患者因素对秋水仙碱人群药代动力学的影响:安全有效给药的意义。

IF 4 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Daniel F B Wright, Hailemichael Z Hishe, Nicola Dalbeth, Anne Horne, Jill Drake, Janine Haslett, Lisa K Stamp
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引用次数: 0

摘要

背景与目的:预测秋水仙碱血药浓度的因素及其对安全性和有效性的影响尚不清楚。我们的目的是确定在0.5-3 ng/mL的标称治疗范围内达到稳态血浆浓度的可能性。方法:采用非线性混合效应分析78例痛风患者秋水仙碱血药浓度。体型、肾功能、伴随药物、种族、性别、年龄和依从性作为模型中的协变量进行检验。通过模拟来确定在不同剂量和不同患者特征下,在0.5- 3ng /mL的治疗范围内达到稳态最小、最大和平均浓度的概率。我们认为秋水仙碱剂量为0.5 ng/mL的稳态平均浓度的80%,具有合理的安全性和有效性可能性。结果:零级吸收的两室药代动力学模型最适合。体重、性别和他汀类药物使用是秋水仙碱药代动力学的重要预测因子,使受试者之间清除率的差异减少了约40%。该模型预测,根据这里定义的标准,秋水仙碱每日剂量≤1.5 mg的毒性风险较低。除每日0.5 mg外,所有试验剂量均达到有效浓度,其中体重50至80公斤的人可能出现低于建议治疗范围的浓度。对许多人来说,秋水仙碱的较高剂量(每天1.5毫克)可能超过建议的安全上限,特别是那些体重较轻且正在服用他汀类药物的人。结论:建立了秋水仙碱的药动学模型并进行了评价。低剂量方案(每日≤1.5 mg)预计在大多数人中不会达到高于建议的安全阈值3 ng/mL的浓度,尽管在那些服用0.5 mg剂量、体重为50 ~ 80 kg的人中可能会出现低于治疗范围下限的浓度。在服用他汀类药物的低体重个体中,较高的秋水仙碱剂量(每天1.5毫克)可能超过建议的安全上限。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The Influence of Patient Factors on the Population Pharmacokinetics of Colchicine: Implications for Safe and Effective Dosing.

Background and objectives: The factors that predict colchicine plasma concentrations and the impact on safety and efficacy are under-researched. We aimed to determine the probability of achieving steady-state plasma concentrations within the nominal therapeutic range of 0.5-3 ng/mL.

Methods: Colchicine plasma concentrations from 78 people with gout were analysed using non-linear mixed effects. Body size, kidney function, concomitant drugs, ethnicity, sex, age and adherence were tested as covariates in the model. Simulations were conducted to determine the probability of achieving steady-state minimum, maximum and average concentrations within the therapeutic range of 0.5-3 ng/mL under different doses and for different patient characteristics. We considered colchicine doses that produced > 80% of steady-state average concentrations < 3 ng/mL and > 0.5 ng/mL to have a reasonable probability of safety and efficacy.

Results: A two-compartment pharmacokinetic model with zero-order absorption was the best fit. Body weight, sex and statin use were significant predictors of colchicine pharmacokinetics, reducing the between-subject variance on clearance by about 40%. The model predicted that colchicine dosages of ≤ 1.5 mg daily carry a low risk of toxicity based on the criteria defined here. Efficacious concentrations were achieved for all dosages tested except 0.5 mg daily, where concentrations below the proposed therapeutic range may occur in those with a body weight > 80 kg. Higher colchicine dosages of > 1.5 mg daily may exceed the proposed upper limit of safety in many individuals, particularly those with low body weight who are taking statins.

Conclusion: A model for the pharmacokinetics of colchicine was developed and evaluated. Low-dose regimes (≤ 1.5 mg daily) are not predicted to achieve concentrations above the proposed safety threshold of 3 ng/mL in most people, although concentrations below the lower limit of the therapeutic range may occur in those taking 0.5-mg doses who are > 80 kg in body weight. Higher colchicine dosages of > 1.5 mg daily may exceed the proposed upper limit of safety in individuals with low body weight who are taking statins.

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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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