Li Guoxing, Guan Ying, Yang YingYing, Xiang Qiulin, Chen Song, Shao Jiaqi, Chen Yue, Yu Xian
Phase I Clinical Trial Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
Joint Institute of Tobacco and Health, Kunming, Yunnan, People's Republic of China.
Drug Des Devel Ther. 2025 Apr 24;19:3193-3207. doi: 10.2147/DDDT.S501762. eCollection 2025.
To quantitatively investigate the influence of various factors, including nicotine, demographics, biochemical index, and genetic polymorphisms of PAHs and drug metabolising enzymes, on the steady-state trough concentrations of levamlodipine besylate and its therapeutic effects in smokers. Using models to promote rational and accurate medication dosing in smoking patients when administered as initial monotherapy.
A prospective study (NCT05126381) enrolled 43 patients receiving levamlodipine monotherapy. Pop PK/PD model of levamlodipine besylate was established to investigate the effects of nicotine concentration, demographics (age, sex, height, weight, BMI), biochemical index (ALT, AST, ALB, UA, eGFR), and the genetic polymorphisms (rs4646903, rs1048943, rs762551, rs12459249, rs776746, rs2740574) on the patients' steady state trough concentrations and the antihypertensive efficacy (ΔSBP) of levamlodipine besylate after dosing.
The Pop PK/PD model was conducted using the study data of 43 patients. One-compartment model was used to describe the PK characteristics, and the direct effect model was used to describe the antihypertensive effect of levamlodipine besylate. The final Pop PK/PD model showed that the typical value of V = 3521L, CL = 62.6L·h, E = 168mmHg, I = 31mmHg, IC = 1.71ng·mL; eGFR and UA were found in the model had significant effect on the CL of levamlodipine besylate.
Patients with lower eGFR and UA levels exhibited lower CL levels, higher dosages may be considered for initial monotherapy in such patients. The current study tentatively do not show that nicotine concentration and PAHs metabolizing enzymes have significant effect on PK and PD in patients taking the drug. More data may be needed in the future to refine the effects of the above covariates on the PK and PD parameters of the levamlodipine besylate.
定量研究包括尼古丁、人口统计学因素、生化指标以及多环芳烃和药物代谢酶的基因多态性等各种因素对苯磺酸左氨氯地平稳态谷浓度及其在吸烟者中的治疗效果的影响。使用模型促进吸烟患者初始单药治疗时合理、准确的给药剂量。
一项前瞻性研究（NCT05126381）纳入了43例接受苯磺酸左氨氯地平单药治疗的患者。建立苯磺酸左氨氯地平的群体药代动力学/药效学（Pop PK/PD）模型，以研究尼古丁浓度、人口统计学因素（年龄、性别、身高、体重、体重指数）、生化指标（谷丙转氨酶、谷草转氨酶、白蛋白、尿酸、估算肾小球滤过率）以及基因多态性（rs4646903、rs1048943、rs762551、rs12459249、rs776746、rs2740574）对患者苯磺酸左氨氯地平稳态谷浓度及给药后降压疗效（收缩压变化值）的影响。
使用43例患者的研究数据构建Pop PK/PD模型。采用一室模型描述药代动力学特征，采用直接效应模型描述苯磺酸左氨氯地平的降压作用。最终的Pop PK/PD模型显示，V的典型值为3521L，CL为62.6L·h，E为168mmHg，I为31mmHg，IC为1.71ng·mL；模型中发现估算肾小球滤过率和尿酸对苯磺酸左氨氯地平的CL有显著影响。
估算肾小球滤过率和尿酸水平较低的患者CL水平较低，此类患者初始单药治疗时可考虑更高剂量。目前的研究初步未显示尼古丁浓度和多环芳烃代谢酶对服药患者的药代动力学和药效学有显著影响。未来可能需要更多数据来完善上述协变量对苯磺酸左氨氯地平药代动力学和药效学参数的影响。
