A Short Guide to Clinical Pharmacokinetics

Foreword
Preface
Acknowledgements
Contents
Editors and Contributors
About the Editors
Contributors
Abbreviations
1: Introduction to Clinical Pharmacokinetics
	1.1	 Introduction
	1.2	 Overview of Clinical Pharmacokinetics (Leary and Williams 2016)
	1.3	 Pharmacokinetic Factors Determining Ideal Therapeutics
		One-Compartment Model
		Curves of Concentration Versus Time
			Zero-Order Elimination
			First-Order Elimination
		Drug Clearance (CL)
		Maintaining a Constant Steady-State Concentration (Cpss)
		Determination of CL
		Volume of Distribution (Vd)
		Vd and Clinical PK
		Half-Life (t1/2)
		Time-Course of Drug Elimination and Accumulation
			Correlation Between Vd, CL, and t1/2
		Oral Availability (F)
		Protein Binding (PB)
		pH and Pharmacokinetics
		Drug Absorption from the Stomach
		Drug Elimination in the Kidney
		Drug Delivery into Third Spaces
		Relationship Between Pharmacokinetics and Effect Kinetics
	1.4	 Pharmacokinetic Parameters
		Permeability
		Bioavailability (F)
		P-Glycoprotein (PGP)
		Volume of Distribution (Vd)
		Blood–Brain Barrier (BBB)
		Cytochrome P450 Enzyme
		Clearance Rate (CL)
		Half-Life (t1/2)
	1.5	 Conclusion
	References
2: Inhibition of Biliary Excretion
	2.1	 Introduction
	2.2	 Enterohepatic Circulation
	2.3	 Clinical Inferences
	2.4	 Mechanisms of Endogenous and Exogenous Compound Excretion into Bile
		ATP-Binding Cassette-Mediated Active Transport (ABC) Movers and Shakers
		Passive Diffusion
		Conjugation and Metabolism
		Bile Acid Transporters
		Enterohepatic Circulation
		Control by Nuclear Receptors
		Creation and Bile Excretion
			Formation of Bile
			Forming Canalicular Bile
				Canalicular Confluence and Bile Ductules
			Bile Excretion
			Regulation
	2.5	 How to Calculate In Vivo Biliary Clearances
		Bile Collection
		Bile Duct Cannulation
		Bile Flow Measurement
		Biliary Excretion Index
		Pharmacokinetic Modelling
	2.6	 Aspiration of Duodenal Fluids
		Procedure
			Patient Preparation
			Endoscopic Aspiration
			Collection of Fluid Samples
			Transport and Processing
		Indications
	2.7	 Techniques for Determining Biliary Excretion In Vivo
		Sandwich-Cultured Hepatocytes (SCH)
		Membrane Vesicle Transport Assays
		Membrane Vesicles Canalicular (CMV)
		Liver Slices
		Perfused Liver Preparations
	2.8	 Conclusion
	References
3: Pharmaceutical Drug Interactions
	3.1	 Introduction
	3.2	 Pharmacokinetic Drug–Drug Interactions
	3.3	 Methods for Preventing Drug–Drug Interactions (DDIs)
	3.4	 Present Situation and Prospects for the Future
	3.5	 Conclusion
	References
4: Therapeutic Drug Monitoring
	4.1	 Introduction
	4.2	 TDM Process
		Choosing to Ask for a Drug Level
		Biological Sample
		The Request
		Laboratory Evaluations
		Conveying Reports to the Laboratory
		Clinical Interpretation
	4.3	 Therapeutic Management
	4.4	 Measurement of Plasma Drug Concentration: TDM
		Monitoring Pharmacokinetic Variability
	4.5	 Termination of Treatment
	4.6	 Challenges and Limitations of Therapeutic Drug Monitoring
	4.7	 Interpretation of Therapeutic and Toxic Effects: TDM
	4.8	 Conclusion
	References
5: Effect of Renal and Hepatic Diseases on Pharmacokinetics
	5.1	 Introduction
	5.2	 Overview of Pharmacokinetics
	5.3	 The Role of the Kidney in Drug Treatment
	5.4	 Effect of Renal Disease on Drug Clearance
	5.5	 Altered Drug Metabolism in Renal Dysfunction
	5.6	 Delayed Excretion and Drug Accumulation
	5.7	 Considerations for Drug Dosage Adjustment
	5.8	 Risk of Drug Interactions
	5.9	 Monitoring Drug Therapy in Renal Patients
	5.10	 Dosage Guidelines in Renal Impairment Conditions
		Chronic Kidney Disease
		Dosage Alterations
		Antihypertensive Drug Dose Adjustment
		Antidiabetic Drugs
		Aminoglycosides
		Analgesics
		Nonsteroidal Anti-Inflammatory Drugs
	5.11	 Renal Failure’s Impact on Drug Kinetics
		Absorption
		Distribution
		Elimination
		Drug Metabolism
	5.12	 Effect of Dialysis on Drug Pharmacokinetics
		Drug Dosing in Hepatic Failure Patients
		Hepatic Drug Clearance
		Absorption
		Plasma Protein Binding and Distribution
		Metabolism
		Biliary Excretion
	5.13	 Tests of Liver Function and Metabolic Indicators
