Immunomodulatory Effects of Atractylodes lancea in Healthy Volunteers with Dosage Prediction for Cholangiocarcinoma Therapy: A Modelling Approach

TL;DR

This study uses a modeling approach to predict safe and effective doses of Atractylodes lancea for treating cholangiocarcinoma based on its immunomodulatory effects in healthy volunteers.

Contribution

The study introduces a PBPK model combined with toxicological and immunomodulatory data to recommend phase 2A dosing for Atractylodes lancea in cholangiocarcinoma therapy.

Findings

A once-daily dose of 1000 mg AL significantly suppressed pro-inflammatory cytokines and increased immune cells.

The PBPK model accurately predicted clinical data and recommended 1500 or 2000 mg as phase 2A dosing.

A 2000 mg dose showed better survival outcomes and tumor control without toxicity compared to control.

Abstract

Background and Aims: According to a recent study on the immunomodulatory activity of Atractylodes lancea (Thunb.) DC. (AL) in healthy Thai subjects, AL significantly inhibited the production of key pro-inflammatory cytokines while stimulating the production of immune cells. However, no maximum tolerated dose (MTD) and phase 2A dosage regimens were reported. The study aimed to evaluate the immunomodulatory effects of Atractylodes lancea (Thunb.) DC. (AL) in healthy subjects, and to recommend optimal dose regimens for intrahepatic cholangiocarcinoma (iCCA) based on toxicity criteria. Methods: A physiologically based pharmacokinetic (PBPK) model, combined with the toxicological approach and the immunomodulatory effect, was used for dose-finding. The safety and efficacy of each AL regimen were evaluated based on the previous study. At least a once-daily dose of 1000 mg AL significantly suppressed the production of all pro-inflammatory cytokines while significantly increasing the number of peripheral immune cells. Results: The developed PBPK model predicted the clinically observed data well. No significant differences in SII index values were found, but a difference in the lymphocyte-monocyte ratio was found on day 4. The dosage regimen for phase 2A is a once-daily dose of 1500 or 2000 mg. Preliminary results in phase 2A revealed that a once-daily dose of 2000 mg had a significantly higher median overall survival, progression-free survival, disease control rate, and inhibition of increased tumor size without toxicities compared with control. Conclusions: A PBPK model, in conjunction with a toxicological approach, could assist in finding the potential dosage regimens for a clinical study, including herbal medicine.

Figures