评估米尔特福辛在成人和儿童中的剂量-暴露-反应关系,使用基于生理学的药理动力学建模方法
Shadrack J Madu1, Ke Wang1, Siri Kalyan Chirumamilla2
1School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK.
Pharmaceutical research
|October 10, 2023
概括
基于生理学上的药理动力学模型显示,儿童和成人之间的米尔特福辛暴露和治愈率不同. 血蛋白分布的差异解释了儿童治愈率较低,为这种抗莱什曼药物提供了最佳剂量策略.
科学领域:
- 药理动力学和药物新陈代谢
- 计算生物学 计算生物学
- 临床药理学 临床药理学
背景情况:
- 米尔特福辛是主要的口服抗莱什曼病药物.
- 临床试验显示,在不同人群中,包括儿童和成年人,米尔特福辛暴露和治愈率是可变的.
- 了解这些人群特异性差异对于优化治疗至关重要.
研究的目的:
- 开发和利用基于人群生理学的药理动力学 (PBPK) 模型来研究米尔特福辛的剂量-暴露-反应关系.
- 为了评估儿科和成人群体之间的药理动力学差异.
- 确定导致不同治愈率的因素.
主要方法:
- 使用Simcyp人口药理动力学平台来模拟血和PBMC中的米尔特福辛暴露.
- 开发成人和儿科PBPK模型来预测药理动力学数据.
- 基于模拟的曲线下面积 (AUC) 值的定义治愈率.
主要成果:
- 经验证的PBPK模型准确地预测了成人和儿童临床试验的药理动力学数据.
- 在相同剂量的模拟种族之间没有观察到剂量-暴露-反应的显著差异.
- 预计小儿科的治愈率较低,因为模拟的米尔特福辛暴露率较低,而成年人服用同等剂量.
结论:
- 由于血蛋白分布的差异,儿科血中米尔特福辛的未结合分数较高,可能导致治疗失败的可能性增加.
- 开发的PBPK模型为优化未来临床试验中的miltefosine剂量方案提供了有价值的工具.
相关概念视频
01:26Pharmacokinetic Models: Comparison and Selection Criterion
83
Physiological and compartmental models are valuable tools used in studying biological systems. These models rely on differential equations to maintain mass balance within the system, ensuring an accurate representation of the dynamic processes at play.
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.
83
01:23Nonlinear Pharmacokinetics: Dependence of Elimination Half-Life and Dose Clearance
173
The elimination half-life and drug clearance of drugs following nonlinear kinetics can vary with dosage. The Michaelis-Menten parameters and drug concentration influence these factors. As the dose increases, the elimination half-life tends to lengthen, resulting in a reduction in clearance and a disproportionately larger area under the curve. The total clearance can be derived from the Michaelis-Menten equation for drugs following a one-compartment model.
A study on guinea pigs examined the...
A study on guinea pigs examined the...
173
01:20Pharmacokinetic Models: Overview
737
Pharmacokinetic models utilize mathematical analysis to achieve a detailed quantitative understanding of a drug's life cycle within the body. They are instrumental in simulating a drug's pharmacokinetic parameters, predicting drug concentrations over time, optimizing dosage regimens, linking concentrations with pharmacologic activity, and estimating potential toxicity.
There are three primary types of models: empirical, compartment, and physiological. Empirical models, with minimal...
There are three primary types of models: empirical, compartment, and physiological. Empirical models, with minimal...
737
01:03Dose-Response Relationship: Overview
3.2K
Agonists can bind with and activate receptors, resulting in the formation of drug-receptor complexes. Once formed, these complexes catalyze many biochemical processes at the cellular level and subsequently induce a pharmacologic response. The degree of response is directly proportional to the fraction of activated receptors, which in turn, depends on the concentration of the drug at the receptor site as well as the sensitivity of the receptor. An increase in the administered dose contributes to...
3.2K
01:12Analysis of Population Pharmacokinetic Data
268
Analysis of population pharmacokinetic data involves studying the behavior of drugs within diverse populations to understand their pharmacokinetic parameters. Traditional pharmacokinetic methods typically involve collecting samples from a few individuals and estimating these parameters. While these methods are commonly used, they have limitations in capturing the variability in drug response among individuals or heterogeneous populations. Population pharmacokinetics is employed to address these...
268
01:07Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
56
Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
A recent model describes pravastatin's hepatobiliary excretion,...
A recent model describes pravastatin's hepatobiliary excretion,...
56