Handbook of LC-MS Bioanalysis

Name: Handbook of LC-MS Bioanalysis | Best Practices, Experimental Protocols, and Regulations
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Best Practices, Experimental Protocols, and Regulations

Wenkui Li Jie Zhang Francis L. S. Tse(Herausgeber*in)

Wiley (Verlag)

Erschienen am 28. August 2013

704 Seiten

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Consolidates the information LC-MS bioanalytical scientistsneed to analyze small molecules and macromolecules The field of bioanalysis has advanced rapidly, propelled by newapproaches for developing bioanalytical methods, new liquidchromatographic (LC) techniques, and new mass spectrometric (MS)instruments. Moreover, there are a host of guidelines andregulations designed to ensure the quality of bioanalyticalresults. Presenting the best practices, experimental protocols, and thelatest understanding of regulations, this book offers acomprehensive review of LC-MS bioanalysis of small molecules andmacromolecules. It not only addresses the needs of bioanalyticalscientists working on routine projects, but also explores advancedand emerging technologies such as high-resolution mass spectrometryand dried blood spot microsampling. Handbook of LC-MS Bioanalysis features contributions froman international team of leading bioanalytical scientists. Theircontributions reflect a review of the latest findings, practices,and regulations as well as their own firsthand analyticallaboratory experience. The book thoroughly examines: * Fundamentals of LC-MS bioanalysis in drug discovery, drugdevelopment, and therapeutic drug monitoring * The current understanding of regulations governing LC-MSbioanalysis * Best practices and detailed technical instructions for LC-MSbioanalysis method development, validation, and stabilityassessment of analyte(s) of interest * Experimental guidelines and protocols for quantitative LC-MSbioanalysis of challenging molecules, including pro-drugs, acylglucuronides, N-oxides, reactive compounds, and photosensitive andautooxidative compounds With its focus on current bioanalytical practice, Handbook ofLC-MS Bioanalysis enables bioanalytical scientists to developand validate robust LC-MS assay methods, all in compliance withcurrent regulations and standards.

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"In that, it serves as a source of information and ofliterature references for further in-depth reading. It is veryuseful to have but, like always, it does not give all answers toevery question one may have." (ChemMedChem, 1June 2014)

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Inhalt

Intro
HANDBOOK OF LC-MS BIOANALYSIS
CONTENTS
PREFACE
CONTRIBUTORS
ABBREVIATIONS
PART I OVERVIEW OF LC-MS BIOANALYSIS
1 ROLES OF LC-MS BIOANALYSIS IN DRUG DISCOVERY, DEVELOPMENT, AND THERAPEUTIC DRUG MONITORING
1.1 INTRODUCTION
1.2 LC-MS BIOANALYSIS IN DRUG DISCOVERY
1.2.1 Structure-Activity Relationships from High-Throughput Screening
1.2.2 Structure-PK-PD Relationships
1.2.3 Candidate Selection
1.3 LC-MS BIOANALYSIS IN PRECLINICAL DEVELOPMENT OF DRUGS
1.3.1 Toxicokinetics
1.3.2 Preclinical ADME and Tissue Distribution Studies in Animals
1.4 LC-MS BIOANALYSIS IN CLINICAL DEVELOPMENT OF DRUGS
1.4.1 First-in-Human Studies
1.4.2 Human ADME Studies
1.4.3 Human Drug-Drug Interaction Studies
1.4.4 Renal Impaired and Hepatic Impaired Studies in Human
1.4.5 Phase II and Phase III Studies
1.4.6 "Fit-for-Purpose" Biomarker Measurement Using LC-MS in Clinical Samples
1.4.7 Other LC-MS Assays Needed for Clinical Development of Drugs
1.4.8 LC-MS Bioanalysis in Postapproval Studies (Phase IV) of Drugs
1.4.9 LC-MS Bioanalysis in BE and BA Studies for Generic Drugs
1.4.10 LC-MS Bioanalysis in Therapeutic Drug Monitoring
1.5 LC-MS BIOANALYSIS OF LARGE MOLECULE DRUGS AND BIOPHARMACEUTICALS
1.6 GUIDANCE AND REGULATIONS FOR LC-MS BIOANALYSIS
1.7 GENERAL CONSIDERATIONS OF A ROBUST LC-MS BIOANALYTICAL METHOD
1.8 CONCLUSIONS
REFERENCES
2 OVERVIEW: FUNDAMENTALS OF A BIOANALYTICAL LABORATORY
2.1 INTRODUCTION
2.2 KEY ELEMENTS OF A BA LABORATORY
2.2.1 Facility
2.2.2 Infrastructure
2.2.3 Compliance
2.2.4 Documentation
2.3 QUALITY ASSURANCE
2.4 SUPPORTING FUNCTIONS
2.4.1 Quality Control
2.4.2 Sample Management
2.4.3 Archivist
2.4.4 Technical Support
2.4.5 Planning
2.4.6 Report Generation
2.5 CRO MONITORING
2.5.1 Personnel
2.5.2 Outsource Process
2.6 CONCLUSIONS
REFERENCES
3 INTERNATIONAL REGULATIONS AND QUALITY STANDARDS OF BIOANALYSIS
3.1 INTRODUCTION
3.2 GLOBAL BIOANALYTICAL GUIDANCE
3.3 BIOANALYTICAL QUALITY
3.3.1 Bioanalytical Quality Strategies
3.3.2 Quantitative Assessment
3.3.3 Qualitative Assessment
3.4 SCIENCE, QUALITY, AND REGULATION
ACKNOWLEDGMENTS
REFERENCES
PART II CURRENT UNDERSTANDING OF LC-MS BIOANALYSIS-RELATED REGULATIONS
4 CURRENT REGULATIONS FOR BIOANALYTICAL METHOD VALIDATIONS
4.1 INTRODUCTION
4.2 CONTEXT OF THE REGULATORY ENVIRONMENT
4.3 VALIDATIONS OF METHODS
4.3.1 Matrix Requirements
4.3.2 Reference Standards
4.3.3 Robustness Testing
4.3.4 Sensitivity
4.3.5 Selectivity
4.3.6 Recovery
4.3.7 Matrix Effects
4.3.8 Calibration Curves
4.3.9 QC Samples
4.3.10 Stability in Matrix
4.3.11 Stock Solution Stability
4.3.12 System Suitability
4.3.13 Carryover
4.3.14 Determination of Metabolites
4.3.15 Incurred Sample Reanalysis
4.3.16 Run Size
4.3.17 Reporting
4.3.18 Other Topics
4.4 CONCLUSION
REFERENCES
5 CURRENT UNDERSTANDING OF BIOANALYTICAL ASSAY REPRODUCIBILITY: INCURRED SAMPLE REANALYSIS, INCURRED SAMPLE STABILITY, AND INCURRED SAMPLE ACCURACY
