Population pharmacokinetics of long-term oral amiodarone therapy
Population pharmacokinetics of long-term oral amiodarone therapy
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DOI：
10.1067/mcp.2000.107047
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发表时间：
2000-06-01
影响因子：
6.7
通讯作者：
Shafer, SL
中科院分区：
文献类型：
--
作者：
Pollak, PT;Bouillon, T;Shafer, SL
背景资料：胺碘酮是一种越来越受欢迎和独特有效的抗糖尿病药物，在接受长期口服治疗的患者的人口药代动力学参数尚未被definedprevious.Methods：我们收集了605观察血清胺碘酮和去乙基胺碘酮代谢物浓度从77例（平均随访，2年）。使用混合效应模型（NONMEM）确定典型的群体药代动力学参数、其各自的变异性以及快速达到并维持1.5 mg/L目标浓度的简单口服给药方案。基于产品各论中概述的方案，模拟研究人群的个体血清浓度-时间曲线，并与拟定给药方案进行比较。胺碘酮治疗持续时间与停药后血药浓度下降率之间的关系进行了探讨。结果：胺碘酮血药浓度最好用二室模型描述，典型参数为+/-个体间变异系数（如适用）如下：分布容积/生物利用度（V-1/F = 882 L; V-2/F = 12，700 L +/- 58%）和清除率/生物利用度（CL 1/F = 229 L/天+/- 31%;和CL 2/F = 599 L/天+/- 56%）。快速分布半衰期为17小时，终末半衰期为55天。拟定的实际给药方案为1600 mg/d持续2天、1200 mg/d持续5天、1000 mg/d持续7天、800 mg/d持续7天、600 mg/d持续7天和400 mg/d持续62天，随后维持剂量为343 mg/d（400 mg/d持续6/7天）。达到稳态后，停止给药产生25%的血清浓度递减在3天和50%在36 days.Conclusions：人口药代动力学证实，胺碘酮有一个非常长的半衰期。缓慢的消除速率使得预测胺碘酮治疗的调整时间以避免毒性异常令人困惑。然而，基于估计的变异性;拟定给药方案将在90%的患者中产生治疗窗内的稳态浓度。
Background: Amiodarone is an increasingly popular and uniquely effective antiarrhythmic agent for which population pharmacokinetic parameters in patients receiving long-term oral therapy have not been defined previously.Methods: We collected 605 observations of serum amiodarone and desethylamiodarone metabolite concentrations from 77 patients (mean follow-up, 2 years). Mixed-effects modeling (NONMEM) was used to determine the typical population pharmacokinetic parameters, their respective variabilities, and a simple oral dosing regimen to rapidly achieve and maintain a target concentration of 1.5 mg/L, Individual serum concentration versus time curves were simulated for the study population based on regimens outlined in the product monograph and were compared with those for the proposed dosing regimen. The relationship between the duration of amiodarone therapy and the rate of decrement in serum concentration after discontinuation was explored.Results: Amiodarone concentrations were best described by a two-compartment model with the typical parameters +/- interindividual coefficients of variation (where applicable) as follows: volumes of distribution/bioavailability (V-1/F = 882 L; V-2/F = 12,700 L +/- 58%) and clearances/bioavailability (CL1/F = 229 L/day +/- 31%; and CL2/F = 599 L/day +/- 56%). Rapid distribution half-life was 17 hours, and terminal half-life was 55 days. A practical dosing regimen of 1600 mg/d for 2 days, 1200 mg/d for 5 days, 1000 mg/d for 7 days, 800 mg/d for 7 days, 600 mg/d for 7 days, and 400 mg/d for 62 days followed by a maintenance dose of 343 mg/d (400 mg/d for 6 of 7 days) is proposed. After steady state is reached, cessation of dosing produces a 25% serum concentration decrement in 3 days and 50% in 36 days.Conclusions: Population pharmacokinetics confirm that amiodarone has an extraordinarily long half-life. The slow elimination rate makes anticipating the timing of adjustments in amiodarone therapy to avoid toxicity unusually perplexing. However, based on the estimated variability; the proposed dosing regimen would produce steady-state concentrations within the therapeutic window for 90% of patients.