Background: Intrahepatic cholangiocarcinoma (ICC), a biliary tract cancer, is a major cause of primary liver cancers. It is recognised as a deadly gastrointestinal cancer with a poor disease prognosis due to the lack of effective biomarkers for early diagnosis and effective treatment. Recently, research has indicated that Atractylodes lancea (Thunb.) DC. (AL) may offer greater clinical benefits for patients with advanced-stage ICC when compared with standard supportive care.
Aim: This study investigated the relationships between clinical
efficacy and pharmacokinetic parameters of serum bioactivity of AL and its
active constituent, “atractylodin,” and determined the therapeutic ranges.
Methods: A retrospective study was conducted as part of a
single-centre, open-label, randomised controlled Phase 2A trial, which took
place over four months at Sakhon Nakhon Hospital, Sakhon Nakhon Province,
Thailand. Patients with advanced-stage ICC were randomised to three groups.
Group 1 received daily doses of 1,000 mg of standardised extract of the capsule
formulation of AL (CMC-AL) for 90 days. Group 2 received daily doses of 1,000
mg of CMC-AL for 14 days, followed by 1,500 mg for 14 days and 2,000 mg for 62
days. Group 3 (the control group) received palliative care. The Cox
proportional hazard model and the Receiver Operating Characteristic (ROC) curve
were applied to determine the cut-off values of AUC0-inf, Cmax, and Cavg
associated with therapeutic outcomes. Number-needed-to-be-treated (NNT) and
relative risk (RR) were also applied to determine potential predictors.
Mann-Whitney U test and Wilcoxon signed-rank test were used for non-normally
distributed data. Paired t-tests and unpaired t-tests were applied to analyse
normally distributed quantitative variables, while chi-square analysis was used
for qualitative variables. A significance level of α = 0.05 was used.
Results: The AUC0-inf of total AL bioactivity of>
96.71 µg*h/ml was identified as a promising predictor of disease prognosis,
specifically progression-free survival (PFS) and disease control rate (DCR).
Cmax of total AL bioactivity of>21.42 was identified as a predictor of the
prognosis of death. The therapeutic range of total AL bioactivity for PFS and
DCR is 14.48-65.8 µg/ml, and for overall survival is 10.97-65.8 µg/ml.
Conclusions: The predictors of ICC disease prognosis were
established based on the pharmacokinetics of total AL bioactivity. The
information could be exploited to improve the clinical efficacy of AL in
patients with advanced-stage ICC. These predictors will be validated in a phase
2B clinical study. Further study is needed to validate the model externally
with a larger sample size to confirm its accuracy and applicability.
Author(s)
Details
Teerachat
Sae-heng
Center of Excellence in Pharmacology and Molecular Biology of
Malaria and Cholangiocarcinoma, Chulabhorn
International College of Medicine, Thammasat University (Rangsit Campus),
Pathumthani, Thailand.
Juntra
Karbwang
Drug Discovery and Development Center, Office of Advanced Science
and Technology, Thammasat University (Rangsit Campus), Thailand.
Anurak Cheomung
Graduate Program in
Bio-clinical Sciences, Chulabhorn International College of Medicine, Thammasat
University, Pathumthani 12120, Thailand.
Nisit
Tongsirid
Sakon Nakorn Hospital, Sakon Nakorn 47000, Thailand.
Tullayakorn
Plengsuriyakarnc
Graduate Program in Bio-clinical Sciences, Chulabhorn
International College of Medicine, Thammasat University, Pathumthani 12120,
Thailand.
Kesara
Na-Bangchanga
Center of Excellence in Pharmacology and Molecular Biology of
Malaria and Cholangiocarcinoma, Chulabhorn
International College of Medicine, Thammasat University (Rangsit Campus),
Pathumthani, Thailand, Drug
Discovery and Development Center, Office of Advanced Science and Technology,
Thammasat University (Rangsit Campus), Thailand and Graduate Program in
Bio-clinical Sciences, Chulabhorn International College of Medicine, Thammasat
University, Pathumthani 12120, Thailand.
Please see the book here:- https://doi.org/10.9734/bpi/aodhr/v4/5794
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