5.1 INTRODUCTION
5.2 INCURRED SAMPLE REANALYSIS
5.2.1 Principles and Practice of ISR
5.2.2 Statistical Approaches for Assessment of ISR
5.2.3 Case Studies on ISR
5.2.4 Dried Blood Spot ISR
5.2.5 Approach for Efficient Conduct of ISR
5.2.6 Recommendations for ISR Investigation
5.3 INCURRED SAMPLE STABILITY
5.4 INCURRED SAMPLE ACCURACY
5.4.1 Methodology for ISA Assessment
5.4.2 ISA Data Interpretation
5.4.3 Reflections on the Use of ISA in Bioanalytical Method Validation
5.5 SUMMARY
REFERENCES
6 LC-MS BIOANALYTICAL METHOD TRANSFER
6.1 INTRODUCTION
6.2 PREPARATION FOR METHOD TRANSFER
6.3 CURRENT UNDERSTANDING ON REGULATORY REQUIREMENTS FOR BIOANALYTICAL METHOD TRANSFER
6.4 METHOD TRANSFER
6.4.1 Partial/Cross-validation versus Full Validation
6.4.2 Method Modification
6.4.3 Acceptance Criteria
6.5 COMMON CAUSES OF BIOANALYTICAL METHOD TRANSFER FAILURE
6.6 INVESTIGATION OF A METHOD TRANSFER FAILURE
6.7 SUMMARY
REFERENCES
7 METABOLITES IN SAFETY TESTING
7.1 INTRODUCTION
7.2 TIMING OF ADME STUDIES WITH RADIOLABELED MATERIALS
7.3 FIH STUDIES
7.4 STANDARD FREE QUANTIFICATION AND ITS LIMITATIONS
7.5 TIERED OPTIONS FOR DETERMINATION OF HUMAN METABOLITE EXPOSURES AND RESPECTIVE LIMITATIONS
7.5.1 Tier 1-Metabolite Profiling Assay
7.5.2 Tier 2-Standard Free Quantification/Response Factor Determination
7.5.3 Tier 3-Qualified Assays
7.5.4 Tier 4-Validated Assays
7.6 SUMMARY
REFERENCES
8 A COMPARISON OF FDA, EMA, ANVISA, AND OTHERS ON BIOANALYSIS IN SUPPORT OF BIOEQUIVALENCE/ BIOAVAILABILITY STUDIES
8.1 INTRODUCTION TO BIOAVAILABILITY/ BIOEQUIVALENCY STUDIES
8.2 REGULATIONS FROM THE US FDA
8.2.1 History and Validation
8.2.2 Conduct of the Bioanalysis
8.3 REGULATIONS FROM THE EUROPEAN MEDICINES AGENCY
8.3.1 The Bioanalytical Method
8.3.2 Bioanalysis of Enantiomers
8.4 REGULATIONS FROM THE BRAZILIAN SANITARY SURVEILLANCE AGENCY (ANVISA)
8.4.1 Method Validation
8.4.2 Conduct of Bioanalysis
8.5 OTHER INTERNATIONAL GUIDELINES
8.5.1 Indian Department of Health
8.5.2 Health Canada
8.5.3 China State FDA
8.6 CONCLUSION
REFERENCES
9 A COMPARISON OF THE GUIDANCE OF FDA, OECD, EPA, AND OTHERS ON GOOD LABORATORY PRACTICE
9.1 INTRODUCTION
9.2 FDA VERSUS EPA ON GLP
9.3 FDA GLP VERSUS OECD GLP PRINCIPLES
9.4 SOME COUNTRY SPECIFIC REQUIREMENTS ON GLP
9.5 GLP INSPECTION
9.6 SUMMARY
REFERENCES
10 CURRENT UNDERSTANDING OF BIOANALYSIS DATA MANAGEMENT AND TREND OF REGULATIONS ON DATA MANAGEMENT
10.1 INTRODUCTION
10.1.1 Historical Overview
10.1.2 The Need for Regulated Bioanalysis Data Management
10.2 BIOANALYTICAL WORKFLOW AND DATA MANAGEMENT
10.2.1 Bioanalytical Workflow and Data Flow
10.2.2 Quality Data Management Software Systems
10.3 COMPUTER SYSTEMS VALIDATION
10.3.1 Overview
10.3.2 Outline of Validation Procedures
10.3.3 Future Direction of Computer Systems Validation
10.3.4 Trend of the Regulations on Data Management
10.4 CHALLENGES FOR BIOANALYTICAL DATA INTEGRITY AND SECURITY
10.5 FUTURE PERSPECTIVES
10.6 CONCLUSIONS
REFERENCES
11 REGULATORY INSPECTION TRENDS AND FINDINGS OF BIOANALYTICAL LABORATORIES
11.1 INTRODUCTION
11.2 CURRENT REGULATORY INSPECTION TRENDS
11.3 INADEQUATE INVESTIGATION-THE MDS CASE
11.4 DATA INTEGRITY CONCERN-THE CETERO CASE
11.5 DISCUSSION AND ANALYSIS OF SPECIFIC REGULATORY INSPECTION FINDINGS
11.5.1 Data Integrity/Electronic Records Issues
11.5.2 Method Validation Issues
11.5.3 Batch Runs Acceptance Criteria Issues
11.5.4 Events/Deviations Investigation/Resolution Issues
11.5.5 Test Specimen Accountability Issue
11.6 RECOMMENDATIONS TO SUPPORT AN EFFECTIVE FDA INSPECTION-READINESS PREPARATION
REFERENCES
PART III BEST PRACTICE IN LC-MS BIOANALYSIS
12 ASSESSMENT OF WHOLE BLOOD STABILITY AND BLOOD/PLASMA DISTRIBUTION OF DRUGS
12.1 ASSESSMENT OF WHOLE BLOOD STABILITY OF DRUGS
12.1.1 Factors Affecting the Stability of Drugs in Blood
12.1.2 Considerations of Experimental Design for Whole Blood Stability Assessment of Drugs
12.1.3 The Choice of Analytical Matrix for Blood Stability Assessment
