SE Rosenbaum
John Wiley & Sons
e druk, 2017
9781119143154
Basic Pharmacokinetics and Pharmacodynamics – An Integrated Textbook and Computer Simulations, 2e
An Integrated Textbook and Computer Simulations
Specificaties
Paperback, 576 blz.
|
Engels
John Wiley & Sons |
e druk, 2017
ISBN13: 9781119143154
Rubricering
Verwachte levertijd ongeveer 9 werkdagen
Samenvatting
Updated with new chapters and topics, this book provides a comprehensive description of all essential topics in contemporary pharmacokinetics and pharmacodynamics. It also features interactive computer simulations for students to experiment and observe PK/PD models in action.
Presents the essentials of pharmacokinetics and pharmacodynamics in a clear and progressive manner
Helps students better appreciate important concepts and gain a greater understanding of the mechanism of action of drugs by reinforcing practical applications in both the book and the computer modules
Features interactive computer simulations, available online through a companion website at: http://www.uri.edu/pharmacy/faculty/rosenbaum/basicmodels.html
Adds new chapters on physiologically based pharmacokinetic models, predicting drug–drug interactions, and pharmacogenetics while also strengthening original chapters to better prepare students for more advanced applications
Reviews of the 1st edition: This is an ideal textbook for those starting out and also for use as a reference book ." (International Society for the Study of Xenobiotics) and I could recommend Rosenbaum s book for pharmacology students because it is written from a perspective of drug action . . . Overall, this is a well–written introduction to PK/PD . (British Toxicology Society Newsletter)
Specificaties
Inhoudsopgave
<p>Preface xix</p>
<p>Contributors xxi</p>
<p>1 Introduction to Pharmacokinetics and Pharmacodynamics 1<br />Sara E. Rosenbaum</p>
<p>1.1 Introduction: Drugs and Doses, 2</p>
<p>1.2 Introduction to Pharmacodynamics, 3</p>
<p>1.3 Introduction to Pharmacokinetics, 9</p>
<p>1.4 Dose Response Relationships, 12</p>
<p>1.5 Therapeutic Range, 14</p>
<p>1.6 Summary, 18</p>
<p>Reference, 18</p>
<p>2 Passage of Drugs Through Membranes 19<br />Sara E. Rosenbaum</p>
<p>2.1 Introduction, 20</p>
<p>2.2 Structure and Properties of Membranes, 20</p>
<p>2.3 Passive Diffusion, 21</p>
<p>2.4 Carrier–Mediated Processes: Transport Proteins, 26</p>
<p>References, 33</p>
<p>3 Drug Administration and Drug Absorption 35<br />Steven C. Sutton</p>
<p>3.1 Introduction: Local and Systemic Drug Administration, 36</p>
<p>3.2 Routes of Drug Administration, 37</p>
<p>3.3 Overview of Oral Absorption, 41</p>
<p>3.4 Extent of Drug Absorption, 44</p>
<p>3.5 Determinants of the Fraction of the Dose Absorbed (F), 46</p>
<p>3.6 Factors Controlling the Rate of Drug Absorption, 61</p>
<p>3.7 Biopharmaceutics Classification System, 64</p>
<p>3.8 Food Effects, 65</p>
<p>Problems, 66</p>
<p>References, 67</p>
<p>4 Drug Distribution 71<br />Sara E. Rosenbaum</p>
<p>4.1 Introduction, 72</p>
<p>4.2 Extent of Drug Distribution, 72</p>
<p>4.3 Rate of Drug Distribution, 89</p>
<p>4.4 Distribution of Drugs to the Central Nervous System, 93</p>
