Development of a Korean‐specific virtual population for physiologically based pharmacokinetic modelling and simulation

Abstract

Physiologically based pharmacokinetic (PBPK) modelling and simulation is a useful tool in predicting the PK profiles of a drug, assessing the effects of covariates such as demographics, ethnicity, genetic polymorphisms and disease status on the PK, and evaluating the potential of drug-drug interactions. We developed a Koreanspecific virtual population for the SimCYP® Simulator (version 15 used) and evaluated the population's predictive performance using six substrate drugs (midazolam, S-warfarin, metoprolol, omeprazole, lorazepam and rosuvastatin) of five major drug metabolizing enzymes (DMEs) and two transporters. Forty-three parameters including the proportion of phenotypes in DMEs and transporters were incorporated into the Korean-specific virtual population. The simulated concentration-time profiles in Koreans were overlapped with most of the observed concentrations for the selected substrate drugs with a < 2-fold difference in clearance. Furthermore, we found some drug models within the SimCYP® library can be improved, e.g., the minor allele frequency of ABCG2 and the fraction metabolized by UGT2B15 should be incorporated for rosuvastatin and lorazepam, respectively. The Korean-specific population can be used to evaluate the impact of ethnicity on the PKs of a drug, particularly in various stages of drug development.

Development of a Virtual Chinese Pediatric Population Physiological Model Targeting Specific Metabolism and Kidney Elimination Pathways

“…In the past decades, the PBPK model has been applied to predict pediatric drug concentrations during drug development to support dosing rationalization in the pediatric clinical trial. For example, the PBPK model was used to set a starting dose for Eribulin in children and adolescents aged 6-18 years old (Shebley et al, 2018 these drugs (Kim et al, 2019). In our study, a similar approach was adopted to develop the Chinese pediatric population model by incorporating Chinese pediatric demographic and physiological information covering a span of children 0-15 years old.…”

“…The model was verified using six substrate drugs of five major metabolic enzymes and two transporters. The model was proved useful in predicting the concentration-time profiles of these drugs ( Kim et al, 2019 ). In our study, a similar approach was adopted to develop the Chinese pediatric population model by incorporating Chinese pediatric demographic and physiological information covering a span of children 0–15 years old.…”

Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

“…Mechanistic models are associated with a Virtual Population (VPop) to introduce interpatient variability. A VPop is a set of virtual patients, each one being characterized by its own set of descriptors (model parameters values) that follow pre-defined joint distributions (41)(42)(43). Simulations can be conducted in varying scenarios (such as different treatment regimens) according to a simulation protocol that defines the entire in silico clinical trial.…”

High fidelity blood flow in a patient-specific arteriovenous fistula

“…The development of the virtual human to recreate an individual's specific physiological processes in a digital format is a major goal of computational biomedicine, heralding truly personalised medicine along with 'healthcasts' [1,2,3,4,5,6,7]. The increasing capability and power of computational software and hardware has allowed significant steps to be made towards this goal [1,8].…”