12.1.4 Stability of Metabolites
12.1.5 Statistical Methods for Blood Stability Assessment
12.2 BLOOD/PLASMA DISTRIBUTION OF DRUGS
12.2.1 Mechanisms of Blood/Plasma Distribution/Partitioning of Drugs
12.2.2 Measurement of the Blood-to-Plasma Partition Ratio
12.2.3 Factors to be Considered in Blood/Plasma Partition Assessment of Drugs
12.3 SUMMARY
ACKNOWLEDGMENT
REFERENCES
13 BEST PRACTICE IN BIOLOGICAL SAMPLE COLLECTION, PROCESSING, AND STORAGE FOR LC-MS IN BIOANALYSIS OF DRUGS
13.1 INTRODUCTION
13.2 SAMPLE COLLECTION
13.2.1 In vivo Sample Collection
13.2.2 Choice of Anticoagulant
13.2.3 Other Sample Tube Additives
13.2.4 Preparing Plasma from Blood
13.2.5 Minimizing Clot Formation
13.2.6 Difference between Plasma and Serum
13.2.7 Collection of Urine Samples
13.2.8 Collection of Tissue Samples
13.2.9 Collection of Fecal Samples
13.2.10 Best Practice for Use of Centrifuges
13.2.11 Time Factors
13.2.12 Working on Ice
13.3 DOCUMENTATION
13.3.1 Procedures for Nonclinical Sample Collection
13.3.2 Procedures for Clinical Sample Collection
13.3.3 Sample Identification and Randomization
13.4 REDUCING ADSORPTION OF ANALYTE TO CONTAINERS
13.5 SAMPLE COLLECTION FOR PEPTIDES AND PROTEINS
13.6 STABILIZING SAMPLES
13.6.1 Physical Factors
13.6.2 Chemical Factors
13.6.3 Stability and Dried Blood Spots
13.7 BIOLOGICALLY HAZARDOUS SAMPLES
13.8 SAMPLE STORAGE
13.8.1 Types of Container for Sample Storage
13.8.2 Material
13.8.3 Temperature of Samples Storage
13.8.4 Disaster Recovery Plan
13.9 TRANSPORT AND SHIPPING OF SAMPLES
13.9.1 Practicalities of Transporting Samples
13.9.2 Packaging
13.9.3 Documentation
13.9.4 Monitoring Samples in Transit
13.9.5 Receipt of Samples
13.10 COMPLIANCE CHECKLIST
13.11 SUMMARY
ACKNOWLEDGMENT
REFERENCES
14 BEST PRACTICES IN BIOLOGICAL SAMPLE PREPARATION FOR LC-MS BIOANALYSIS
14.1 WHY DO SAMPLE PREPARATION?
14.2 WHAT SHOULD YOU KNOWABOUT THE SAMPLE?
14.2.1 Analyte of Interest
14.2.2 Matrix
14.3 KNOWYOUR TOOLS
14.3.1 Dilution
14.3.2 Protein Precipitation
14.3.3 Liquid-Liquid Extraction
14.3.4 Solid Phase Extraction
14.3.5 Analyte Specific Extraction Techniques
14.3.6 Sample Preparation Techniques for Special Samples
14.4 KNOWYOUR NEEDS
14.5 CONCLUSION AND PERSPECTIVES
REFERENCES
15 BEST PRACTICE IN LIQUID CHROMATOGRAPHY FOR LC-MS BIOANALYSIS
15.1 INTRODUCTION
15.2 THEORETICAL CONSIDERATIONS
15.2.1 Parameters Affecting Column Efficiency
15.2.2 Peak Capacity and Two-Dimensional Chromatography
15.2.3 Chromatographic Secondary Interactions
15.2.4 Isocratic versus Gradient Chromatography
15.2.5 Injection Solution
15.2.6 Retention Factor
15.2.7 High Speed LC-MS
15.2.8 Major Types of Stationary Phases
15.2.9 Choice of the Right Column Sizes
15.3 PRACTICAL CONSIDERATIONS FOR METHOD DEVELOPMENT
15.3.1 Holistic View of Practical Bioanalytical LC-MS Method Development
15.3.2 Matrix Effects
15.3.3 Metabolites
15.3.4 Biomarkers
15.3.5 Coadministration of Drugs
15.4 SAMPLE ANALYSIS
15.4.1 Batch Runs
15.4.2 Carryover
15.4.3 Peak Tailing
15.4.4 Conditioning
15.4.5 Diversion of LC Flow
15.4.6 Column Use in Sample Analysis
15.4.7 Instrument Communication
15.4.8 Data Processing
15.5 MAKING RUGGED METHODS
15.5.1 Column Selection
15.5.2 Optimizing the Separation
15.5.3 Changes Across Species and Matrices
15.5.4 Column Lifetime
15.6 LESS IS MORE
15.6.1 Microseparations
15.6.2 Microsampling
15.7 HIGH-RESOLUTION AND HIGH-SPEED ANALYSIS
15.7.1 UPLC
15.7.2 Monolithic Columns
15.7.3 Fused-Core Particles (Superficially Porous Silica Microspheres)
15.7.4 Multiplexing
15.8 SPECIAL CHALLENGES AND OPPORTUNITIES
15.8.1 Enantiomers
15.8.2 Polar Analytes and HILIC
15.9 CONCLUSIONS
REFERENCES
16 BEST PRACTICE IN MASS SPECTROMETRY FOR LC-MS
16.1 INTRODUCTION
16.2 ANALYZERS MOST OFTEN USED FOR LC-MS AND LC-MS/MS BIOANALYSIS
16.2.1 Low-Resolution Mass Spectrometers and Tandem Mass Spectrometers (Quadrupole, Triple Quadrupole, Ion Trap, and Q-trap)