<p>Problems, 96</p>
<p>References, 98</p>
<p>5 Drug Elimination and Clearance 99<br />Sara E. Rosenbaum</p>
<p>5.1 Introduction, 100</p>
<p>5.2 Clearance, 102</p>
<p>5.3 Renal Clearance, 108</p>
<p>5.4 Hepatic Elimination and Clearance, 119</p>
<p>Problems, 139</p>
<p>References, 142</p>
<p>6 Compartmental Models in Pharmacokinetics 145<br />Sara E. Rosenbaum</p>
<p>6.1 Introduction, 146</p>
<p>6.2 Expressions for Component Parts of the Dose Plasma Concentration Relationship, 146</p>
<p>6.3 Putting Everything Together: Compartments and Models, 149</p>
<p>6.4 Examples of Complete Compartment Models, 152</p>
<p>6.5 Use of Compartmental Models to Study Metabolite Pharmacokinetics, 155</p>
<p>6.6 Selecting and Applying Models, 156</p>
<p>Problems, 157</p>
<p>Suggested Readings, 157</p>
<p>7 Pharmacokinetics of an Intravenous Bolus Injection in a One–Compartment Model 159<br />Sara E. Rosenbaum</p>
<p>7.1 Introduction, 160</p>
<p>7.2 One–Compartment Model, 160</p>
<p>7.3 Pharmacokinetic Equations, 162</p>
<p>7.4 Simulation Exercise, 163</p>
<p>7.5 Application of the Model, 165</p>
<p>7.6 Determination of Pharmacokinetic Parameters Experimentally, 168</p>
<p>7.7 Pharmacokinetic Analysis in Clinical Practice, 173</p>
<p>Problems, 174</p>
<p>Suggested Reading, 176</p>
<p>8 Pharmacokinetics of an Intravenous Bolus Injection in a Two–Compartment Model 177<br />Sara E. Rosenbaum</p>
<p>8.1 Introduction, 178</p>
<p>8.2 Tissue and Compartmental Distribution of a Drug, 179</p>
<p>8.3 Basic Equation, 181</p>
<p>8.4 Relationship Between Macro and Micro Rate Constants, 183</p>
<p>8.5 Primary Pharmacokinetic Parameters, 183</p>
<p>8.6 Simulation Exercise, 188</p>
<p>8.7 Determination of the Pharmacokinetic Parameters of the Two–Compartment Model, 191</p>
<p>8.8 Clinical Application of the Two–Compartment Model, 194</p>
<p>Problems, 197</p>
<p>Suggested Readings, 199</p>
<p>9 Pharmacokinetics of Extravascular Drug Administration 201<br />Dr. Steven C. Sutton</p>
<p>9.1 Introduction, 202</p>
<p>9.2 First–Order Absorption in a One–Compartment Model, 203</p>
<p>9.3 Modified Release and Gastric Retention Formulations, 214</p>
<p>9.4 Bioavailability, 215</p>
<p>9.5 In Vitro–In Vivo Correlation, 219</p>
<p>9.6 Simulation Exercise, 222</p>
<p>Problems, 223</p>
<p>References, 224</p>
<p>10 Introduction to Noncompartmental Analysis 225<br />Sara E. Rosenbaum</p>
<p>10.1 Introduction, 225</p>
<p>10.2 Mean Residence Time, 226</p>
<p>10.3 Determination of Other Important Pharmacokinetic Parameters, 229</p>
<p>10.4 Different Routes of Administration, 231</p>
<p>10.5 Application of Noncompartmental Analysis to Clinical Studies, 232</p>
<p>Problems, 234</p>
<p>11 Pharmacokinetics of Intravenous Infusion in a One–Compartment Model 237<br />Sara E. Rosenbaum</p>
<p>11.1 Introduction, 238</p>
<p>11.2 Model and Equations, 239</p>
<p>11.3 Steady–State Plasma Concentration, 242</p>
<p>11.4 Loading Dose, 246</p>
<p>11.5 Termination of Infusion, 248</p>
<p>11.6 Individualization of Dosing Regimens, 249</p>
<p>Problems, 252</p>
<p>12 Multiple Intravenous Bolus Injections in the One–Compartment Model 255<br />Sara E. Rosenbaum</p>
<p>12.1 Introduction, 256</p>
