1st Edition

Radiopharmaceuticals
Introduction to Drug Evaluation and Dose Estimation



ISBN 9781439810675
Published December 14, 2010 by CRC Press
326 Pages - 48 B/W Illustrations

 
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Book Description

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:

  1. Differentiate one radiopharmaceutical (RP) from another
  2. Estimate radiation doses
  3. 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.

Table of Contents

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

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Author(s)

Biography

Lawrence E. Williams, Ph.D., is a professor of radiology and an imaging physicist
at City of Hope National Medical Center in Duarte, California. In addition, he is an
adjunct professor of radiology at University of California–Los Angeles (UCLA).

While in high school, he was one of 40 national winners of the Westinghouse (now
Intel) Science Talent Search. Dr. Williams obtained his B.S. from Carnegie Mellon
University and his M.S. and Ph.D. degrees (both in physics) from the University of
Minnesota, where he was a National Science Foundation (NSF) fellow. His initial
graduate training was in nuclear reactions at Minnesota, where he demonstrated
excited states of the mass-4 system (4He*). He later extended this work by finding
excited levels of mass-3 nuclides while working at the Rutherford High Energy
Laboratory in England. Since obtaining the National Institutes of Health (NIH) support
to become a medical physicist, Dr. Williams has devoted most of his research to
tumor detection and treatment and has written approximately 250 total publications
as well as a number of patents in nuclear imaging and radionuclide therapy. He is a
coauthor of Biophysical Science (Prentice Hall, 1979) and editor of Nuclear Medicine
Physics (CRC Press, 1987). He has been a grant and site reviewer for NIH since the
mid-1990s. Dr. Williams is associate editor of Medical Physics and a reviewer for
several other journals. He is a member of the American Association of Physicists
in Medicine (AAPM), the Society of Nuclear Medicine, the New York Academy of
Sciences, Sigma Xi, Society of Imaging Informatics in Medicine (SIIM), and the
Society of Breast Imaging. Dr. Williams has received a lifetime service award from
the American Board of Radiology.

Among Dr. Williams’ most significant biophysical discoveries is the mass-law
for tumor uptake as a function of tumor size. He was also codiscoverer (with Richard
Proffitt) of tumor targeting with liposomes. This work involved one of the first applications of normal organ blockage by use of an unlabeled agent—that is, a two-step
process. Dr. Williams has developed a pair of indices for quantifying the ability of a
radiopharmaceutical to permit imaging or therapy of lesions in animals or patients. He
has also demonstrated that radioactive decay must be considered inherently as one possible exit route in modeling analysis of radioactive drugs. With his colleagues at City of Hope, Dr. Williams measured and calculated the brake radiation dose result for a source of 90Y in a humanoid phantom. This study remains as one of the few examples of a comparison of dose estimates and measurement in the nuclear medicine literature.

Reviews

This high-quality hardcover volume is a textbook providing an exposition … on the development and evaluation of antibody-based and other targeted radionuclide therapies … unique in the targeted radionuclide therapy literature.
Medical Physics, May 2012

The book covers a very important topic and fills a gap not covered by others. I believe that it will be a very valuable in our education of Ph.D. students and also very valuable for researchers in this area. I will recommend the book to my colleagues.
—Professor Sven-Erik Strand, University of Lund

The reader is taken on a journey to discover radiopharmaceutical evaluation and dose estimation. The various chapters cover all aspects of radiopharmaceutical development (tumor targeting, preclinical development, selection of radiopharmaceuticals for clinical trials, etc). Chapters dedicated to dosimetry go beyond the usual discussion to cover aspects more related to pharmacokinetics assessment (modeling and temporal integration). Of particular interest are the chapters dedicated to absorbed dose/effect correlation. This is very relevant, especially since recent publications indicate that, in the context of molecular radiotherapy, if the biological end-point is clearly defined and the dosimetric approach is carried out in a rational way, absorbed dose (or derivates) will correlate with observed toxicity or efficacy.
The book is written in a very clear style, and is accessible not only to physicists, but to any professional involved in radiopharmaceutical development and clinical or preclinical experiments. All chapters end with a summary that recapitulates the important points addressed in the chapter, and this a very helpful feature of this book.
Through 30 years of experience, Prof. Williams shares with us ideas, caveats, and hints applicable to the domain. In the acknowledgements, he indicates his will to ‘put some chips back in the pot.’ This is exactly how I receive this book: a senior scientist in our field is sharing his experience—and I dare say his wisdom—with us. This atypical book is going to be an essential part of my library.
—Manuel Bardies, Director of Research, INSERM