16.2.2 High-Resolution Mass Spectrometers (Tof, Q-Tof, Tof-Tof, Ion Trap-Tof, FTICR, Orbitrap)
16.3 IONIZATION TECHNIQUES FOR UHPLC-MS
16.3.1 Electrospray
16.3.2 APCI
16.3.3 APPI
16.4 LC-MS IN QUANTITATIVE ANALYSIS
16.5 PERSPECTIVES
REFERENCES
17 USE OF INTERNAL STANDARDS IN LC-MS BIOANALYSIS
17.1 INTRODUCTION
17.2 SELECTION AND USE OF IS
17.2.1 Selection of IS
17.2.2 Determination of IS Concentration
17.2.3 Addition of IS
17.2.4 Chromatography and MS Detection of IS
17.3 PERFORMANCE OF IS
17.3.1 SIL IS versus Structural Analog One
17.3.2 Precautions when using SIL IS
17.3.3 Variation in IS Response during Incurred Sample Analysis
17.4 CONCLUSION
ACKNOWLEDGMENT
REFERENCES
18 SYSTEM SUITABILITY IN LC-MS BIOANALYSIS
18.1 OVERVIEW
18.2 REGULATORY REQUIREMENTS FOR SYSTEM SUITABILITY
18.3 MONITORING INSTRUMENT PERFORMANCE
18.3.1 Setting Up for Success
18.3.2 Chromatographic Systems
18.3.3 Mass Spectrometry Issues
18.3.4 Applications in LC-MS/MS Bioanalysis
18.3.5 Restarts and Reinjections
18.4 CONCLUSIONS
REFERENCES
19 DERIVATIZATION IN LC-MS BIOANALYSIS
19.1 INTRODUCTION
19.2 DERIVATIZATION REAGENTS ENHANCING IONIZATION EFFICIENCY IN LC/ESI-MS
19.3 DERIVATIZATION REAGENTS IN LC/ESI-MS/MS
19.3.1 For Ketones and Aldehydes
19.3.2 For Phenols and Alcohols
19.3.3 For Carboxylic Acids
19.3.4 For Amines
19.4 CONCLUSION
REFERENCES
20 EVALUATION AND ELIMINATION OF MATRIX EFFECTS IN LC-MS BIOANALYSIS
20.1 INTRODUCTION
20.2 POTENTIAL IMPACT OF MATRIX EFFECTS
20.3 COMMON CAUSES OF MATRIX EFFECTS
20.4 MECHANISM OF MATRIX EFFECTS
20.5 METHODS TO IDENTIFY AND EVALUATE MATRIX EFFECTS
20.6 REGULATORY GUIDANCE ON EVALUATION AND AVOIDANCE OF MATRIX EFFECTS
20.7 METHODS TO AVOID OR ELIMINATE MATRIX EFFECTS
20.8 FUTURE PROSPECTS
ACKNOWLEDGMENTS
REFERENCES
21 EVALUATION AND ELIMINATION OF CARRYOVER AND/OR CONTAMINATION IN LC-MS BIOANALYSIS
21.1 OVERVIEW
21.2 CURRENT UNDERSTANDING OF REGULATORY PERSPECTIVES ON CARRYOVER AND CONTAMINATION
21.2.1 FDA Perspective
21.2.2 EMA Perspective
21.3 CARRYOVER-WHAT IS IT?
21.4 CONTAMINATION-WHAT IS IT?
21.4.1 Atmospheric Contamination
21.4.2 Contamination during Dosing, Sample Collection, and Storage
21.4.3 Contamination during Sample Preparation
21.4.4 Reagents as a Source of Contamination
21.4.5 Internal Standards as a Source of Contamination
21.5 WHAT DO THE MANUFACTURERS SAY?
21.5.1 Shimadzu
21.5.2 LEAP Technologies
21.5.3 Waters
21.5.4 Agilent
21.5.5 Thermo Scientific
21.6 MANAGING CARRYOVER AND CONTAMINATION IN LC-MS BIOANALYSIS
21.6.1 Identification and Confirmation of Carryover and Contamination
21.6.2 Impact Assessment of Carryover and Contamination on Study Outcomes
21.6.3 Minimizing and/or Eliminating Carryover and Contamination
21.7 SUMMARY
ACKNOWLEDGMENTS
REFERENCES
22 AUTOMATION IN LC-MS BIOANALYSIS
22.1 INTRODUCTION
22.2 AN OVERVIEW OF AUTOMATED SAMPLE PREPARATION IN LC-MS BIOANALYSIS
22.3 ROBOTIC LIQUID HANDLING PIPETTING MODES AND ASSOCIATED TECHNOLOGY
22.4 OPTIMIZING ROBOTIC LIQUID HANDLING PERFORMANCE
22.5 SOLID PHASE EXTRACTION
22.6 PROTEIN PRECIPITATION
22.7 LIQUID-LIQUID EXTRACTION
22.8 PRACTICAL CONSIDERATIONS: STRATEGY, QUALITY, AND COMPLIANCE
22.9 CONCLUDING REMARKS
REFERENCES
23 LC-MS BIOANALYSIS OF DRUGS IN TISSUE SAMPLES
23.1 INTRODUCTION
23.2 CLASSIFICATION OF TISSUES
23.3 WORKFLOW
23.4 TISSUE SAMPLE COLLECTION
23.5 TISSUE SAMPLE PREPARATION
23.5.1 Rotor-Stator Homogenization
23.5.2 Bead Beating
23.5.3 Acoustic Disruption
23.5.4 Other Techniques
23.6 CALIBRATION STANDARD AND QC SAMPLE PREPARATION
23.6.1 Matching Blank Tissue Matrix
23.6.2 Surrogate Matrix