<p>12.2 Terms and Symbols Used in Multiple–Dosing Equations, 257</p>
<p>12.3 Monoexponential Decay During a Dosing Interval, 259</p>
<p>12.4 Basic Pharmacokinetic Equations for Multiple Doses, 260</p>
<p>12.5 Steady State, 262</p>
<p>12.6 Basic Formula Revisited, 270</p>
<p>12.7 Pharmacokinetic–Guided Dosing Regimen Design, 270</p>
<p>12.8 Simulation Exercise, 276</p>
<p>Problems, 277</p>
<p>Reference, 278</p>
<p>13 Multiple Intermittent Infusions 279<br />Sara E. Rosenbaum</p>
<p>13.1 Introduction, 279</p>
<p>13.2 Steady–State Equations for Multiple Intermittent Infusions, 281</p>
<p>13.3 Monoexponential Decay During a Dosing Interval: Determination of Peaks, Troughs, and Elimination Half–Life, 284</p>
<p>13.4 Determination of the Volume of Distribution, 286</p>
<p>13.5 Individualization of Dosing Regimens, 289</p>
<p>13.6 Simulation, 289</p>
<p>Problems, 290</p>
<p>14 Multiple Oral Doses 293<br />Sara E. Rosenbaum</p>
<p>14.1 Introduction, 293</p>
<p>14.2 Steady–State Equations, 294</p>
<p>14.3 Equations Used Clinically to Individualize Oral Doses, 298</p>
<p>14.4 Simulation Exercise, 300</p>
<p>References, 301</p>
<p>15 Nonlinear Pharmacokinetics 303<br />Sara E. Rosenbaum</p>
<p>15.1 Linear Pharmacokinetics, 304</p>
<p>15.2 Nonlinear Processes in Absorption, Distribution, Metabolism, and Elimination, 306</p>
<p>15.3 Pharmacokinetics of Capacity–Limited Metabolism, 307</p>
<p>15.4 Phenytoin, 310</p>
<p>Problems, 321</p>
<p>References, 322</p>
<p>16 Introduction to Pharmacogenetics 323<br />Dr. Daniel Brazeau</p>
<p>16.1 Introduction, 324</p>
<p>16.2 Genetics Primer, 324</p>
<p>16.3 Pharmacogenetics, 328</p>
<p>16.4 Genetics and Pharmacodynamics, 334</p>
<p>16.5 Summary, 335</p>
<p>Reference, 335</p>
<p>Suggested Readings, 335</p>
<p>17 Models Used to Predict Drug Drug Interactions for Orally Administered Drugs 337<br />Sara E. Rosenbaum</p>
<p>17.1 Introduction, 338</p>
<p>17.2 Mathematical Models for Inhibitors and Inducers of Drug Metabolism Based on In Vitro Data, 340</p>
<p>17.3 Surrogate In Vivo Values for the Unbound Concentration of the Perpetrator at the Site of Action, 345</p>
<p>17.4 Models Used to Predict DDIs In Vivo, 347</p>
<p>17.5 Predictive Models for Transporter–Based DDIs, 359</p>
<p>17.6 Application of Physiologically Based Pharmacokinetic Models to DDI Prediction: The Dynamic Approach, 362</p>
<p>17.7 Conclusion, 362</p>
<p>Problems, 363</p>
<p>References, 364</p>
<p>18 Introduction to Physiologically Based Pharmacokinetic Modeling 367<br />Sara E. Rosenbaum</p>
<p>18.1 Introduction, 368</p>
<p>18.2 Components of PBPK Models, 369</p>
<p>18.3 Equations for PBPK Models, 369</p>
<p>18.4 Building a PBPK Model, 373</p>
<p>18.5 Simulations, 377</p>
<p>18.6 Estimation of Human Drug–Specific Parameters, 378</p>
<p>18.7 More Detailed PBPK Models, 381</p>
<p>18.8 Application of PBPK Models, 387</p>
<p>References, 388</p>
<p>19 Introduction to Pharmacodynamic Models and Integrated Pharmacokinetic Pharmacodynamic Models 391<br />Drs. Diane Mould and Paul Hutson</p>
<p>19.1 Introduction, 392</p>
<p>19.2 Classic Pharmacodynamic Models Based on Receptor Theory, 393</p>
