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Updated: Jul 1, 2025

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
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通过PBPK建模来理解CYP3A4和P-gp介导的药物相互作用 - - 实例例是pralsetinib

Christine Bowman1, Michael Dolton1, Fang Ma1

  • 1Genentech, Inc., South San Francisco, California, USA.

CPT: pharmacometrics & systems pharmacology
|March 14, 2024
PubMed
概括

使用基于生理学的药理动力学模型预测了pralsetinib的药物相互作用. 这种模型有助于了解药物代谢和转运体相互作用如何影响pralsetinib的药理动力学,指导安全的同时使用.

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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.
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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...
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Nonlinear Pharmacokinetics: Dependence of Elimination Half-Life and Dose Clearance01:23

Nonlinear Pharmacokinetics: Dependence of Elimination Half-Life and Dose Clearance

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.
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When a drug follows nonlinear pharmacokinetics, its bioavailability, the amount of the drug that reaches the systemic circulation, can change with different doses. This is due to the presence of a saturable pathway. The pathway becomes saturated as the drug concentration increases, decreasing the absorption rate. Consequently, the drug's bioavailability may be lower than expected at higher doses.
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Protein-Drug Binding: Mechanism and Kinetics01:16

Protein-Drug Binding: Mechanism and Kinetics

Protein-drug binding refers to the interaction between drugs and proteins within the body. This binding process can occur intracellularly, involving drug interactions with enzymes or receptors within cells, or extracellularly, involving plasma proteins in the blood.
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