This protocol aims to profile the pharmacokinetics of metformin and Andrographis paniculata (AP) and continue with untargeted pharmacometabolomics analysis on pre-dose and post-dose samples to characterise the metabolomics profiling associated with the human metabolic pathways. This is a single-centre, open-labelled, three periods, crossover, randomised-controlled, single-dose oral administration pharmacokinetics and metabolomics trial of metformin 1000 mg (n = 18), AP 1000 mg (n = 18), or AP 2000 mg (n = 18) in healthy volunteers under the fasting condition. Subjects will be screened according to a list of inclusion and exclusion criteria. Investigational products will be administered according to the scheduled timeline. Vital signs and adverse events will be monitor periodically, and standardized meals will be provided to the subjects. Fifteen blood samples will be collected over 24 h, and four urine samples will be collected within a 12 h period. Onsite safety monitoring throughout the study and seven-day phone call safety follow-up will be compiled after the last dose of administration. The plasma samples will be analysed for the pharmacokinetics parameters to estimate the drug maximum plasma concentration. Untargeted metabolomic analysis between pre-dose and maximum plasma concentration (Cmax) samples will be performed for metabolomic profiling to identify the dysregulation of human metabolic pathways that link to the pharmacodynamics effects. The metformin arm will focus on the individualised Cmax plasma concentration for metabolomics study and used as a model drug. After this, an investigation of the dose-dependent effects will be performed between pre-dose samples and median Cmax concentration samples in the AP 1000 mg and AP 2000 mg arms for metabolomics study. The study protocol utilises a crossover study design to incorporate a metabolomics-based study into pharmacokinetics trial in the drug development program. The combination analyses will complement the interpretation of pharmacological effects according to the bioavailability of the drug.
Keywords: Andrographis paniculata; clinical trials; metabolomics; metformin; pharmacokinetics.