BASIC PHARMACOKINETICS

Transcription

1 BASIC PHARMACOKINETICS MOHSEN A. HEDAYA CRC Press Taylor & Francis Croup Boca Raton London New York CRC Press is an imprint of the Taylor & Francis Group, an informa business

2 Table of Contents Chapter 1 Introduction to Biopharmaceutics and Pharmacokinetics Introduction Application of Biopharmaceutic and Pharmacokinetic Principles in Biomedical Fields Drug Formulation Design Drug Dosage Form Design Pharmacological Testing Toxicological Testing Evaluation of Organ Function Dosing Regimen Design Drug Concentration-Time Profile Linear and Nonlinear Pharmacokinetics Linear Pharmacokinetics Nonlinear Pharmacokinetics Pharmacokinetic Modeling Compartmental Modeling Physiological Modeling Noncompartmental Approach Pharmacokinetic Simulation 5 Questions 5 Chapter 2 Drug Pharmacokinetics Following Single Intravenous Administration Introduction Elimination Rate Constant Rate of Drug Elimination Rate Constant for Drug Elimination Order of Drug Elimination Zero-Order Elimination First-Order Elimination Determination of the First-Order Elimination Rate Constant k Mathematical Expressions That Describe the Amount of the Drug in the Body When Elimination Process Follows First-Order Elimination Clinical Importance of the Elimination Rate Constant Summary 16

3 2.3 Volume of Distribution Relationship between the Drug Amount in the Body and Drug Blood Concentration Drug Protein Binding and Volume of Distribution Determination of Volume of Distribution Clinical Importance of Volume of Distribution Summary Half-Life Half-Life during Zero-Order and First-Order Elimination Zero-Order Elimination First-Order Elimination Graphical Determination of Half-Life Clinical Importance of Half-Life Summary Total Body Clearance Relationship between Total Body Clearance, Volume of Distribution, and the Elimination Rate Constant Determination of Total Body Clearance Total Body Clearance and Volume of Distribution Are Independent Pharmacokinetic Parameters Clinical Importance of Total Body Clearance Summary Area Under the Curve Factors Affecting Area Under the Curve after a Single IV Bolus Dose Calculation of Area Under the Curve after a Single IV Bolus Dose Clinical Importance of Area Under the Curve Factors Affecting the Drug Blood Concentration-Time Profile after a Single IV Bolus Dose Dose Volume of Distribution Total Body Clearance 31 Practice Problems 31 Chapter 3 Drug Absorption Following Oral Administration: Biopharmaceutical Considerations Introduction Physiological Factors Affecting Oral Drug Absorption Nature of the GIT Membrane Passive Diffusion Carrier-Mediated Transport Paracellular Other Mechanisms Gastrointestinal Physiology 39

4 Buccal Cavity Esophagus Stomach Small Intestine Large Intestine Rectum Effect of Food on Drug Absorption Pathological Conditions Affecting Drug Absorption Physical Factors Affecting Oral Drug Absorption Drug Physicochemical Properties Drug Lipid Solubility ph Partition Theory Dissolution of the Drug Surface Area Diffusion Coefficient Thickness of the Unstirred Layer Drug Solubility Dosage Form Characteristics Types of Oral Dosage Forms Solutions Suspensions Capsules Tablets Coated Tablets Sustained-Release Tablets In Vitro Disintegration Test In Vitro Dissolution Test Rotating Basket Paddle Method Other Methods Dissolution Requirements Correlation of In Vitro Drug Dissolution with In Vivo Drug Absorption 49 Questions 50 Chapter 4 Drug Pharmacokinetics Following Single Oral Drug Administration: Rate of Drug Absorption Introduction Drug Absorption after Oral Administration Plasma Concentration-Time Profile after a Single Oral Dose Determination of Absorption Rate Constant Method of Residuals Lag Time Flip Flop of k a and k Wagner-Nelson Method 60

