Williams, Ph.D. / Williams Radiopharmaceuticals

Introduction to Drug Evaluation and Dose Estimation
1. Auflage 2016
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.

Williams, 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