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

Background A 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. Objective: This 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 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. Results: The 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. Conclusion: A PBPK model, in conjunction with a toxicological approach, could assist in finding the potential dosage regimens for a clinical study, including herbal medicine. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial TCTR20201020001 ### Funding Statement This study was supported by Thammasat Postdoctoral Fellowship, Thammasat University Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma (No. 1/2556, dated 12 October 2013), and the National Research Council of Thailand (No. 45/2561, dated 10 September 2018). K.N. is supported by the National Research Council of Thailand under the Research Team Promotion grant (grant number NRCT 820/2563, dated 12 November 2020). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This project has approval from the Human Research Ethics Committee of Thammasat University (Medicine) affiliated to Thammasat University (No. MTU-EC-00-3075/61). All participants signed written informed consent forms prior to enrollment. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.