis/drug therapy
MH  - Models, Biological
MH  - *Mycoses/prevention & control
MH  - Retrospective Studies
MH  - *Voriconazole/administration & dosage/adverse effects/pharmacokinetics
OTO - NOTNLM
OT  - Child-Pugh class
OT  - adverse events
OT  - liver cirrhosis
OT  - model-based simulation
OT  - population pharmacokinetics
OT  - voriconazole
EDAT- 2020/10/17 06:00
MHDA- 2022/01/07 06:00
CRDT- 2020/10/16 17:11
PHST- 2020/10/17 06:00 [pubmed]
PHST- 2022/01/07 06:00 [medline]
PHST- 2020/10/16 17:11 [entrez]
AID - 10.1002/phar.2474 [doi]
PST - ppublish
SO  - Pharmacotherapy. 2021 Feb;41(2):172-183. doi: 10.1002/phar.2474.