Abstract：
OBJECTIVE: A population-based pharmacokinetic (PK) modeling approach (PopPK) was used to investigate the impact of Roux-en-Y gastric bypass (RYGB) on the PK of (R)- and (S)-carvedilol. We aimed to optimize carvedilol dosing for these patients utilizing a pharmacokinetic/pharmacodynamic (PK/PD) link model.
METHODS: PopPK models were developed utilizing data from 52 subjects, including nonobese, obese, and post- RYGB patients who received rac- carvedilol orally. Covariate analysis included anthropometric and laboratory data, history of RYGB surgery, CYP2D6 and CYP3A4 in vivo activity, and relative intestinal abundance of major drug- metabolizing enzymes and transporters. A direct effect inhibitory Emax pharmacodynamic model was linked to the PK model of (S)- carvedilol to simulate the changes in exercise- induced heart rate.
RESULTS: A 2-compartmental model with linear elimination and parallel first-order absorptions best described (S)-carvedilol PK. RYGB led to a twofold reduction in relative oral bioavailability compared to nonoperated subjects, along with delayed absorption of both enantiomers. The intestinal ABCC2 mRNA expression increases the time to reach the maximum plasma concentration. The reduced exposure (AUC) of (S)-carvedilol post-RYGB corresponded to a 33% decrease in the predicted area under the effect curve (AUEC) for the 24-hour β-blocker response. Simulation results suggested that a 50-mg daily dose in post-RYGB patients achieved comparable AUC and AUEC to 25-mg dose in nonoperated subjects.
CONCLUSIONS: Integrated PK/PD modeling indicated that standard dosage regimens for nonoperated subjects do not provide equivalent β-blocking activity in RYGB patients. This study highlights the importance of personalized dosing strategies to attain desired therapeutic outcomes in this patient cohort.
METHODS: PopPK models were developed utilizing data from 52 subjects, including nonobese, obese, and post- RYGB patients who received rac- carvedilol orally. Covariate analysis included anthropometric and laboratory data, history of RYGB surgery, CYP2D6 and CYP3A4 in vivo activity, and relative intestinal abundance of major drug- metabolizing enzymes and transporters. A direct effect inhibitory Emax pharmacodynamic model was linked to the PK model of (S)- carvedilol to simulate the changes in exercise- induced heart rate.
RESULTS: A 2-compartmental model with linear elimination and parallel first-order absorptions best described (S)-carvedilol PK. RYGB led to a twofold reduction in relative oral bioavailability compared to nonoperated subjects, along with delayed absorption of both enantiomers. The intestinal ABCC2 mRNA expression increases the time to reach the maximum plasma concentration. The reduced exposure (AUC) of (S)-carvedilol post-RYGB corresponded to a 33% decrease in the predicted area under the effect curve (AUEC) for the 24-hour β-blocker response. Simulation results suggested that a 50-mg daily dose in post-RYGB patients achieved comparable AUC and AUEC to 25-mg dose in nonoperated subjects.
CONCLUSIONS: Integrated PK/PD modeling indicated that standard dosage regimens for nonoperated subjects do not provide equivalent β-blocking activity in RYGB patients. This study highlights the importance of personalized dosing strategies to attain desired therapeutic outcomes in this patient cohort.
摘要：
目的：使用基于人群的药代动力学（PK）建模方法（PopPK）来研究Roux-en-Y胃旁路术（RYGB）对（R）-和（S）-卡维地洛的PK的影响。我们旨在使用药代动力学/药效学（PK/PD）链接模型优化这些患者的卡维地洛剂量。
方法：PopPK模型是利用52名受试者的数据开发的，包括非肥胖，肥胖，以及口服rc-卡维地洛的RYGB后患者。协变量分析包括人体测量和实验室数据，RYGB手术史,CYP2D6和CYP3A4的体内活性，以及主要药物代谢酶和转运蛋白的相对肠道丰度。将直接效应抑制Emax药效学模型与(S)-卡维地洛的PK模型相联系以模拟运动诱导的心率的变化。
结果：具有线性消除和平行一阶吸收的2室模型最好地描述了（S）-卡维地洛PK。与非手术受试者相比，RYGB导致相对口服生物利用度降低两倍，以及两种对映异构体的延迟吸收。肠道ABCC2mRNA表达增加了达到最大血浆浓度的时间。RYGB后(S)-卡维地洛的减少暴露(AUC)对应于24小时β-阻断剂反应的效应曲线下预测面积(AUEC)减少33%。模拟结果表明，RYGB后患者的每日50mg剂量可达到与非手术受试者中25mg剂量相当的AUC和AUEC。
结论：综合PK/PD模型表明，非手术受试者的标准剂量方案在RYGB患者中不能提供等效的β-阻断活性。这项研究强调了个性化给药策略在该患者队列中获得所需治疗结果的重要性。
方法：PopPK模型是利用52名受试者的数据开发的，包括非肥胖，肥胖，以及口服rc-卡维地洛的RYGB后患者。协变量分析包括人体测量和实验室数据，RYGB手术史,CYP2D6和CYP3A4的体内活性，以及主要药物代谢酶和转运蛋白的相对肠道丰度。将直接效应抑制Emax药效学模型与(S)-卡维地洛的PK模型相联系以模拟运动诱导的心率的变化。
结果：具有线性消除和平行一阶吸收的2室模型最好地描述了（S）-卡维地洛PK。与非手术受试者相比，RYGB导致相对口服生物利用度降低两倍，以及两种对映异构体的延迟吸收。肠道ABCC2mRNA表达增加了达到最大血浆浓度的时间。RYGB后(S)-卡维地洛的减少暴露(AUC)对应于24小时β-阻断剂反应的效应曲线下预测面积(AUEC)减少33%。模拟结果表明，RYGB后患者的每日50mg剂量可达到与非手术受试者中25mg剂量相当的AUC和AUEC。
结论：综合PK/PD模型表明，非手术受试者的标准剂量方案在RYGB患者中不能提供等效的β-阻断活性。这项研究强调了个性化给药策略在该患者队列中获得所需治疗结果的重要性。