<p>19.3 Direct Effect Pharmacodynamic Models, 402</p>
<p>19.4 Integrated PK PD Models: Intravenous Bolus Injection in the One–Compartment Mode and the Sigmoidal Emax Model, 406</p>
<p>19.5 Pharmacodynamic Drug Drug Interactions, 410</p>
<p>Problems, 411</p>
<p>References, 412</p>
<p>20 Semimechanistic Pharmacokinetic Pharmacodynamic Models 413<br />Drs. Diane Mould and Paul Hutson</p>
<p>20.1 Introduction, 414</p>
<p>20.2 Hysteresis and the Effect Compartment, 416</p>
<p>20.3 Physiological Turnover Models and Their Characteristics, 419</p>
<p>20.4 Indirect Effect Models, 422</p>
<p>20.5 Other Indirect Effect Models, 432</p>
<p>20.6 Models of Tolerance, 442</p>
<p>20.7 Irreversible Drug Effects, 450</p>
<p>20.8 Disease Progression Models, 452</p>
<p>Problems, 459</p>
<p>References, 465</p>
<p>Appendix A Review of Exponents and Logarithms 469<br />Sara E. Rosenbaum</p>
<p>A.1 Exponents, 469</p>
<p>A.2 Logarithms: Log and Ln, 470</p>
<p>A.3 Performing Calculations in the Logarithmic Domain, 471</p>
<p>A.4 Calculations Using Exponential Expressions and Logarithms, 472</p>
<p>A.5 Decay Function: e kt, 474</p>
<p>A.6 Growth Function: 1 e kt, 475</p>
<p>A.7 Decay Function in Pharmacokinetics, 475</p>
<p>Problems, 476</p>
<p>Appendix B Rates of Processes 479<br />Sara E. Rosenbaum</p>
<p>B.1 Introduction, 479</p>
<p>B.2 Order of a Rate Process, 480</p>
<p>B.3 Zero–Order Processes, 480</p>
<p>B.4 First–Order Processes, 482</p>
<p>B.5 Comparison of Zero– and First–Order Processes, 484</p>
<p>B.6 Detailed Example of First–Order Decay in Pharmacokinetics, 484</p>
<p>B.7 Examples of the Application of First–Order Kinetics to Pharmacokinetics, 487</p>
<p>Appendix C Creation of Excel Worksheets for Pharmacokinetic Analysis 489<br />Sara E. Rosenbaum</p>
<p>C.1 Measurement of AUC and Clearance, 489</p>
<p>C.2 Analysis of Data from an Intravenous Bolus Injection in a One–Compartment Model, 494</p>
<p>C.3 Analysis of Data from an Intravenous Bolus Injection in a Two–Compartment Model, 496</p>
<p>C.4 Analysis of Oral Data in a One–Compartment Model, 498</p>
<p>C.5 Noncompartmental Analysis of Oral Data, 501</p>
<p>Appendix D Derivation of Equations for Multiple Intravenous Bolus Injections 505<br />Sara E. Rosenbaum</p>
<p>D.1 Assumptions, 505</p>
<p>D.2 Basic Equation for Plasma Concentration After Multiple Intravenous Bolus Injections, 505</p>
<p>D.3 Steady–State Equations, 508</p>
<p>Appendix E Enzyme Kinetics: Michaelis Menten Equation and Models for Inhibitors and Inducers of Drug Metabolism 509<br />Sara E. Rosenbaum and Roberta S. King</p>
<p>E.1 Kinetics of Drug Metabolism: The Michaelis Menten Model, 510</p>
<p>E.2 Effect of Perpetrators of DDI on Enzyme Kinetics and Intrinsic Clearance, 515</p>
<p>References, 526</p>
<p>Appendix F Summary of the Properties of the Fictitious Drugs Used in the Text 527<br />Sara E. Rosenbaum</p>
<p>Appendix G Computer Simulation Models 529<br />Sara E. Rosenbaum</p>
<p>Glossary of Terms 531</p>
<p>Index 537</p>
<p>Contributors xxi</p>
<p>1 Introduction to Pharmacokinetics and Pharmacodynamics 1<br />Sara E. Rosenbaum</p>
<p>1.1 Introduction: Drugs and Doses, 2</p>
<p>1.2 Introduction to Pharmacodynamics, 3</p>
