Journal Article

Population-pharmacokinetic/pharmacodynamic model of atractylodes lancea (Thunb.) DC. administration in patients with advanced-stage intrahepatic cholangiocarcinoma: a dosage prediction

Saeheng, Teerachat, Karbwang, Juntra, Na-Bangchang, Kesara

2024

Overview

Background A recent phase 2A clinical study of Atractylodes lancea (Thunb.) DC. (AL) in patients with advanced-stage intrahepatic cholangiocarcinoma (iCCA) demonstrated significant reduction of the risk of tumor progression and mortality with a dose ranging from 1,000 to 2,000 mg. The present study aimed to determine the potential dosage regimen of AL for further phase 2B clinical study. Methods Plasma-concentration time profiles of total AL bioactivity and clinical efficacy in patients with advanced-stage iCCA were obtained from Phase 2 A study. The population pharmacokinetic (pop-PK) model was developed. The pop-PK model and Monte-Carlo (MC) simulation, in conjunction with maximum concentration of AL (C max ) as a cut-off criterion, was performed and validated with clinical data. The optimal model was used to simulate further dosage regimens and clinical efficacy of AL. Results The pop-PK properties of total AL bioactivity were best described by a compartmental model with zero-order absorption (without delay) and linear clearance. None of the investigated covariates improved model accuracy.The developed pop-PK with MC simulations following once-daily dosing of 1,000 mg and 2,000 mg adequately predicted the clinical efficacy (tumor progression and mortality). The once-daily dose of 2,500 mg is recommended for further phase 2B clinical study due to its relatively high efficacy on tumor progression inhibition (73%) and mortality rate reduction (71%) without excessive number of the administered capsules (23 capsules) and low risk of toxicities (<5%). Conclusions The applied pop-PK model with MC simulation, along with the appropriate cut-off pharmacokinetic parameters, can be used as a potential tool for supporting dosage prediction and selection for clinical studies, and thus reducing the rate of drug development failures. Trial registration www.thaiclinicaltrials.org , WHO ICTRP search, TCTR20210129007 , Registed 29 January 2021.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: absorption / Adult / Aged / Analysis / Atractylodes - chemistry / Atractylodes Lancea / Bile Duct Neoplasms - drug therapy / Biliary tract cancer / bioactive properties / Biological activity / Cancer / Chi-square test / Chiropractic Medicine / Cholangiocarcinoma / Cholangiocarcinoma - drug therapy / Clinical study / complement / Complementary & Alternative Medicine / Concentration time / Disease prevention / Dosage / Dose prediction / Drug development / Drug dosages / Effectiveness / Female / Health aspects / Humans / Internal Medicine / Intrahepatic cholangiocarcinoma / Male / Medical prognosis / Medicine / Medicine & Public Health / Middle Aged / Models, Biological / Monte Carlo Method / Mortality / neoplasm progression / Oncology / Oncology, Experimental / Patients / Pharmacodynamics / Pharmacokinetics / Plant Extracts - pharmacokinetics / Plant Extracts - pharmacology / Population studies / Population-pharmacokinetic model / prediction / risk / Simulation / Simulation methods / Tumors