5 4.5 Clinical Importance of Absorption Rate Constant Summary 63 Practice Problems 64 Chapter 5 Drug Pharmacokinetics Following Single Oral Drug Administration: Extent of Drug Absorption Introduction General Definitions Purpose of Bioavailability and Bioequivalence Studies Causes for Variation in Drug Bioavailability Factors Related to Drug Formulation and Route of Administration Route of Administration Dosage Form Excipient Factors Related to the Drug Drug Solubility Drug Partition Coefficient Stability and Drug Interaction Factors Related to the Patient Individual Variability Site of Administration Diseases First-Pass Effect Pharmacokinetic Basis of Drug Bioavailability and Bioequivalence Determination of Drug Bioavailability Expected Values for Drug Bioavailability Clinical Importance of Bioavailability and Bioequivalence Calculation of Area under the Curve (Linear Trapezoidal Rule) Regulatory Requirements for Bioavailability and Bioequivalence Design and Evaluation of Bioequivalence Studies Criteria for Waiver of Bioavailability Requirements Factors Affecting the Blood Concentration-Time Profile after a Single Oral Dose Dose Bioavailability Total Body Clearance Volume of Distribution Absorption Rate Constant 82 Practice Problems 82

6 Chapter 6 Steady-State Principle and Drug Pharmacokinetics during Constant-Rate Intravenous Infusion Introduction Plasma Concentration during Continuous Constant-Rate IV Drug Administration Time Required to Reach Steady State Loading Dose Determination of the Pharmacokinetic Parameters Total Body Clearance Elimination Rate Constant Volume of Distribution Effect of Changing the Pharmacokinetic Parameters on Steady-State Plasma Concentration during Constant-Rate IV Infusion Infusion Rate Volume of Distribution Total Body Clearance 94 Practice Problems 95 Chapter 7 Steady State during Multiple Drug Administrations Introduction Drug Plasma Concentration-Time Profile during Multiple Drug Administrations Average Plasma Concentration at Steady State Time Required to Reach Steady State Loading Dose Intravenous Drug Administration Extravascular Drug Administration Drug Accumulation Controlled-Release Formulations Effect of Changing the Pharmacokinetic Parameters on Steady-State Plasma Concentration during Repeated Drug Administration Dosing Rate Total Body Clearance Volume of Distribution Absorption Rate Constant Dosage Regimen Design Factors to Be Considered Therapeutic Range of the Drug Required Onset of Effect Drug Formulation Patient Disease State 108

7 7.9.2 Estimation of Patient Pharmacokinetic Parameters Lack of the Patient's Medical History Information Available about the Patient's Medical History Patient with History of Using the Drug Selection of Dose and Dosing Interval Controlled-Release Oral Formulation Fast-Release Oral Formulations and IV Bolus Administration Selection of Loading Dose 110 Practice Problems 111 Chapter 8 Renal Drug Elimination Introduction Mechanisms of Renal Excretion of Drugs Glomerular Filtration Tubular Secretion Tubular Reabsorption Determination of Renal Excretion Rate Experimental Determination of Renal Excretion Rate Renal Excretion Rate-Time Profile Renal Clearance Creatinine Clearance as a Measure of Kidney Function Cumulative Amount of the Drug Excreted in Urine Determination of Renal Clearance from the Cumulative Amount Excreted in Urine Determination of Pharmacokinetic Parameters from Renal Excretion Rate Data Elimination Rate Constant and Half-Life (k and t ]/2 ) Renal Excretion Rate Constant k e Volume of Distribution Vd Renal Clearance CL R Fraction of Dose Excreted Unchanged in Urine Bioavailability Effect of Changing the Pharmacokinetic Parameters on Urinary Excretion of Drugs Dose Total Body Clearance Renal Clearance 127 Practice Problems 128 Chapter 9 Metabolite Pharmacokinetics Introduction Simple Model for Metabolite Kinetics 133

