Jie En Valerie Sia (1,2), Xuan Lai (3), Wen Yao Mak (1), Xinyi Wu (2), Fan Zhang (3), Cheng Cui (2)*, Dongyang Liu (2,4,5)*, Xiaoqiang Xiang (1)*
(1) Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, China, (2) Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China, (3) Geriatrics Department, Peking University Third Hospital, Beijing, China, (4) Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China, (5) Beijing Key Laboratory of Cardiovascular Receptors Research.
Introduction: The conventional wisdom holds that oxidative CYP-mediated clearance would decrease with age, but some recent clinical trials refuted such claims. In addition, the greater inter-individual variability observed in the older population could obscure the detection of significant differences in CYP3A function, leading to inconclusive results. Traditional clinical trials often do not fully represent the older population due to the selective criteria and focus on chronological aging rather than biological aging. Conversely, real-world data (RWD) could capture a broader and more representative sample of older adults to provide comprehensive understanding on how aging affects CYP3A function. Combining RWD with the population pharmacokinetic-physiologically based pharmacokinetic (PPK-PBPK) modeling approach not only compensates the sparse PK sampling that are typically employed clinically, but also account for physiological variations, providing insights for personalized and effective treatment strategies, particularly those using high-risk CYP3A substrates.[1]
Objectives:
- To develop a PPK model for Chinese older inpatients and identify factors affecting the PK of amlodipine, the CYP3A probe substrate used in this study;
- To quantify aging-related changes in physiological parameters of CYP3A function using PBPK modeling approach, based on PPK modeling results.
Methods: 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 an observational clinical study conducted in Peking University Third Hospital. Aging-related covariates, including demographic characteristics, frailty phenotype, sarcopenia risk, and degree of comorbidities were comprehensively collected for the analysis. PPK approach was utilized to derive population estimates parameters and stepwise covariate model with stage-wise filtering approach was used to identify clinically relevant factors efficiently. PBPK approach which added a physiological dimension, was subsequently employed to assess and quantify the covariate effects on physiological parameters of CYP3A function. A fully validated amlodipine compound model and a Chinese geriatric population model that was developed in our previous study were used.[2]
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, in agreement with previous study.[3] Our study confirmed the previous findings that sex affected the CL/F of amlodipine, and frailty phenotype was significantly associated with the CL/F of amlodipine in the Chinese older population. Although age groups (chronological age) and frailty phenotype (a practical measure of biological age) have similar trend of association with CL/F, frailty phenotype but not age group produced significant effect on the PK parameters, suggesting that biological age could be a more sensitive indicator than the chronological age in characterizing CYP3A function in the older adults. Based on the final model, the apparent clearance is 26% lower in female than that in male, and 18% lower in frail subjects than that in non-frail subjects. The estimated values of population CL/F and V/F for final model were 22.1 L/h and 1430 L respectively, with good precision, as indicated by the relative standard error of estimates of 7.2% and 7.4%.
Subsequent assessment using PBPK modeling approach demonstrated a 12% underprediction and 16% overprediction in the area under concentration-time curve (AUC) for frail and non-frail subjects, and were improved when 41.6% decrease and 58.3% increase in CYP3A relative abundance was used in the simulations. The results from the global sensitivity analysis, with the physicochemical parameters validated during model validation, also showed that CYP3A relative abundance was the most influential parameter on the AUC, supporting its explanation to prediction bias.
Conclusion: Frail and non-frail subjects showed different CYP3A functional phenotype, where frail and non-frail subjects have decreased and increased CYP3A function, respectively. The results of this study suggested a need to shift the current research focus from chronological age to biological age for a more nuanced characterization of CYP3A function in the older population.
References:
[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.
Reference: PAGE 32 (2024) Abstr 11214 [www.page-meeting.org/?abstract=11214]
Poster: Real-world data (RWD) in pharmacometrics