23.6.3 Calibration Standard and QC Preparation
23.7 ANALYTE EXTRACTION
23.8 LC-MS/MS ANALYSIS
23.9 FIT-FOR-PURPOSE LC-MS/MS METHOD QUALIFICATION
23.9.1 Recovery
23.9.2 Stability
23.9.3 Linearity, Sensitivity, Accuracy, and Precision
23.9.4 Qualification and Acceptance Criteria
23.10 DATA ANALYSIS AND REPORTING
23.11 SUMMARY
ACKNOWLEDGMENT
REFERENCES
24 LC-MS BIOANALYSIS OF DRUGS IN URINE
24.1 INTRODUCTION
24.2 BEST PRACTICE IN DEVELOPING A ROBUST URINE LC-MS QUANTITATION METHOD
24.2.1 Identification and Resolution of Analyte Loss due to Urine Nonspecific Binding
24.2.2 Sample Preparation Approaches for Urine Bioanalysis
24.2.3 Sample Analysis and Calculation of Percent Dose Recovered in Urine
24.2.4 Summary of TroubleShooting Urine Sample Analysis
24.3 SUMMARY
REFERENCES
25 LC-MS BIOANALYSIS OF UNBOUND DRUGS IN PLASMA AND SERUM
25.1 INTRODUCTION
25.2 PROTEIN BINDING
25.3 REGULATORY REQUIREMENTS REGARDING UNBOUND DRUG CONCENTRATIONS IN SPECIAL POPULATIONS
25.4 TECHNIQUES FOR THE BIOANALYSIS OF UNBOUND DRUGS IN PLASMA AND SERUM
25.4.1 (Rapid) Equilibrium Dialysis
25.4.2 Ultrafiltration
25.4.3 Analytical Ultracentrifugation
25.4.4 Solid Phase Microextraction
25.4.5 Considerations in Developing and Validating a Robust LC-MS/MS Method for the Analysis of Unbound Drugs in Biological Matrices
25.5 EXAMPLES
25.5.1 General Applications
25.5.2 Special Applications I: Steroids
25.5.3 Special Applications II: Drugs Affecting the Central Nervous System
25.5.4 Special Applications III: Chiral Drugs
REFERENCES
26 LC-MS BIOANALYSIS OF DRUGS IN BILE
26.1 BILE AND BILIARY EXCRETION
26.2 BILE SAMPLE COLLECTION
26.3 BILE SAMPLE PREPARATION
26.4 BILE SAMPLE LC-MS BIOANALYSIS
26.5 SUMMARY
REFERENCES
27 LC-MS BIOANALYSIS OF INTRACELLULAR DRUGS
27.1 INTRODUCTION
27.2 SAMPLE PREPARATION
27.2.1 Cell Separation and Counting
27.2.2 Cell Lysis
27.2.3 Extraction and Isolation Methods
27.3 LC-MS INTRACELLULAR DRUG BIOANALYSIS
27.3.1 LC-MS Interfaces
27.3.2 MS Detection Techniques
27.3.3 Liquid Chromatography
27.3.4 Method Validations
27.4 APPLICATION
27.4.1 LC-MS Bioanalysis of Intracellular Drugs in PMBC
27.4.2 LC-MS Bioanalysis of Intracellular Drugs in Cultured Cells
27.5 CONCLUSIONS
REFERENCES
28 LC-MS BIOANALYSIS OF ENDOGENOUS COMPOUNDS AS BIOMARKERS
28.1 INTRODUCTION
28.2 APPROACHES FOR BIOMARKER QUANTITATION
28.2.1 Authentic Analyte in Authentic Matrix
28.2.2 Authentic Analyte in Surrogate Matrix
28.2.3 Surrogate Analyte in Authentic Matrix
28.2.4 Enzyme Activity Assays
28.3 BIOMARKER ASSAY VALIDATION AND STUDY CONDUCT
28.3.1 Fit-for-Purpose
28.3.2 Prevalidation Considerations
28.3.3 Assay Validation
28.3.4 Study Support
28.4 SUMMARY AND PROSPECTIVE
REFERENCES
29 LC-MS BIOANALYSIS OF DRUGS IN HEMOLYZED AND LIPEMIC SAMPLES
29.1 INTRODUCTION
29.2 HEMOLYSIS
29.2.1 Current Status Regarding Hemolysis for LC-MS/MS Analysis
29.2.2 Analysis and Interpretation of Case Studies
29.2.3 Pros and Cons of the Known Hemolysis Experiment Procedures
29.2.4 Recommended Hemolysis Experiment Procedures
29.2.5 Best Practice and Strategy to Evaluate Hemolysis Effect
29.3 LIPEMIA
29.3.1 Current Status Regarding Lipemia for LC-MS/MS Analysis
29.3.2 Recommended Lipemia Experiment Procedures
29.3.3 Best Practice and Strategy to Evaluate Lipemia
29.4 CONCLUSION
ACKNOWLEDGMENT
REFERENCES
30 BEST PRACTICES IN LC-MS METHOD DEVELOPMENT AND VALIDATION FOR DRIED BLOOD SPOTS
30.1 INTRODUCTION
30.2 METHOD DEVELOPMENT
30.2.1 Preparation of Calibration Standard and QC Samples in Whole Blood
30.2.2 Selection of DBS Card
30.2.3 Spotting Volume, Spotting Techniques, and Punch Size