8 9.2.1 Elimination Rate Limitation Formation Rate Limitation Mathematical Description of Elimination Rateand Formation Rate-Limited Metabolites Time to Achieve Maximum Metabolite Concentration General Model for Metabolite Kinetics Estimation of Metabolite Pharmacokinetic Parameters Metabolite Elimination Rate Constant Elimination Rate-Limited Metabolites Formation Rate-Limited Metabolites Fraction of the Parent Drug Converted to a Specific Metabolite (or Amount of Metabolite Formed) Metabolite Clearance Metabolite Volume of Distribution Metabolite Formation Clearance Effect of Changing the Pharmacokinetic Parameters on Drug and Metabolite Concentration-Time Profiles after a Single IV Drug Administration Drug Dose Drug Total Body Clearance CLp Drug Volume of Distribution Vd Fraction of Drug Dose Converted to Metabolite f m Metabolite Total Body Clearance CL^, Metabolite Volume of Distribution Vd (m, Steady-State Metabolite Concentration during Repeated Administrations of Parent Drug Effect of Changing the Pharmacokinetic Parameters on the Steady-State Drug and Metabolite Concentrations during Repeated Drug Administrations Drug Dose Drug Total Body Clearance CI^ Drug Volume of Distribution Vd Fraction of Drug Dose Converted to Metabolite f m Metabolite Total Body Clearance CL^,, Metabolite Volume of Distribution Vd, m, Metabolite Kinetics after Extravascular Administration of the Parent Drug Kinetics of Sequential Metabolism 152 Practice Problems 153 Chapter 10 Disease State and Drug Pharmacokinetics Introduction Patients with Kidney Dysfunction 159

9 Factors Affecting the Change in Drug Pharmacokinetics in Patients with Kidney Dysfunction Fraction of Dose Excreted Unchanged in Urine Degree of Kidney Dysfunction Dosage Adjustment in Patients with Renal Dysfunction Determination of Kidney Function Determination of the Fraction of Dose Excreted Unchanged in Urine Determination of Dosage Requirements in Patients with Reduced Kidney Function Patients with Liver Diseases Child-Pugh Score 164 Practice Problems 165 Chapter 11 Nonlinear Pharmacokinetics Introduction Causes of Nonlinear Pharmacokinetics Saturable Drug Absorption Saturable Protein Binding Saturable Renal Elimination Saturable Drug Metabolism Others Evidence of Nonlinear Pharmacokinetics Michaelis-Menten Enzyme Kinetics Pharmacokinetic Parameters Plasma Concentration-Time Profile after a Single Intravenous Dose of a Drug Eliminated by a Metabolic Pathway That Follows Michaelis-Menten Kinetics After a Single Drug Administration After Multiple Drug Administrations Determination of the Pharmacokinetic Parameters Total Body Clearance Half-Life Effect of Changing the Pharmacokinetic Parameters on Plasma Concentration-Time Profile Dose V max K m Oral Administration of Drugs Eliminated by a Michaelis-Menten Process Pharmacokinetic Parameter Determination and Dosage Recommendation Mathematical Method Direct Linear Plot Linear Transformation Method 180

10 11.7 Multiple Elimination Pathways 180 Practice Problems 181 Chapter 12 Multicompartment Pharmacokinetic Models Introduction Two-Compartment Pharmacokinetic Model Two-Compartment Pharmacokinetic Model Parameters Definition of the Pharmacokinetic Parameters Mathematical Equation That Describes the Plasma Concentration-Time Profile Determination of Two-Compartment Pharmacokinetic Model Parameters Method of Residuals Determination of Model Parameters Volume of Central Compartment V c Area under the Curve (AUC) Total Body Clearance CL[ First-Order Elimination Rate Constant from Central Compartment k First-Order Transfer Rate Constant from Peripheral Compartment to Central Compartment k First-Order Transfer Rate Constant from Central Compartment to Peripheral Compartment k, Volume of Distribution at Steady State Vd ss Volume of Distribution in Elimination Phase Vd g Effect of Changing the Pharmacokinetic Parameters on Drug Concentration-Time Profile after a Single IV Dose Dose Volume of Distribution Hybrid Distribution Rate Constant a Hybrid Elimination Rate Constant P Oral Administration of Drugs That Follow the Two-Compartment Pharmacokinetic Model Constant Rate IV Administration of Drugs That Follow the Two-Compartment Pharmacokinetic Model Multiple Drug Administrations Renal Excretion of Drugs That Follow the Two-Compartment Pharmacokinetic Model Effect of Changing the Pharmacokinetic Parameters on Drug Distribution between Central and Peripheral Compartments Dose First-Order Transfer Rate Constant from Central to Peripheral Compartment k, 200