<p>1.3 Introduction to Pharmacokinetics, 9</p>
<p>1.4 Dose Response Relationships, 12</p>
<p>1.5 Therapeutic Range, 14</p>
<p>1.6 Summary, 18</p>
<p>Reference, 18</p>
<p>2 Passage of Drugs Through Membranes 19<br />Sara E. Rosenbaum</p>
<p>2.1 Introduction, 20</p>
<p>2.2 Structure and Properties of Membranes, 20</p>
<p>2.3 Passive Diffusion, 21</p>
<p>2.4 Carrier–Mediated Processes: Transport Proteins, 26</p>
<p>References, 33</p>
<p>3 Drug Administration and Drug Absorption 35<br />Steven C. Sutton</p>
<p>3.1 Introduction: Local and Systemic Drug Administration, 36</p>
<p>3.2 Routes of Drug Administration, 37</p>
<p>3.3 Overview of Oral Absorption, 41</p>
<p>3.4 Extent of Drug Absorption, 44</p>
<p>3.5 Determinants of the Fraction of the Dose Absorbed (F), 46</p>
<p>3.6 Factors Controlling the Rate of Drug Absorption, 61</p>
<p>3.7 Biopharmaceutics Classification System, 64</p>
<p>3.8 Food Effects, 65</p>
<p>Problems, 66</p>
<p>References, 67</p>
<p>4 Drug Distribution 71<br />Sara E. Rosenbaum</p>
<p>4.1 Introduction, 72</p>
<p>4.2 Extent of Drug Distribution, 72</p>
<p>4.3 Rate of Drug Distribution, 89</p>
<p>4.4 Distribution of Drugs to the Central Nervous System, 93</p>
<p>Problems, 96</p>
<p>References, 98</p>
<p>5 Drug Elimination and Clearance 99<br />Sara E. Rosenbaum</p>
<p>5.1 Introduction, 100</p>
<p>5.2 Clearance, 102</p>
<p>5.3 Renal Clearance, 108</p>
<p>5.4 Hepatic Elimination and Clearance, 119</p>
<p>Problems, 139</p>
<p>References, 142</p>
<p>6 Compartmental Models in Pharmacokinetics 145<br />Sara E. Rosenbaum</p>
<p>6.1 Introduction, 146</p>
<p>6.2 Expressions for Component Parts of the Dose Plasma Concentration Relationship, 146</p>
<p>6.3 Putting Everything Together: Compartments and Models, 149</p>
<p>6.4 Examples of Complete Compartment Models, 152</p>
<p>6.5 Use of Compartmental Models to Study Metabolite Pharmacokinetics, 155</p>
<p>6.6 Selecting and Applying Models, 156</p>
<p>Problems, 157</p>
<p>Suggested Readings, 157</p>
<p>7 Pharmacokinetics of an Intravenous Bolus Injection in a One–Compartment Model 159<br />Sara E. Rosenbaum</p>
<p>7.1 Introduction, 160</p>
<p>7.2 One–Compartment Model, 160</p>
<p>7.3 Pharmacokinetic Equations, 162</p>
<p>7.4 Simulation Exercise, 163</p>
<p>7.5 Application of the Model, 165</p>
<p>7.6 Determination of Pharmacokinetic Parameters Experimentally, 168</p>
<p>7.7 Pharmacokinetic Analysis in Clinical Practice, 173</p>
<p>Problems, 174</p>
<p>Suggested Reading, 176</p>
<p>8 Pharmacokinetics of an Intravenous Bolus Injection in a Two–Compartment Model 177<br />Sara E. Rosenbaum</p>
<p>8.1 Introduction, 178</p>
<p>8.2 Tissue and Compartmental Distribution of a Drug, 179</p>
<p>8.3 Basic Equation, 181</p>
<p>8.4 Relationship Between Macro and Micro Rate Constants, 183</p>
<p>8.5 Primary Pharmacokinetic Parameters, 183</p>
<p>8.6 Simulation Exercise, 188</p>
<p>8.7 Determination of the Pharmacokinetic Parameters of the Two–Compartment Model, 191</p>
<p>8.8 Clinical Application of the Two–Compartment Model, 194</p>
<p>Problems, 197</p>
<p>Suggested Readings, 199</p>
<p>9 Pharmacokinetics of Extravascular Drug Administration 201<br />Dr. Steven C. Sutton</p>