30.2.4 Spot Homogeneity
30.2.5 DBS Sample Drying, Storage, and Transportation
30.2.6 Internal Standard
30.2.7 Extraction Solvent, Procedure, and Recovery
30.2.8 Matrix Effects
30.2.9 Assay Sensitivity
30.2.10 On-Card Stabilization for Unstable Compounds
30.3 METHOD VALIDATION
30.3.1 Selectivity, Sensitivity, and Linearity
30.3.2 Inter- and Intraday Accuracy and Precision
30.3.3 HCT and Its Effects on the Assay
30.3.4 Impact of Blood Volume and Spot Size on the Accuracy of Determination
30.3.5 Impact of Homogeneity on the Accuracy of Determination
30.3.6 Temperature Impact
30.3.7 Dilution Integrity
30.3.8 Intercard Variability
30.3.9 Stability Determination
30.3.10 Carryover
30.4 CONCLUSIONS
REFERENCES
31 LC-MS METHOD DEVELOPMENT STRATEGIES FOR ENHANCING MASS SPECTROMETRIC DETECTION
31.1 INTRODUCTION
31.2 DIFFERENTIAL MOBILITY SPECTROMETRY
31.3 MULTIPLE REACTION MONITORING CUBED
31.4 ATMOSPHERIC PRESSURE PHOTOIONIZATION
31.5 MS SIGNAL ENHANCEMENT VIA MOBILE PHASE ADDITIVES AND ANIONIC AND CATIONIC ADDUCTS PRECURSOR IONS
31.6 CONCLUSIONS
REFERENCES
32 LC-MS BIOANALYSIS-RELATED STATISTICS
32.1 INTRODUCTION
32.2 BASIC STATISTICS
32.2.1 Regression
32.3 CALIBRATION
32.4 BIAS AND PRECISION
32.5 STABILITY
32.6 INCURRED SAMPLE REPRODUCIBILITY
REFERENCES
33 SIMULTANEOUS LC-MS QUANTITATION AND METABOLITE IDENTIFICATION IN DRUG METABOLISM AND PHARMACOKINETICS
33.1 INTRODUCTION
33.2 UNIT RESOLUTION MASS SPECTROMETERS IN DRUG METABOLISM AND PHARMACOKINETICS
33.3 HIGH-RESOLUTION MASS SPECTROMETRY IN DRUG METABOLISM AND PHARMACOKINETICS
33.4 MASS DEFECT FILTER IN LC-MS
33.5 SIMULTANEOUS LC-MS QUANTITATION/ METABOLITE IDENTIFICATION
33.6 LC-MS WORKFLOW: QqQLIT
33.7 LC-MS WORKFLOW: HIGH-RESOLUTION MASS SPECTROMETRY
33.8 CONCLUSIONS
ACKNOWLEDGMENTS
REFERENCES
PART IV REPRESENTATIVE GUIDELINES AND/OR EXPERIMENTAL PROTOCOLS OF LC-MS BIOANALYSIS
34 LC-MS BIOANALYSIS OF ESTER PRODRUGS AND OTHER ESTERASE LABILE MOLECULES
34.1 INTRODUCTION
34.2 COMMON ESTERASES THAT CATALYZE HYDROLYSIS OF ESTER PRODRUGS AND OTHER MOLECULES
34.3 METHODOLOGY AND APPROACHES
34.3.1 Common Precautions
34.3.2 Stability Assessment of Prodrugs and/or Other Esterase Labile Compounds
34.3.3 Evaluation and Optimization of Stabilization Measures
34.3.4 Confirmation of Effectiveness of Stabilization Measures in Method Validation and Sample Analysis
34.3.5 Use of DBS for Stabilization of Ester Prodrugs and Other Enzyme Labile Compounds
34.3.6 Representative Examples
34.4 SUMMARY
34.5 A REPRESENTATIVE PROTOCOL-LC-MS BIOANALYSIS OF BMS-068645 AND ITS ACID METABOLITE IN HUMAN PLASMA
REFERENCES
35 LC-MS BIOANALYSIS OF ACYL GLUCURONIDES
35.1 INTRODUCTION
35.2 CHEMICAL REACTIVITY AND BIOANALYTICAL IMPLICATIONS
35.3 SAMPLE COLLECTION AND STORAGE
35.4 SAMPLE PREPARATION
35.5 LC-MS/MS QUANTIFICATION
35.5.1 Direct Analysis of AG
35.5.2 In-source Fragmentation
35.5.3 Quantification of AG in the Absence of a Reference Standard (Indirect Quantification)
35.6 INCURRED SAMPLE REANALYSIS OF AGs
35.7 SUMMARY
35.8 REPRESENTATIVE PROTOCOLS
REFERENCES
36 REGULATED BIOASSAY OF N-OXIDE METABOLITES USING LC-MS: DEALING WITH POTENTIAL INSTABILITY ISSUES
36.1 INTRODUCTION
36.2 FORMATION OF N-OXIDE METABOLITES
36.3 DISTRIBUTION AND EXCRETION OF N-OXIDES
36.4 METABOLISM OF N-OXIDES
36.5 BIOLOGICAL ACTIVITIES OF N-OXIDES
36.6 EXPERIMENTAL PROTOCOL
36.6.1 Sample Collection
36.6.2 Sample Preparation
36.6.3 Extraction
36.6.4 Chromatographic Separation
36.6.5 MS/MS Analysis
36.7 REGULATORY CONSIDERATIONS
36.8 EXAMPLES
36.8.1 Nicotine and Metabolites Including N-Oxides
