预测T细胞激活剂的药理动力学作为目标介导药物处置的函数
Mark Penney1, Alberto Ippolito1, Elisa Fevola1
1Early Oncology DMPK, Oncology Targeted Discovery, AstraZeneca, Cambridge, UK.
Clinical and translational science
|November 10, 2025
概括
由于目标介导的药物处置,T细胞参与剂 (TCE) 的半衰期很短. 一种新的方法准确地预测了跨物种的TCE药理动力学,改进了传统的全量学.
科学领域:
- 药理学 药理学是指药理学的学科.
- 免疫学 免疫学 免疫学
- 生物技术是生物技术.
背景情况:
- 参与T细胞 (TCEs) 是两种特异性分子,旨在将T细胞和细胞连接起来进行破坏.
- TCE 的半衰期通常比预期的更短,它们的药理动力学 (PK) 在人类和非人类灵长类动物 (NHP) 之间有所不同.
- 传统的全尺度缩放方法对TCEs的人类PK的预测很差.
研究的目的:
- 确定目标介导药物处置 (TMDD) 在跨物种TCE PK确定中的作用.
- 开发一种TCE PK在NHP和人类中的预测方法.
主要方法:
- 研究了与T细胞和瘤相关抗原上的CD3相互作用的TCEs的TMDD.
- 开发并验证了一种新的PK预测方法,使用已发表的TCE数据.
主要成果:
- 开发的方法预测了18个TCE中的16个半衰期的半衰期,准确度为2倍.
- 这显著优于单独的全量计,它预测了17个TCE中的10个在2倍之内.
- 这种新方法的平均绝对误差为1.48,而全量计的平均误差为2.22.
结论:
- TMDD是影响跨物种TCE PK的关键因素.
- 这种新的预测方法为预测人类和NHP TCE PK提供了更高的准确性.
- 这一进步有助于TCE疗法的开发和临床转化.
相关概念视频
Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
257
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,...
257
Physiological Pharmacokinetic Models: Assumption with Protein Binding
204
Physiological models with protein binding in pharmacokinetics offer a sophisticated approach to understanding drug disposition. These models consider drug-protein interactions, enabling them to effectively predict drug concentrations in different organs and tissues. This precision aids in accurate drug dosing, providing a significant advantage over conventional models. A key process within these models is equilibration, which ensures that drug concentrations achieve a steady state within the...
204
Nonlinear Pharmacokinetics: Role of Transporters
266
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...
266
Pharmacodynamics: Overview and Principles
2.7K
Pharmacodynamics is a scientific field that delves into drugs' intricate biochemical, cellular, and physiological effects on the human body. The study of pharmacodynamics helps us understand how drugs interact with the body and elicit various responses.
Most drugs' effects result from their interactions with drug receptors or targets within the body. These interactions trigger specific responses at the cellular or systemic level. Drug receptors can be found on the surfaces of cells or...
Most drugs' effects result from their interactions with drug receptors or targets within the body. These interactions trigger specific responses at the cellular or systemic level. Drug receptors can be found on the surfaces of cells or...
2.7K
Pharmacokinetic Models: Overview
1.8K
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...
1.8K
Dosage Regimens: Partial Pharmacokinetic Parameters
141
It is not uncommon for complete drug pharmacokinetic profiles to remain elusive in pharmacokinetics. This necessitates certain educated assumptions by pharmacokineticists to determine appropriate dosage regimens without comprehensive pharmacokinetic data from animal or human studies. One prevalent assumption is setting the bioavailability factor, denoted as F, to 1 or 100%. This assumption caters to the scenario where a drug doesn't achieve full systemic absorption, resulting in the patient...
141


