Carlton L D, Patterson J H, Mattson C N, Schmith V D
School of Pharmacy, University of North Carolina at Chapel Hill, USA.
J Clin Pharmacol. 1996 Mar;36(3):247-56. doi: 10.1002/j.1552-4604.1996.tb04195.x.
The influence of epoprostenol on the pharmacokinetics of drugs administered concurrently to patients with congestive heart failure (CHF) receiving epoprostenol was evaluated as a secondary objective of a Phase II pilot study. A total of 278 blood samples were collected from 30 patients with end-stage CHF receiving conventional therapy alone or conventional therapy plus epoprostenol. Estimates of oral clearance (Cl), volume of distribution, and absorption rate constant of digoxin were generated from plasma digoxin concentrations using nonlinear mixed effects modeling, and the effect of epoprostenol on Cl of digoxin was evaluated by univariate analysis. Additional factors that were evaluated by univariate analysis included age, obesity, time since study entry, cardiac output, concomitant use of angiotensin-converting enzyme (ACE) inhibitor, concomitant dobutamine, and estimated creatinine clearance. Backward elimination was used to arrive at a final model that included concomitant epoprostenol as a covariate. The final model revealed an approximate 15% decrease in Cl of digoxin in response to short-term administration of epoprostenol that was no longer apparent by the end of the 12-week treatment phase. Simulations revealed that this effect, although statistically significant, would not be clinically significant in most patients; however, the potential exists for short-term elevation of digoxin concentrations in response to concurrent administration of epoprostenol.
作为一项II期初步研究的次要目标，评估了依前列醇对接受依前列醇治疗的充血性心力衰竭（CHF）患者同时服用的药物药代动力学的影响。从30例仅接受常规治疗或接受常规治疗加依前列醇的终末期CHF患者中总共采集了278份血样。使用非线性混合效应模型从血浆地高辛浓度生成地高辛口服清除率（Cl）、分布容积和吸收速率常数的估计值，并通过单因素分析评估依前列醇对地高辛Cl的影响。通过单因素分析评估的其他因素包括年龄、肥胖、入组研究后的时间、心输出量、同时使用血管紧张素转换酶（ACE）抑制剂、同时使用多巴酚丁胺以及估计的肌酐清除率。采用向后剔除的方法得出最终模型，该模型将同时使用的依前列醇作为协变量。最终模型显示，短期给予依前列醇后，地高辛的Cl约降低15%，在12周治疗阶段结束时这种降低不再明显。模拟结果显示，尽管这种效应具有统计学意义，但在大多数患者中不会具有临床意义；然而，同时给予依前列醇可能会使地高辛浓度短期升高。