36.8.2 Clozapine and Metabolites
36.8.3 Propiverine and Its N-Oxide Metabolite
36.8.4 Other Basic Drugs and Their Metabolites
36.9 CONCLUSIONS
REFERENCES
37 HYDROLYSIS OF PHASE II CONJUGATES FOR LC-MS BIOANALYSIS OF TOTAL PARENT DRUGS
37.1 INTRODUCTION
37.2 METHODS AND APPROACHES
37.2.1 Principles and Methodology
37.2.2 Method Optimization
37.3 EXAMPLE PROTOCOL
REFERENCES
38 LC-MS BIOANALYSIS OF REACTIVE COMPOUNDS
38.1 INTRODUCTION
38.2 DETERMINATION OF REACTIVE COMPOUND EXPOSURE IN VIVO
38.2.1 Determination of Adduct Formation from Genotoxic Compounds with Macromolecules
38.2.2 Determination of Free Reactive Compounds in Biological Matrices
38.3 MEASUREMENT OF SULFHYDRYLCONTAINING COMPOUNDS
38.4 CONCLUSION
38.5 REPRESENTATIVE PROTOCOLS
REFERENCES
39 LC-MS BIOANALYSIS OF PHOTOSENSITIVE AND OXIDATIVELY LABILE COMPOUNDS
39.1 INTRODUCTION
39.2 PHOTOSENSITIVE COMPOUNDS
39.2.1 Background
39.2.2 Photochemical Processes
39.2.3 Preventive Care and Handling of Photosensitive Compounds
39.2.4 Bioanalytical Consequences of Photosensitive Compounds
39.3 OXIDATION OF COMPOUNDS
39.3.1 Background
39.3.2 Oxidation Process
39.3.3 Preventive Care and Handling of Oxidatively Labile Compounds
39.3.4 Bioanalytical Consequences of Oxidatively Labile Compounds
39.4 SUMMARY
39.5 PROTOCOL FOR DEVELOPING LC-MS/MS METHOD FOR BIOANALYSIS OF PHOTOSENSITIVE AND OXIDATIVELY LABILE COMPOUNDS
REFERENCES
40 LC-MS BIOANALYSIS OF INTERCONVERTIBLE COMPOUNDS
40.1 INTRODUCTION
40.2 INTERCONVERSION OF LACTONES AND HYDROXY ACIDS
40.2.1 Background
40.2.2 Statin Drugs
40.2.3 Camptothecin Drugs
40.2.4 Other Lactone Drugs
40.3 STEREOISOMERIC INTERCONVERSION
40.3.1 Background
40.3.2 Interconversion
40.3.3 Bioanalytical Consequences
40.4 CONSIDERATIONS FOR DEVELOPING BIOANALYTICAL METHODS FOR INTERCONVERTIBLE COMPOUNDS
40.5 VALIDATION AND QUALITY CONTROL OF METHODS FOR INTERCONVERTIBLE COMPOUNDS
40.6 SUMMARY
40.7 REPRESENTATIVE PROTOCOL FOR LC-MS/MS METHOD DEVELOPMENT FOR BIOANALYSIS OF INTERCONVERTIBLE COMPOUNDS
REFERENCES
41 LC-MS BIOANALYSIS OF CHIRAL COMPOUNDS
41.1 INTRODUCTION
41.2 APPLICATIONS
41.2.1 Chiral Derivatization
41.2.2 Direct Separation
41.2.3 Cyclodextrins Stationary Phase-Based Chiral LC-MS/MS Bioanalysis
41.2.4 Chirobiotic Stationary Phase-Based Chiral LC-MS/MS Bioanalysis
41.2.5 Protein Stationary Phase-Based Chiral LC-MS/MS Bioanalysis
41.2.6 Polysaccharide Stationary Phase-Based Chiral LC-MS/MS Bioanalysis
41.2.7 Two-Dimensional Enantioselective LC-MS/MS Bioanalysis
41.2.8 Chiral Supercritical Fluid Chromatography-MS/MS for Bioanalysis
41.3 CURRENT CONSIDERATIONS AND PROTOCOLS IN DEVELOPING A ROBUST CHIRAL LC-MS/MS BIOANALYTICAL METHOD
41.3.1 Define Project Purpose
41.3.2 Establish Chiral Chromatographic Separation
41.3.3 Selection of Internal Standard
41.3.4 Sample Extraction
41.4 CURRENT METHOD VALIDATION CONSIDERATIONS AND PROTOCOLS FOR CHIRAL BIOANALYTICAL LC-MS/MS
41.4.1 Reference Standards
41.4.2 Stability
41.4.3 Accuracy, Precision, Linearity, and Sensitivity
41.4.4 Selectivity, Specificity, Recovery, and Matrix Effect
41.4.5 Incurred Sample Reanalysis
41.5 CONCLUSION
REFERENCES
42 LC-MS BIOANALYSIS OF PEPTIDES AND POLYPEPTIDES
42.1 INTRODUCTION
42.2 METHODS AND APPROACHES
42.2.1 Peptide Characteristics and Peptide Handling
42.2.2 Methods for MS Detection
42.2.3 Methods for LC Separation
42.2.4 Biological Sample Preparation
42.3 EXAMPLE EXPERIMENTAL PROTOCOLS
42.4 CONCLUSIONS
ACKNOWLEDGMENTS
REFERENCES
43 LC-MS BIOANALYSIS OF NUCLEOSIDES
43.1 INTRODUCTION
43.2 METHODS AND APPROACHES
43.2.1 Principles and Methodology
