Williams, Ph.D. Radiopharmaceuticals

Introduction to Drug Evaluation and Dose Estimation
1. Auflage 2010
ISBN: 978-1-4665-0282-6
Verlag: Taylor & Francis
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 326 Seiten

Nanoengineering, energized by the desire to find specific targeting agents, is leading to dramatic acceleration in novel drug design. However, in this flurry of activity, some issues may be overlooked. This is especially true in the area of determining dosage and evaluating the effects of multiple agents designed to target more than one site of metastasis.

Offering the unique perspective of a medical physicist who has worked directly with cancer patients for over three decades, Radiopharmaceuticals: Introduction to Drug Evaluation and Dose Estimation starts by exploring the recent history and current state of the field. Then, citing key research and practical examples, the author looks at how to run studies and employ estimation and evaluation methods that lead to the best multiple agents with the least amount of trial and error. He discusses methods that will allow researchers to more rigorously:

- Differentiate one radiopharmaceutical (RP) from another

- Estimate radiation doses

- Correlate results across various species to realize more informed data from clinical trials

Incorporating developments in nanotechnology and radiology, with the ultimate goal of achieving personalized patient-specific treatment, this book crosses disciplines to addresses a range of topics including:

- Preclinical RP development

- Organization of clinical trials

- Determination of activity in vivo

- Modeling and temporal integration with a look at the mass law for tumor uptake as a function of tumor size (discovered by the author)

- Absorbed dose estimates with and without clinical correlations

- Multiple-modality therapy

Dr. Lawrence Williams has devoted most of his life’s research to tumor detection and treatment, and his discoveries continue to influence evolving therapies. As s a medical physicist, he is eminently qualified to bring unique insight into the discussion of radiopharmaceutical dosage rates and efficacy.

Autoren/Hrsg.

Williams, Ph.D., Lawerence E.

Fachgebiete

• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Medizinische Fachgebiete Pharmakologie, Toxikologie

Inhaltsverzeichnis

Tumor Targeting and a Problem of Plenty
Introduction

The Extent of Disease

Radioactive Decay

Radionuclide Labels

Radionuclide Emissions

Charged Particles

Uncharged Particles

Methods of Labeling

Nanoengineering

Colloidal Designs

Liposomes

Antibodies

Small Proteins

Oligonucleotides

Aptamers

RNA Interference

Morpholino Adaptations

Summary

References

Preclinical Development of Radiopharmaceuticals and Planning of Clinical Trials

Introduction: Nuclear Medicine

The Tools of Ignorance: Photon Detection and Imaging Devices

Single Probes

Well Counters

Gamma Cameras

SPECT Imaging

PET Imaging

SPECT–CT Hybrid Systems

PET–CT

Miniature Gamma, SPECT, and PET Cameras

Animal Biodistributions

Specific Targeting In Vivo

Biodistributions in Mice

Logistics of Human Trials

Cost of Human Trials

Summary

References

Selection of Radiopharmaceuticals for Clinical Trials

Introduction

Tumor Uptake as a Function of Tumor Mass

Derivation of the Imaging Figure of Merit

Application of IFOM to Five Anti-CEA Cognate Antibodies

Iodine versus Indium Labeling

PET Application of the IFOM

Verification of the IFOM

Finding Potentially Useful Imaging Agents by Deconvolution

Therapy Figure of Merit

Summary

References

Absorbed Dose Estimation and Measurement

Introduction

Absorbed Dose

Absorbed Dose as a Concept

Geometry of Absorbed Dose Estimation

Biological Applications of the Dose Estimation Process

Reasons for Clinical Absorbed Dose Estimation

Dose Measurements

Corrections to the Dose Estimates

Ionization Energy Density and Absorbed Dose

Temporal Variation in Dose Rate

Organ Heterogeneity

Effective Dose

Methods for Estimating Absorbed Dose for Internal Emitters

The Canonical MIRD Estimation Method for Internal
Emitter Doses

Types of MIRD Human Dose Estimates

Point Source Functions for Dose Estimation

Absorbed Dose Estimates Using Voxel Source Kernels

Measurement of Radiation Dose by Miniature Dosimeters in a
Liquid Medium

Measurement of Brake Radiation Absorbed Dose in a Phantom
Using TLDs

Summary

References

Determination of Activity In Vivo

Introduction

Activity Data Acquisition via Nonimaging Methods

Blood Curve and Other Direct Organ Samplings

Probe Counting

Activity Data Acquisition via Imaging

Camera Imaging to Determine Activity

Geometric Mean Imaging to Determine Activity

CAMI Imaging to Determine A(t)

Quantitative SPECT Imaging to Determine A(t)

