Radiopharmaceuticals: Introduction to Drug Evaluation and Dose Estimation

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 A 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