Gaspar Frédéric, Jacost-Descombes Celestin, Gosselin Pauline, Reny Jean-Luc, Guidi Monia, Csajka Chantal, Samer Caroline, Daali Youssef, Terrier Jean
Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
Clin Pharmacokinet. 2025 Feb;64(2):275-283. doi: 10.1007/s40262-024-01470-4. Epub 2025 Jan 11.
Fexofenadine is commonly used as a probe substrate to assess P-glycoprotein (Pgp) activity. While its use in healthy volunteers is well documented, data in older adult and polymorbid patients are lacking. Age- and disease-related physiological changes are expected to affect the pharmacokinetics of fexofenadine. This study aims to investigate the pharmacokinetics of fexofenadine in hospitalized older adult patients as a potential marker of Pgp activity, using data from the OptimAT study (ClinicalTrials.gov identifier: NCT03477331).
Population pharmacokinetic (popPK) modeling was conducted using data from 449 hospitalized patients with a median age of 71 years (range: 25-97) and 10 healthy volunteers (median age: 23 years, range: 20-36). Fexofenadine plasma concentrations were analyzed using a refined two-compartment model with sequential zero/first-order absorption, while investigating the impact of covariates such as age, renal function, and Pgp inhibitors on fexofenadine pharmacokinetics.
Age, renal insufficiency, and Pgp inhibitors significantly influenced fexofenadine exposure. Renal function was a key factor, with AUC increasing by 79% in mild-to-moderate and by 154% in moderate-to-severe renal impairment compared with normal renal function. Co-administration of Pgp inhibitors led to a 35% increase in AUC. Across chronic kidney disease (CKD) stages, age, and Pgp inhibitor status, fexofenadine AUC ratio ranged from 1.15 (stage 1, 20-30 years) to 4.59 (stage 5, 91-100 years, with Pgp inhibitors), relative to a reference subject of 20 years, normal renal function, and no Pgp inhibitors.
Clinicians should consider the risk of Pgp substrate accumulation in older adults, particularly those with advanced renal impairment. We propose typical values stratified by age and renal function to assist in interpreting Pgp phenotyping using fexofenadine exposure, thereby supporting drug optimization in this population. Further studies are needed to explore underlying mechanisms, such as reduced Pgp activity or expression.
非索非那定通常用作评估P-糖蛋白（Pgp）活性的探针底物。虽然其在健康志愿者中的使用已有充分记录，但老年和多病患者的数据却很缺乏。预计与年龄和疾病相关的生理变化会影响非索非那定的药代动力学。本研究旨在利用OptimAT研究（ClinicalTrials.gov标识符：NCT03477331）的数据，调查住院老年患者中非索非那定的药代动力学，作为Pgp活性的潜在标志物。
采用来自449例住院患者（中位年龄71岁，范围：25 - 97岁）和10名健康志愿者（中位年龄：23岁，范围：20 - 36岁）的数据进行群体药代动力学（popPK）建模。使用具有序贯零级/一级吸收的精细二室模型分析非索非那定血浆浓度，同时研究年龄、肾功能和Pgp抑制剂等协变量对非索非那定药代动力学的影响。
年龄、肾功能不全和Pgp抑制剂显著影响非索非那定的暴露。肾功能是一个关键因素，与正常肾功能相比，轻度至中度肾功能损害时AUC增加79%，中度至重度肾功能损害时增加154%。联合使用Pgp抑制剂导致AUC增加35%。在慢性肾脏病（CKD）各阶段、年龄和Pgp抑制剂状态中，相对于20岁、肾功能正常且未使用Pgp抑制剂的参考受试者，非索非那定的AUC比值范围为1.15（1期，20 - 30岁）至4.59（5期，91 - 100岁，使用Pgp抑制剂）。
临床医生应考虑老年患者，尤其是晚期肾功能损害患者中Pgp底物蓄积的风险。我们提出按年龄和肾功能分层的典型值，以协助利用非索非那定暴露来解释Pgp表型，从而支持该人群的药物优化。需要进一步研究以探索潜在机制，如Pgp活性或表达降低。