11 First-Order Transfer Rate Constant from Peripheral to Central Compartment k First-Order Elimination Rate Constant from Central Compartment k Three-Compartment Pharmacokinetic Model 201 Practice Problems 202 Chapter 13 Drug Pharmacokinetics Following Administration by Intermittent Intravenous Infusion Introduction Drug Concentration-Time Profile during Intermittent IV Infusion After First Dose After Repeated Administration before Reaching Steady State At Steady State Effect of Changing the Pharmacokinetic Parameters on Steady-State Plasma Concentration during Repeated Intermittent IV Infusion Dose Infusion Time Total Body Clearance Volume of Distribution Application of Pharmacokinetic Principles for Intermittent IV Infusion to Therapeutic Use of Aminoglycoside Pharmacokinetic Characteristics Absorption Distribution Excretion Guidelines for Aminoglycoside Plasma Concentration Extended-Interval Aminoglycoside Dosing Regimen Individualization of Aminoglycoside Therapy Determination of Initial Dosing Regimen Based on Population Parameters Determination of Patient-Specific Pharmacokinetic Parameters If the Patient Is to Receive the First Aminoglycoside Dose If the Patient Received Aminoglycosides before but the Steady State Was Not Achieved If the Patient Received Aminoglycosides and Steady State Has Been Achieved Determination of the Dosing Regimen Based on the Patient's Specific Parameters 217

12 Selection of Dosing Interval x Selection of Dose Selection of Loading Dose 217 Practice Problems 221 Chapter 14 Noncompartmental Approach to Pharmacokinetic Data Analysis Introduction Noncompartmental Approach in Data Analysis Mean Residence Time Calculation of AUC and AUMC Area Under the Plasma Concentration-Time Curve Area Under the First Moment-Time Curve Mean Residence Time after Different Routes of Administration Mean Residence Time after Extravascular Administration The Mean Residence Time after Constant-Rate IV Infusion Other Pharmacokinetic Parameters That Can Be Determined Using the Noncompartmental Approach Determination of Mean Residence Time for Compartmental Models Practice Problems 235 Chapter 15 Physiological Approach to Hepatic Clearance Introduction Organ Clearance Hepatic Extraction Ratio Intrinsic Clearance (CL int ) Systemic Bioavailability Effect of Change in Intrinsic Clearance and Hepatic Blood Flow on Hepatic Clearance, Systemic Availability, and Drug Concentration-Time Profile Low Extraction Ratio Drugs High Extraction Ratio Drugs Protein Binding and Hepatic Extraction 250 Practice Problems 250 Chapter 16 Pharmacokinetic-Pharmacodynamic Relationship Introduction Pharmacodynamic Models Fixed-Effect Model Linear Model Log-Linear Model 256

13 E max Model Sigmoid E max Model Link between Pharmacokinetic and Pharmacodynamic Models Application of Pharmacodynamic Models Duration of Drug Effect Dosing Regimen 261 Practice Problems 261 Chapter 17 Therapeutic Drug Monitoring Introduction General Principles of Initiation and Management of Drug Therapy Drug Blood Concentration versus Drug Dose Therapeutic Range Variability in Drug Pharmacokinetics and Response Body Weight Age Pediatrics Geriatrics Drug-Drug Interactions Genetic Factors Pregnancy Diseases Other Factors Advantages of Therapeutic Drug Monitoring Facilitate Rapid Achievement of an Appropriate Dosing Regimen Evaluate Existing Dosing Regimen Prophylaxis against Toxicity Distinguish between Pharmacokinetic and Pharmacodynamic Causes of Therapeutic Failure Cost-Effectiveness Candidate Drugs For Therapeutic Drug Monitoring Drugs with Low Therapeutic Index Drugs with Great Variability in Their Pharmacokinetic Properties Drugs Used in Patients Who Are at High Risk of Toxicity Methods for Measuring Drug Blood Concentrations Establishing a Therapeutic Drug Monitoring Service Major Requirements Procedures Determination of Initial Dosing Regimen 271

14 Determination of the Patient's Specific Pharmacokinetic Parameters Calculation of Dosage Requirements Based on the Patient's Specific Pharmacokinetic Parameters of the Drug 272 Questions 272 Chapter 18 Solutions to Practice Problems 273 Index 285