	5.14	 Liver Dysfunction
		Pharmacotherapeutic Monitoring of Drugs
	5.15	 Conclusion
	References
6: Individualization of Drug Dosage
	6.1	 Introduction
	6.2	 Importance of Individualized Drug Dosage
		Maximizing Therapeutic Efficacy
		Minimizing Adverse Drug Reactions
		Tailoring Treatment to Patients’ Preferences and Needs
		Optimizing Healthcare Resource Utilization
	6.3	 Approaches to Individualization
		Pharmacogenomics
		Pharmacokinetic Modeling
		Therapeutic Drug Monitoring (TDM)
		Patient-Specific Factors
		Precision Dosing Algorithms
	6.4	 Considerations in Individualizing Drug Dosage
		Patient-Specific Factors
		Pharmacokinetic Parameters
		Pharmacogenomics
		Therapeutic Goals
		Patient Engagement
	6.5	 Role of Technology in Personalized Dosing
		Electronic Health Records (EHRs)
		Pharmacogenomics
		Clinical Decision Support Systems (CDSS)
		Wearable Devices and Remote Monitoring
		Precision Dosing Algorithms
	6.6	 Adjusting the Rate of the Maintenance Dose
		Adjusting the Maintenance Dose Based on Readily Available Patient Demographics
	6.7	 Regulatory and Ethical Considerations
		Regulatory Considerations
		Ethical Considerations
	6.8	 Challenges in Implementing Individualized Dosing
		Technological and Infrastructure Challenges
		Regulatory and Compliance Challenges
		Education and Training Challenges
		Cost and Reimbursement Challenges
		Implementation and Adoption Challenges
	6.9	 Patient Education and Engagement
	6.10	 Importance of Patient Education and Engagement
	6.11	 Challenges in Patient Education and Engagement
	6.12	 Strategies to Enhance Patient Education and Engagement
	6.13	 Continuous Feedback and Evaluation
	6.14	 Conclusion
	References
7: Correlation of Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics
	7.1	 Introduction
	7.2	 Pharmacokinetics
	7.3	 Pharmacodynamics: Mechanisms of Drug Action and Response
	7.4	 Pharmacogenomics: Genetic Variability and Drug Response
		Genetic Variability and Drug Response
		Mechanisms of Genetic Variability in Drug Response
	7.5	 Genetic Factors in Drug Metabolism
	7.6	 Clinical Implications of Pharmacogenomics
	7.7	 Future Directions in Pharmacogenomics Research
	7.8	 Interplay Between Pharmacokinetics and Pharmacodynamics
		Pharmacokinetics
		Pharmacodynamics
	7.9	 Interplay Between Pharmacokinetics and Pharmacodynamics
	7.10	 Clinical Applications and Future Directions
		Biomarker Discovery
	7.11	 Integration of Pharmacogenomics into Pharmacokinetic and Pharmacodynamic Models
		Pharmacogenomics
		Pharmacokinetic Modeling
		Integrating Pharmacogenomics into Pharmacokinetic Models
		Pharmacodynamic Modeling
		Integration of Pharmacogenomics into Pharmacodynamic Models
		Clinical Applications and Challenges
	7.12	 Future Directions
	7.13	 Clinical Applications and Implications of PK, PD, and PGx Correlation
		Clinical Applications
			Personalized Dosing Regimens
			Predictive Modeling and Simulation
		Pharmacovigilance and Post-Marketing Surveillance
			Therapeutic Monitoring and Adherence
		Clinical Implications
			Precision Medicine and Personalized Therapy
			Drug Development and Clinical Trials
			Healthcare Policy and Economic Considerations
		Challenges and Future Directions
			Data Integration and Standardization
			Clinical Implementation and Workflow Integration
			Ethical, Legal, and Social Implications
			Health Equity and Access to Care
	7.14	 Challenges and Future Directions in Studying PK/PD/PGx Correlations
		Data Integration and Standardization
		Sample Size and Statistical Power
		Complexity of Genetic Architecture
		Clinical Implementation and Translation
		Future Directions
			Extensive Joint Efforts
			Advanced Analytical Methods
			Multi-omic Integration
			Ethical, Legal, and Social Aspects
	7.15	 Case Studies and Examples Illustrating Correlations
		Case Study 1: Warfarin Dosing Optimization
		Case Study 2: Prediction of Response to Clopidogrel
		Example 1: Abacavir Hypersensitivity Testing
		Example 2: Tamoxifen Metabolism and Efficacy
	7.16	 Conclusion and Perspectives of Increasing Drug Efficacy and Safety Through Correlational Analysis
		Key Takeaways
		Perspectives
	7.17	 Conclusion
	References