43.2.2 Troubleshooting
REFERENCES
44 LC-MS BIOANALYSIS OF NUCLEOTIDES
44.1 INTRODUCTION
44.2 PREANALYTICAL METHODS AND APPROACHES
44.2.1 Matrix Used for the Determination of Nucleotides
44.2.2 Extraction from Cell Matrix
44.2.3 Preparation of Calibration Standard Standards and QCs and Use of Internal Standard
44.2.4 Expression of Nucleotide Concentrations
44.2.5 LC-MS/MS
44.3 TROUBLESHOOTING
REFERENCES
45 LC-MS BIOANALYSIS OF STEROIDS
45.1 INTRODUCTION
45.2 METHODS AND APPROACHES
45.2.1 Calibration Standards and Quality Control Samples
45.2.2 Internal Standards
45.2.3 Sensitivity Enhancement via Derivatization
45.2.4 Extraction for LC-MS Analysis
45.2.5 Hydrolysis of Steroid Phase II Conjugates
45.2.6 LC-MS
45.2.7 Major Challenges of LC-MS Assays for Steroid Hormones
45.3 REPRESENTATIVE PROTOCOLS OF LC-MS BIOANALYSIS OF STEROID HORMONES
45.3.1 Estrogens
45.3.2 Androgen
45.3.3 Pregnane Derivatives
ACKNOWLEDGMENTS
REFERENCES
46 LC-MS BIOANALYSIS OF LIPOSOMAL DRUGS AND LIPIDS
46.1 INTRODUCTION
46.2 METHODS AND APPROACHES
46.2.1 Principles
46.2.2 Methodology
46.3 PROTOCOLS
46.3.1 Quantitative Determination of Free Doxorubicin and Doxorubicinol in Human Plasma Using LC-MS/MS (Figures 46.1, 46.2, and 46.3)
46.3.2 Quantitative Determination of Total Doxorubicin in Human Plasma Using LC-MS/MS
46.3.4 Quantitative Determination of Pegylated Lipids in Human Plasma Using LC-MS/MS
REFERENCES
47 LC-MS BIOANALYSIS OF PROTEINS
47.1 INTRODUCTION
47.2 METHODS
47.2.1 Selection of Signal Peptide(s)
47.2.2 Internal Standard
47.2.3 Sample Enrichment
47.2.4 Sample Protein Digest
47.2.5 Sample Digest Cleanup
47.2.6 LC-MS/MS
47.3 SUMMARY
REFERENCES
48 LC-MS BIOANALYSIS OF OLIGONUCLEOTIDES
48.1 INTRODUCTION
48.2 PHYSIOCHEMICAL PROPERTIES AND MODIFICATIONS OF OLIGONUCLEOTIDES
48.2.1 Physiochemical Properties of Oligonucleotides
48.2.2 Modifications
48.3 METHODS AND APPROACHES
48.3.1 Sample Preparation
48.3.2 Chromatography
48.3.3 Tandem Mass Spectrometry of Oligonucleotides
48.3.4 LC-MS/MS
48.4 PROTOCOLS
48.4.1 Antisense DNA
48.4.2 Small Interfering RNA and Micro RNA
48.4.3 Transfer and Ribosomal RNA
48.5 TROUBLESHOOTING OLIGONUCLEOTIDE LC-MS BIOANALYSIS
48.5.1 Ion-Pair Selection
48.5.2 Solvent and Buffer Compatibility
48.5.3 Stability and Storage
48.5.4 Ion Suppression
48.6 SUMMARY
REFERENCES
49 LC-MS BIOANALYSIS OF PLATINUM DRUGS
49.1 INTRODUCTION
49.2 METHODS AND APPROACHES
49.2.1 Principles
49.2.2 Methodology
49.3 TROUBLESHOOTING
REFERENCES
50 MICROFLOW LC-MS FOR QUANTITATIVE ANALYSIS OF DRUGS IN SUPPORT OF MICROSAMPLING
50.1 INTRODUCTION
50.2 METHODS AND APPROACHES
50.2.1 Principles of Microsampling in Mice
50.2.2 Principles of Microbore LC-MS/MS
50.3 PROTOCOLS
50.3.1 Study Design, Plasma Sample Collection, and Microbore LC-MS/MS Analysis After Oral Dosing of PF-A in Solution and Suspension in Mice
50.4 TROUBLESHOOTING
ACKNOWLEDGMENTS
REFERENCES
51 QUANTIFICATION OF ENDOGENOUS ANALYTES IN BIOFLUIDS BY A COMBINATION OF LC-MS AND CONSTRUCTION OF CALIBRATION CURVES USING STABLE-ISOTOPES AS SURROGATE ANALYTES WITH TRUE BIOLOGICAL CONTROL MATRICES
51.1 INTRODUCTION
51.2 METHODS AND APPROACHES
51.2.1 Principles of "Surrogate Analyte" Approach
51.2.2 General Applications
51.2.3 Methodology
REFERENCES
APPENDIX 1 BODY AND ORGAN WEIGHTS AND PHYSIOLOGICAL PARAMETERS IN LABORATORY ANIMALS AND HUMANS
APPENDIX 2 ANTICOAGULANTS COMMONLY USED IN BLOOD SAMPLE COLLECTION
APPENDIX 3 SOLVENTS AND REAGENTS COMMONLY USED IN LC-MS BIOANALYSIS
APPENDIX 4 GLOSSARY OF TERMS USED IN LC-MS BIOANALYSIS
INDEX

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