PMID- 29849129
OWN - NLM
STAT- MEDLINE
DCOM- 20190415
LR  - 20190901
IS  - 1745-7254 (Electronic)
IS  - 1671-4083 (Print)
IS  - 1671-4083 (Linking)
VI  - 39
IP  - 9
DP  - 2018 Sep
TI  - Whole-body physiology-based pharmacokinetics of caspofungin for general patients, 
      intensive care unit patients and hepatic insufficiency patients.
PG  - 1533-1543
LID - 10.1038/aps.2017.176 [doi]
AB  - Caspofungin is an echinocandin antifungal agent licensed as a first-line therapy 
      for invasive candidiasis in patients with moderate to severe illness or recent 
      exposure to azoles. In this study we developed a whole-body physiology-based 
      pharmacokinetics (WB-PBPK) model to predict the pharmacokinetics (PK) of 
      caspofungin, and combined with Monte Carlo simulation (MCS) to optimize clinical 
      dosage regimens of caspofungin in different kinds of patients. A WB-PBPK model of 
      caspofungin was built and validated with raw data from 4 previous trials of 
      general patients, intensive care unit (ICU) patients with Child-Pugh B, ICU 
      patients on continuous renal replacement therapy, mild and moderate hepatic 
      insuffciency (HI) patients. MCS was used to optimize clinical dosage regimens of 
      caspofungin in these patients. A cumulative fraction of response (CFR) value of 
      >/=90% was considered to be the minimum for achieving optimal empirical therapy. 
      The simulated results of the WB-PBPK model were in good agreement with observed 
      values of all trials. For general and ICU patients with caspofungin 70/50 mg, AUC 
      and Cmax were decreased with the increase of body weight (BW) and showed great 
      variation. MCS showed all general patients achieved CFR>/=90% regardless of BW. But 
      not all ICU patients with higher BW (>/=70 kg) could achieve CFR>/=90%. Compared with 
      standard dosage regimens in general patients, caspofungin 70/35 mg in ICU 
      patients with Child-Pugh B achieved significantly decreased AUC and Cmax, but 
      obtained similar AUC and Cmax in moderate HI patients with Child-Pugh B. The 
      WB-PBPK model of caspofungin is able to predict PK of all populations correctly. 
      The combined WB-PBPK model with MCS can successfully optimize clinical dosage 
      regimens of caspofungin in all patient populations.
FAU - Yang, Qian-Ting
AU  - Yang QT
AD  - Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, 710061, China.
FAU - Zhai, Ya-Jing
AU  - Zhai YJ
AD  - Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, 710061, China.
FAU - Chen, Lu
AU  - Chen L
AD  - Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, 710061, China.
FAU - Zhang, Tao
AU  - Zhang T
AD  - Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, 710061, China.
FAU - Yan, Yan
AU  - Yan Y
AD  - Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, 710061, China.
FAU - Meng, Ti
AU  - Meng T
AD  - Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, 710061, China.
FAU - Liu, Lei-Chao
AU  - Liu LC
AD  - Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, 710061, China.
FAU - Chen, Li-Mei
AU  - Chen LM
AD  - Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, 710061, China.
FAU - Wang, Xue
AU  - Wang X
AD  - Central Intensive Care Unit, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, 710061, China.
FAU - Dong, Ya-Lin
AU  - Dong YL
AD  - Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, 710061, China. dongyalin@mail.xjtu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20180531
PL  - United States
TA  - Acta Pharmacol Sin
JT  - Acta pharmacologica Sinica
JID - 100956087
RN  - 0 (Antifungal Agents)
RN  - F0XDI6ZL63 (Caspofungin)
SB  - IM
MH  - Adult
MH  - Antifungal Agents/administration & dosage/*pharmacokinetics
MH  - Caspofungin/administration & dosage/*pharmacokinetics
MH  - Hepatic Insufficiency/metabolism
MH  - Humans
MH  - Intensive Care Units
MH  - Male
MH  - *Models, Biological
MH  - Monte Carlo Method
MH  - Young Adult
PMC - PMC6289327
OTO - NOTNLM
OT  - antifungal agent
OT  - caspofungin
OT  - cumulative fraction of response
OT  - hepatic insuffciency
OT  - intensive care unit
OT  - whole-body physiology-based pharmacokinetics model
EDAT- 2018/06/01 06:00
MHDA- 2019/04/16 06:00
PMCR- 2019/09/01
CRDT- 2018/06/01 06:00
PHST- 2017/07/30 00:00 [received]
PHST- 2017/11/26 00:00 [accepted]
PHST- 2018/06/01 06:00 [pubmed]
PHST- 2019/04/16 06:00 [medline]
PHST- 2018/06/01 06:00 [entrez]
PHST- 2019/09/01 00:00 [pmc-release]
AID - 10.1038/aps.2017.176 [pii]
AID - 123 [pii]
AID - 10.1038/aps.2017.176 [doi]
PST - ppublish
SO  - Acta Pharmacol Sin. 2018 Sep;39(9):1533-1543. doi: 10.1038/aps.2017.176. Epub 
      2018 May 31.