Basic Pharmacokinetics

This is the essential guide to the study of absorption, distribution, metabolism and elimination of drugs in the body. Pharmacokinetics and biopharmaceutics courses have been included in pharmacy curricula in the USA and Europe for several years. Pharmacokinetics is the study of absorption, distribution, metabolism and elimination of drugs in the body. Pharmacists must understand this to ensure appropriate drug regimen for patients. The scope and the intent of this textbook is to provide the reader with a basic intuitive understanding of the principles of pharmacokinetics and biopharmaceutics and how these principles, along with the equations presented in each chapter, can be applied to achieve successful drug therapy. The application of pharmacokinetics principles and equations are illustrated by providing the reader with data available in the literature. As pharmacokinetics is basically mathematical in nature, a chapter has been included to provide the reader with a basic review of the mathematical principles and graphing techniques necessary to understand pharmacokinetics. At the start of each chapter, important objectives are listed to accentuate and identify the key points of the chapter. When an important and clinically applicable equation appears in the text, a paragraph will follow explaining the significance and therapeutic applications of that equation. Additionally, this paragraph includes and explains relevant factors influencing parameters in an equation. When applicable, at the end of an important equation, a general profile illustrating the relationship between the two variables of an equation will be presented. This approach should make the subject matter much more accessible to the student. Each chapter concludes with related problem sets and problem solving exercises for the student to work through. This should enable the reader to become more adept at solving pharmacokinetic problems arising in drug therapy and understanding the applications and utility of equations in clinical pharmacokinetics and practice. As you can see from the contents, the book is organised into eighteen chapters, the first consists of mathematical principles necessary to understand pharmacokinetics and an overview of the subject matter. The remaining chapters are organised in an order which should be easy for the reader to follow. Clearance and other essential fundamental pharmacokinetic parameters are introduced early in the book as the student will need to apply these concepts in subsequent chapters. A uniform set of notation will be adopted throughout the textbook (a table of which will be at start of the book). Cover......Page 1 Table of Contents......Page 6 Preface......Page 14 About the authors......Page 16 1.1 Use of drugs in disease states......Page 18 1.2 Important definitions and descriptions......Page 19 1.3 Sites of drug administration......Page 21 1.4 Review of ADME processes......Page 23 1.5 Pharmacokinetic models......Page 24 1.6 Rate processes......Page 29 2.2 A brief history of pharmacokinetics......Page 34 2.4 Exponents and logarithms......Page 35 2.5 Variables, constants and parameters......Page 36 2.8 Slopes, rates and derivatives......Page 38 2.10 Construction of pharmacokinetic sketches (profiles)......Page 40 3.1 Introduction......Page 46 3.2 Useful pharmacokinetic parameters......Page 47 3.3 The apparent volume of distribution (V)......Page 49 3.4 The elimination half life (t1/2)......Page 53 3.5 The elimination rate constant (K or Kel)......Page 55 3.6 Plotting drug concentration versus time......Page 57 3.8 Intravenous bolus administration: monitoring drug in urine......Page 59 3.9 Use of urinary excretion data......Page 61 4.1 Introduction......Page 70 4.2 Clearance definitions......Page 72 4.4 Clearance: tank and faucet analogy......Page 73 4.5 Organ clearance......Page 75 4.6 Physiological approach to clearance......Page 76 4.8 Calculating renal clearance (Clr) and metabolic clearance (Clm)......Page 81 4.9 Determination of the area under the plasma concentration versus time curve: application of the trapezoidal rule......Page 82 4.10 Elimination mechanism......Page 84 4.11 Use of creatinine clearance to determine renal function......Page 85 Problem set 1......Page 94 5.1 Gastrointestinal tract......Page 104 5.2 Mechanism of drug absorption......Page 106 5.3 Factors affecting passive drug absorption......Page 109 5.4 pH--partition theory of drug absorption......Page 110 6.1 Introduction......Page 114 6.2 Drug remaining to be absorbed, or drug remaining at the site of administration......Page 116 6.3 Determination of elimination half life (t1/2) and elimination rate constant (K or Kel)......Page 118 6.4 Absorption rate constant (Ka)......Page 119 6.5 Lag time (t0)......Page 120 6.6 Some important comments on the absorption rate constant......Page 121 6.8 Time of maximum drug concentration, peak time (tmax)......Page 122 6.9 Maximum (peak) plasma concentration (Cp)max......Page 124 6.10 Some general comments......Page 126 6.11 Example for extravascular route of drug administration......Page 127 6.12 Flip-flop kinetics......Page 131 Problem set 2......Page 134 7.1 Introduction......Page 142 7.3 Types of bioavailability......Page 143 7.4 Bioequivalence......Page 146 7.6 The first-pass effect (presystemic clearance)......Page 147 7.7 Determination of the area under the plasma concentration--time curve and the cumulative amount of drug eliminated in urine......Page 148 7.8 Methods and criteria for bioavailability testing......Page 152 7.9 Characterizing drug absorption from plasma concentration versus time and urinary data following the administration of a drug via different extravascular routes and/or dosage forms......Page 160 7.11 Food and Drug Administration codes......Page 162 7.12 Fallacies on bioequivalence......Page 164 7.13 Evidence of generic bioinequivalence or of therapeutic inequivalence for certain formulations approved by the Food and Drug Administration......Page 165 Problem set 3......Page 166 8.2 Dissolution process......Page 176 8.3 Noyes--Whitney