Immunomodulatory Effects of Atractylodes Lancea in Healthy Volunteers with Dosage Prediction for Cholangiocarcinoma Therapy: a modelling approach

BackgroundA recent study on the immunomodulatory activity of Atractylodes Lancea (Thunb.) DC. (AL) in healthy Thai subjects revealed that a once daily dose of 1,000 mg AL administered for 21 days significantly inhibited the production of key pro-inflammatory cytokines, while stimulating the production of immune cells. There is however, no reported maximum tolerated dose (MTD) and suggested phase 2A dosage regimens in the literature. ObjectiveThis 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. MethodsA physiologically-based pharmacokinetic (PBPK) model, combined with the toxicological approach and the immunomodulatory effect, was used for a dose-finding. The safety and efficacy of each AL regimen were evaluated based on the previous study. At least, a daily OD dose of 1,000 mg AL significantly suppressed the production of all proinflammatory cytokines while significantly increasing the number of peripheral immune cells. ResultsThe developed PBPK model well predicted clinical observed data. No significant differences in SII index values were found, but a difference in the lymphocyte-monocyte ratio was found on day 4. The dosage regimens for phase 2A are BID doses of 1,000 or 2,000 mg or OD doses of 2,000 mg. Preliminary results in phase 2A revealed that a once-daily dose of 2,000 mg had a significantly higher median overall survival, progression-free survival, disease control rate, and inhibition of increased tumor size without toxicities compared with a once-daily dose of 1,000 mg and standard supportive care. ConclusionA PBPK model, in conjunction with a toxicological approach, could assist in finding the potential dosage regimens for a clinical study, including herbal medicine.