PET Image Quantitation and the SUV Value

Diagnostic Use of the Standard Uptake Value Parameter

Other PET Radionuclides and Image Quantitation

Bone Marrow A(t) Values

Combinations of Methods for Practical Activity Measurements

Summary

References

Modeling and Temporal Integration

Reasons for Modeling

Correction for Radiodecay

Two Formats for Modeling

Compartment Models

Noncompartment Models

Multiple-Exponential Functions

Power-Law Modeling

Tumor Uptake as a Function of Tumor Mass

Sigmoidal Functions

Basis Functions

Data Representation with Trapezoids and Splines

Deconvolution as a Modeling Strategy

Statistical Matters

Methods to Estimate Errors in Calculated Parameters Such as
AUC

Bootstrapping

Monte Carlo Methods

Differential Methods to Estimate AUC Errors

Partial Differential Equations as a More General Modeling Format

Some Standard Software Packages for Modeling

ADAPT II

SAAM II

The R Development

Summary

References

Functions Used to Determine Absorbed Dose Given Activity Integrals

Introduction

Point-Source Function

Voxel Source Kernel

S Matrix Considerations

Methodology of the S Matrix

S Matrix Symmetry

Target Organ Mass Dependence of S for Particles

Target Organ Mass Dependence of S for Photons

Applications of S Matrices

Applications of Standard (Phantom) S Values

An Aside: Changes in à Needed in Phantom Studies

Elaboration of Standard S Matrices for Kidney

Modification of S for Patient-Specific Absorbed Dose Estimates

Inverting the S Matrix to Measure Activity

Variation of Target Mass during Therapy

Murine S Values Estimated Using Monte Carlo Techniques

Summary

References

Absorbed Dose Estimates without Clinical Correlations

Introduction

Absorbed Dose Estimates for Animal Models

Absorbed Dose Estimates for I-MIBG Therapy

Lymphoma Therapy Absorbed Dose Estimates

Treatment of Lymphoma Using Lym- Antibody

Zevalin Absorbed Dose Estimates for Lymphoma Patients

Bexxar Absorbed Dose Estimates for Lymphoma Patients

Interventional Therapy of Hepatic Malignancies Using
Microspheres

Colorectal Cancer Therapy Using TRT

Summary

References

Dose Estimates and Correlations with Laboratory and Clinical Results

Introduction

Animal Results Correlating Absorbed Dose and Effects

Lymphocyte Chromosome Defects Observed Following TRT

Lymphoma Tumor Dose Estimates and Disease Regression

Improving Hematological Toxicity Correlations with Red Marrow
Absorbed Dose Estimates

Renal Toxicity Following Peptide Radionuclide Therapy

Summary

References

Multiple-Modality Therapy of Tumors

Introduction

Surgery and Targeted Radionuclide Therapy

Treatment of Residual Thyroid Tissue

Breast Cancer Treatment Postsurgery

Brain Tumor Therapy Postsurgery

Hepatic Tumor Therapy to Expedite Subsequent Surgery

Hyperthermia and TRT

External Beam and TRT

Chemotherapy and TRT

TRT and Cisplatin

TRT and Taxanes

TRT and Gemcitabine

TRT and -Fluorouracil (-FU)

Immune Manipulation and TRT

Increasing the CEA Content of Colorectal Tumors

Using Cold anti-CD Antibody to Enhance TRT in
Lymphoma Therapies

Zevalin therapy

Tositumomab (Bexxar) therapy

Vaccination and TRT in Colorectal Cancer Therapy in Mice

Summary

References

Allometry (Of Mice and Men)

Introduction

Allometry in Nature

Historical Temporal and Kinetic Correspondences

Measured Protein Kinetic Parameters Using Simple
Allometry

Kinetic Variations Using a More Sophisticated Analysis

Comparisons of Tumor Uptake as a Function of Tumor Mass

Single-Parameter Comparisons of Mouse and Human Kinetics

Comparing the Rate Constants in a Compartmental Model:

Human versus Mouse

Summary

References

Summary of Radiopharm-aceuticals and Dose Estimation

Introduction (Chapter 1)
Animal Results (Chapter 2)

Figures of Merit for Clinical Trials (Chapter 3)

Absorbed Dose Estimation (Chapter 4)

Determining Activity at Depth in the Patient (Chapter 5)

Modeling of Biodistributions and Other Data (Chapter 6)

Numerical Values of S and Other Dose Estimation Functions (Chapter 7)

Absorbed Dose Estimates without Correlations (Chapter 8)
Absorbed Dose Correlations with Biological Effects (Chapter 9)

Combinations of Radiation and Other Therapies (Chapter 10)

Allometry (Chapter 11)

Summary

References

Index