equation and drug dissolution......Page 177 8.4 Factors affecting the dissolution rate......Page 178 9.1 Introduction......Page 188 9.3 Suspension as a dosage form......Page 189 9.5 Tablet as a dosage form......Page 190 9.7 Formulation and processing factors......Page 192 9.8 Correlation of in vivo data with in vitro dissolution data......Page 195 10.1 Introduction......Page 202 10.2 Monitoring drug in the body or blood (plasma/serum)......Page 205 10.3 Sampling drug in body or blood during infusion......Page 206 10.4 Sampling blood following cessation of infusion......Page 220 10.5 Use of post-infusion plasma concentration data to obtain half life, elimination rate constant and the apparent volume of distribution......Page 221 10.6 Rowland and Tozer method......Page 225 Problem set 4......Page 228 11.1 Introduction......Page 238 11.2 Useful pharmacokinetic parameters in multiple dosing......Page 242 11.4 Concept of drug accumulation in the body (R)......Page 250 11.5 Determination of fluctuation (F): intravenous bolus administration......Page 253 11.7 Calculation of loading and maintenance doses......Page 256 11.8 Maximum and minimum drug concentration at steady state......Page 257 12.1 Introduction......Page 260 12.2 The peak time in multiple dosing to steady state (t0max)......Page 262 12.3 Maximum plasma concentration at steady state......Page 263 12.4 Minimum plasma concentration at steady state......Page 264 12.5 ‘‘Average’’ plasma concentration at steady state: extravascular route......Page 265 12.6 Determination of drug accumulation: extravascular route......Page 266 12.7 Calculation of fluctuation factor (F) for multiple extravascular dosing......Page 267 12.8 Number of doses required reaching a fraction of steady state: extravascular route......Page 268 12.9 Determination of loading and maintenance dose: extravascular route......Page 269 12.10 Interconversion between loading, maintenance, oral and intravenous bolus doses......Page 270 Problem set 5......Page 274 13.1 Introduction......Page 286 13.2 Intravenous bolus administration: two-compartment model......Page 289 13.3 Determination of the postdistribution rate constant (β) and the coefficient (B)......Page 293 13.4 Determination of the distribution rate constant (α) and the coefficient (A)......Page 294 13.5 Determination of micro rate constants: the inter-compartmental rate constants (K21 and K12) and the pure elimination rate constant (K10)......Page 295 13.6 Determination of volumes of distribution (V)......Page 297 13.8 General comments......Page 299 13.9 Example......Page 300 13.10 Futher calculations to perform and determine the answers......Page 303 Problem set 6......Page 304 14.1 Introduction......Page 306 14.2 Drug concentration guidelines......Page 308 14.3 Example: determination of a multiple intermittent infusion dosing regimen for an aminoglycoside antibiotic......Page 309 14.4 Dose to the patient from a multiple intermittent infusion......Page 310 14.5 Multiple intermittent infusion of a two-compartment drug: vancomycin ‘‘peak’’ at 1 h post-infusion......Page 311 14.6 Vancomycin dosing regimen problem......Page 312 14.7 Adjustment for early or late drug concentrations......Page 313 Problem set 7......Page 316 15.1 Introduction......Page 318 15.2 Capacity-limited metabolism......Page 321 15.3 Estimation of Michaelis-- Menten parameters (Vmax and Km)......Page 322 15.4 Relationship between the area under the plasma concentration versus time curve and the administered dose......Page 326 15.5 Time to reach a given fraction of steady state......Page 328 15.6 Example: calculation of parameters for phenytoin......Page 330 Problem set 8......Page 334 16.1 Introduction......Page 336 16.2 The effect of protein-binding interactions......Page 337 16.3 The effect of tissue-binding interactions......Page 344 16.4 Cytochrome P450-based drug interactions......Page 345 17.1 Introduction......Page 354 17.2 Generation of a pharmacokinetic-- pharmacodynamic (PKPD) equation......Page 355 17.3 Pharmacokinetic and pharmacodynamic drug interactions......Page 359 18.2 Proteins and peptides......Page 362 18.3 Monoclonal antibodies......Page 368 18.4 Oligonucleotides......Page 372 18.5 Vaccines (immunotherapy)......Page 373 18.6 Gene therapies......Page 374 A.1 Introduction......Page 378 A.2 Statistical moment theory......Page 379 A.3 Applications......Page 391 Glossary......Page 394 References......Page 400 Index......Page 408 This Is An Essential Guide To The Study Of Absorption, Distribution, Metabolism And Elimination Of Drugs In The Body. Introduction And Overview -- Mathematical Review -- Intravenous Bolus Administration (one-compartment Model) -- Clearance Concepts -- Drug Absorption From The Gastrointestinal Tract -- Extravascular Routes Of Drug Administration -- Bioavailability/bioequivalence -- Factors Affecting Drug Absorption: Physicochemical Factors -- Gastrointestinal Absorption: Role Of The Dosage Form -- Continous Intravenous Infusion (one-compartment Model) -- Multiple Dosing: Intravenous Bolus Administration -- Multiple Dosing: Extravascular Routes Of Drug Administration -- Two-compartment Model -- Multiple Intermittent Infusions -- Non-linear Pharmacokinetics -- Drug Interactions -- Pharmacokinetics And Pharmacodynamic Relationships -- Pharmacokinetics And Pharmacodynamics Of Biotechnology Drugs -- Appendix: Statistical Moment Theory In Pharmacokinetics. Sunil S. Jambhekar And Philip J. Breen. Includes Bibliographical References (p. 383-390) And Index. Basic Pharmacokinetics provides an understanding of the principles of pharmacokinetics and biopharmaceutics. It addresses clearly and concisely how these principles can be applied to achieve successful drug therapy. The application of principles and equations are illustrated with related problem sets and problem solving exercises. Novel features of this text include: the use of profiles (sketches of relationships among pharmacokinetic variables and parameters) to help the reader understand pharmacokinetics intuitively; a set of learning objectives provided at the beginning of each chapter; a c