比尼米提尼布在肝功能障碍的参与者中的药理动力学
Joseph Piscitelli1, Erik Hahn2, Lance Wollenberg2
1Pfizer Inc, San Diego, CA, 92121, USA. joseph.piscitelli@pfizer.com.
Clinical pharmacokinetics
|June 23, 2025
概括
对于中度至重度肝功能障碍的癌症患者,建议对本美提尼布剂量进行调整. 这项研究评估了在不同程度的肝功能障碍患者中比尼米丁的药理动力学.
科学领域:
- 药理学 药理学是指药理学的学科.
- 在瘤学瘤学.
- 临床药理学 临床药理学
背景情况:
- 比尼米提尼布是一种经批准的癌症治疗药物,通常每天两次用45毫克与encorafenib一起使用.
- 肝功能障碍 (HI) 可以显著改变药物的药理动力学 (PK).
- 进行了一项临床研究,以评估binimetinib PK,肝功能障碍患者的安全性和耐受性.
研究的目的:
- 评估binimetinib在患有轻度,中度和重度肝功能障碍的患者中的药理动力学,安全性和耐受性.
- 为了将HI患者的比尼米丁尼布暴露与健康对照进行比较.
- 在患有肝功能障碍的患者中告知binimetinib的潜在剂量调整.
主要方法:
- 对正常,轻度,中度和重度肝功能的参与者进行了单次口服比尼米蒂尼布剂量.
- 参与者根据年龄,性别和体重进行了匹配.
- 分析了剂量正常化的PK参数 (Cmax/D,AUCinf/D,未结合的AUClast/D).
主要成果:
- 轻度HI显示了比尼米提尼布PK参数的最小变化.
- 中度和严重的HI组在AUCinf/D上显著增加 (81%和111%).
- 在中度 (280%) 和严重 (248%) 的HI组中,未结合的AUClast/D显著增加.
结论:
- 在中度至重度肝功能障碍患者中,丁美提尼布的暴露显著增加.
- 对于中度和重度HI的癌症患者,建议减少比尼米蒂尼布的剂量.
- 这些发现支持基于肝功能的binimetinib个性化剂量策略.
相关概念视频
Renal Failure: Dose Adjustments
167
In patients with renal impairment, drugs undergo significant changes in their pharmacokinetics, which require dosage adjustments to ensure safe and effective therapy.
Reduced renal clearance and elimination rate are common outcomes of renal impairment. These alterations lead to a prolonged elimination half-life and an altered apparent volume of distribution for drugs. As a result, dosage adjustments are typically necessary to maintain optimal drug levels in the body.
However, dosage adjustments...
Reduced renal clearance and elimination rate are common outcomes of renal impairment. These alterations lead to a prolonged elimination half-life and an altered apparent volume of distribution for drugs. As a result, dosage adjustments are typically necessary to maintain optimal drug levels in the body.
However, dosage adjustments...
167
Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
88
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,...
88
Nonlinear Pharmacokinetics: Michaelis-Menten Equation
533
The Michaelis–Menten equation is a fundamental model for describing capacity-limited kinetics in drug metabolism. It offers insights into the rate of decline of plasma drug concentration Cp over time, with Vmax and KM as pivotal parameters.
Vmax represents the maximum achievable process rate, while KM, known as the Michaelis constant, signifies the drug concentration at which the process rate reaches half its maximum. This relationship between Vmax, KM, and Cp gives rise to three distinct...
Vmax represents the maximum achievable process rate, while KM, known as the Michaelis constant, signifies the drug concentration at which the process rate reaches half its maximum. This relationship between Vmax, KM, and Cp gives rise to three distinct...
533
Determination of Michaelis Constant and Maximum Elimination Rate
173
The Michaelis constant (KM) and the theoretical maximum process rate (Vmax) are vital parameters in the Michaelis-Menten equation, central to many biochemical reactions. They provide essential insights into enzyme kinetics and drug metabolism.
These parameters can be estimated by analyzing plasma concentration data post-drug administration. A notable example of this application is phenytoin, a drug with capacity-limited kinetics. It's recommended that phenytoin should be administered at two...
These parameters can be estimated by analyzing plasma concentration data post-drug administration. A notable example of this application is phenytoin, a drug with capacity-limited kinetics. It's recommended that phenytoin should be administered at two...
173
Nonlinear Pharmacokinetics: Role of Transporters
101
A drug's nonlinear kinetics can be influenced by a diverse range of transporter proteins that serve as crucial players in drug distribution. These transporters, found within cells, can enhance or reduce local drug concentrations by facilitating the influx or efflux of drugs. For instance, the expression of xenobiotic transporters can be influenced by factors such as age and gender, potentially impacting the linearity of drug response.
Polymorphisms occurring in drug transporters can alter...
Polymorphisms occurring in drug transporters can alter...
101
Nonlinear Pharmacokinetics: Dependence of Elimination Half-Life and Dose Clearance
312
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...
312


