Related Experiment Video

Updated: May 18, 2026

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
10:49

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Published on: September 18, 2013

Using pharmacokinetic and pharmacodynamic data in early decision making regarding drug development: a phase I

José Baselga1, Alain C Mita, Patrick Schöffski

  • 1Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA. baselgaj@mskcc.org

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|September 28, 2012
PubMed
Abstract

Insights

AEE788, a tyrosine kinase inhibitor, effectively inhibited epidermal growth factor receptor (EGFR) in cancer patients at tolerable doses. However, it did not inhibit VEGFR, leading to the discontinuation of its development.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • AEE788 is a novel tyrosine kinase inhibitor targeting EGFR, HER-2, and VEGFR-2.
  • Early clinical development requires comprehensive safety, pharmacokinetic, and pharmacodynamic assessments.

Purpose of the Study:

  • To evaluate the safety, pharmacokinetics, and preliminary efficacy of AEE788 in cancer patients.
  • To implement a pharmacodynamic program to understand AEE788's mechanism of action.

Main Methods:

  • First-in-human study with escalating oral doses of AEE788 in advanced solid tumor patients.
  • Determined dose-limiting toxicities (DLTs) and maximum-tolerated dose (MTD).
  • Utilized Emax modeling to correlate AEE788 exposure with target-pathway modulation in skin and tumor tissues.

Main Results:

  • MTD was 450 mg/day, with rash and diarrhea as DLTs.
  • AEE788 demonstrated effective EGFR inhibition in skin and tumor tissues, with skin serving as a potential surrogate.
  • No significant inhibition of VEGFR was observed at doses up to MTD; limited clinical activity noted.

Conclusions:

  • AEE788 effectively inhibits EGFR but not VEGFR at tolerable doses.
  • Pharmacodynamic modeling guided early drug development decisions.
  • Discontinuation of AEE788 development due to selective EGFR inhibition despite some clinical activity.

More Related Videos

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays07:42

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Published on: September 19, 2018

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays13:22

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Published on: October 23, 2019

Related Concept Videos

Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions01:15

Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions

PK–PD modeling has significantly influenced FDA regulatory decisions, particularly drug approval, dosage optimization, and labeling. These models integrate pharmacokinetics (PK) and pharmacodynamics (PD) to predict drug behavior and effects, aiding in optimizing dosing regimens and enhancing the probability of clinical trial success.One notable example is Nesiritide (Natrecor®), a recombinant human brain natriuretic peptide for treating acute decompensated congestive heart failure (CHF).
Pharmacokinetic–Pharmacodynamic Relationship: Problems01:24

Pharmacokinetic–Pharmacodynamic Relationship: Problems

The empirical approach to drug therapy optimization relies on correlating pharmacological response with administered dosage. Such an approach can be costly, time-consuming, and often yields poor correlation due to variables like formulation factors and drug elimination characteristics. A more precise approach correlates response with plasma drug concentration or the amount of drug in the body, rather than dosage. This is achieved through pharmacokinetic-pharmacodynamic (PK/PD) modeling, which...
Clinical Trials: Overview01:11

Clinical Trials: Overview

Clinical development focuses on how the drug will interact with the human body and encompasses four key phases of clinical trials, each serving a specific purpose in assessing the safety and effectiveness of new drugs. These phases overlap and build upon one another. Phase I involves a small group of healthy volunteers (typically 20-80 individuals) or, in cases where significant toxicity is expected, patients with the targeted disease, such as cancer or AIDS. The volunteers are tested for...
Measurement of Bioavailability: Pharmacodynamic Methods01:20

Measurement of Bioavailability: Pharmacodynamic Methods

Pharmacodynamic methods provide insights into a drug's effects on physiological processes over time and play a crucial role in understanding bioavailability and therapeutic efficacy. These methods can be broadly classified into acute pharmacological and therapeutic response approaches, each with distinct mechanisms and applications.The acute pharmacological response method directly correlates a drug's physiological effects, such as ECG or pupil diameter changes, to its time course in the body.
Preclinical Development: Overview01:28

Preclinical Development: Overview

Preclinical development consists of a series of tests that ensure the safety and efficacy of a new therapeutic compound before it is tested in humans. There are four main phases to this process. First, safety pharmacology tests are conducted to ensure the drug does not produce any acutely harmful effects. These tests examine parameters such as bronchoconstriction, cardiac dysrhythmias, blood pressure changes, and ataxia. Next, preliminary toxicological testing is performed to determine the...
Pharmacokinetic–Pharmacodynamic Relationship: Model Components01:14

Pharmacokinetic–Pharmacodynamic Relationship: Model Components

Pharmacokinetic-pharmacodynamic (PK–PD) modeling is essential in drug development and clinical pharmacology. It provides a quantitative framework to predict drug behavior and response over time. This approach integrates pharmacokinetics (PK), which describes the drug's absorption, distribution, metabolism, and excretion, with pharmacodynamics (PD), which characterizes the drug’s biological effects and mechanisms of action.The disposition kinetics of a drug determine its plasma...