Frailty phenotype as a sensitive indicator of aging-related Cytochrome P450 3A functional changes：Application of dose optimization recommendations for ticagrelor in the Chinese frail older population
Authors: Sia Jie En Valerie , Lai Xuan , Mak Wen Yao , Wu Xinyi , Zhang Fan , Cui Cheng , Xiang Xiaoqiang , Liu Dongyang 
Published: February 2025

Objectives:Frail older individuals often use drugs and are susceptible to adverse reactions due to the physiological changes related to frailty. Frailty status may influence CYP3A, which is responsible for metabolizing almost half of commonly prescribed medications in older adults. This is particularly critical for ticagrelor, an antiplatelet drug that is mainly metabolized by the enzyme CYP3A. It poses a heightened bleeding risk in frail older individuals, leading to the underutilization of this medication.Our objective is to propose a reference framework for dose optimization strategy for ticagrelor among Chinese older patients with different frailty phenotypes.Methods: Initially, we assessed how frailty impacts drug metabolism using PopPK and PBPK modeling approach. Exogenous probe substrate method, with amlodipine as the probe substrate, was used to assess the in vivo functionality of hepatic CYP3A function in the Chinese older population. Plasma amlodipine concentration data were collected from a non-intervention, observational clinical study conducted in Peking University Third Hospital. PopPK approach was utilized to derive population estimates parameters and PBPK approach which added a physiological dimension, was subsequently employed to assess and quantify the covariate effects on physiological parameters of CYP3A function. Later, we integrated these effects into a PBPK model, which allowed us to simulate ticagrelor's pharmacokinetics in frail versus non-frail Chinese older individuals across various dosing regimens.Results: A total of 132 plasma concentrations were obtained from 69 Chinese older inpatients. One-compartment model with first-order elimination and absorption well described the data with good precision. Frailty phenotype but not age group showed significant effect on the PK parameters. Subsequent assessment using PBPK modeling approach demonstrated a 11.0% underprediction and 20.5% overprediction in the area under concentration-time curve (AUC) for frail and non-frail subjects, and were improved when 41.6% decreased CYP3A relative abundance and 58.3% increased CYP3A relative abundance was used in the simulations. For frail individuals, all three doses of ticagrelor posed substantial risks of bleeding, as the mean trough concentrations either exceeded or were close to the threshold, suggesting a need for closer monitoring.Conclusion: We have successfully quantified the influence of frailty on the functional changes in CYP3A among Chinese older adults, and used these models to optimize the doses of ticagrelor based on frailty. Understanding how to adjust medication dosages for frail elderly patients ensures more effective and safer therapeutic outcomes. Our study provides a crucial step toward personalized medication management in geriatric care.Encore disclosure:The results in this abstract have been previously presented at the World Smart Medication Day, organized by IUPHAR on 2nd May 2024.Citations: [1] Hilmer SN, Kirkpatrick CMJ. New Horizons in the impact of frailty on pharmacokinetics: latest developments. Age Ageing. Jun 28 2021;50(4):1054-1063.[2] Cui C, Valerie Sia JE, Tu S, et al. Development of a physiologically based pharmacokinetic (PBPK) population model for Chinese elderly subjects. Br J Clin Pharmacol. 2021;87(7):2711-2722.[3] Zuo XC, Zhang WL, Yuan H, et al. ABCB1 polymorphism and gender affect the pharmacokinetics of amlodipine in Chinese patients with essential hypertension: a population analysis. Drug Metab Pharmacokinet. 2014;29(4):305-11.