<p>9.1 Introduction, 202</p>
<p>9.2 First–Order Absorption in a One–Compartment Model, 203</p>
<p>9.3 Modified Release and Gastric Retention Formulations, 214</p>
<p>9.4 Bioavailability, 215</p>
<p>9.5 In Vitro–In Vivo Correlation, 219</p>
<p>9.6 Simulation Exercise, 222</p>
<p>Problems, 223</p>
<p>References, 224</p>
<p>10 Introduction to Noncompartmental Analysis 225<br />Sara E. Rosenbaum</p>
<p>10.1 Introduction, 225</p>
<p>10.2 Mean Residence Time, 226</p>
<p>10.3 Determination of Other Important Pharmacokinetic Parameters, 229</p>
<p>10.4 Different Routes of Administration, 231</p>
<p>10.5 Application of Noncompartmental Analysis to Clinical Studies, 232</p>
<p>Problems, 234</p>
<p>11 Pharmacokinetics of Intravenous Infusion in a One–Compartment Model 237<br />Sara E. Rosenbaum</p>
<p>11.1 Introduction, 238</p>
<p>11.2 Model and Equations, 239</p>
<p>11.3 Steady–State Plasma Concentration, 242</p>
<p>11.4 Loading Dose, 246</p>
<p>11.5 Termination of Infusion, 248</p>
<p>11.6 Individualization of Dosing Regimens, 249</p>
<p>Problems, 252</p>
<p>12 Multiple Intravenous Bolus Injections in the One–Compartment Model 255<br />Sara E. Rosenbaum</p>
<p>12.1 Introduction, 256</p>
<p>12.2 Terms and Symbols Used in Multiple–Dosing Equations, 257</p>
<p>12.3 Monoexponential Decay During a Dosing Interval, 259</p>
<p>12.4 Basic Pharmacokinetic Equations for Multiple Doses, 260</p>
<p>12.5 Steady State, 262</p>
<p>12.6 Basic Formula Revisited, 270</p>
<p>12.7 Pharmacokinetic–Guided Dosing Regimen Design, 270</p>
<p>12.8 Simulation Exercise, 276</p>
<p>Problems, 277</p>
<p>Reference, 278</p>
<p>13 Multiple Intermittent Infusions 279<br />Sara E. Rosenbaum</p>
<p>13.1 Introduction, 279</p>
<p>13.2 Steady–State Equations for Multiple Intermittent Infusions, 281</p>
<p>13.3 Monoexponential Decay During a Dosing Interval: Determination of Peaks, Troughs, and Elimination Half–Life, 284</p>
<p>13.4 Determination of the Volume of Distribution, 286</p>
<p>13.5 Individualization of Dosing Regimens, 289</p>
<p>13.6 Simulation, 289</p>
<p>Problems, 290</p>
<p>14 Multiple Oral Doses 293<br />Sara E. Rosenbaum</p>
<p>14.1 Introduction, 293</p>
<p>14.2 Steady–State Equations, 294</p>
<p>14.3 Equations Used Clinically to Individualize Oral Doses, 298</p>
<p>14.4 Simulation Exercise, 300</p>
<p>References, 301</p>
<p>15 Nonlinear Pharmacokinetics 303<br />Sara E. Rosenbaum</p>
<p>15.1 Linear Pharmacokinetics, 304</p>
<p>15.2 Nonlinear Processes in Absorption, Distribution, Metabolism, and Elimination, 306</p>
<p>15.3 Pharmacokinetics of Capacity–Limited Metabolism, 307</p>
<p>15.4 Phenytoin, 310</p>
<p>Problems, 321</p>
<p>References, 322</p>
<p>16 Introduction to Pharmacogenetics 323<br />Dr. Daniel Brazeau</p>
<p>16.1 Introduction, 324</p>
<p>16.2 Genetics Primer, 324</p>
<p>16.3 Pharmacogenetics, 328</p>
<p>16.4 Genetics and Pharmacodynamics, 334</p>
<p>16.5 Summary, 335</p>
<p>Reference, 335</p>
<p>Suggested Readings, 335</p>
<p>17 Models Used to Predict Drug Drug Interactions for Orally Administered Drugs 337<br />Sara E. Rosenbaum</p>
<p>17.1 Introduction, 338</p>
<p>17.2 Mathematical Models for Inhibitors and Inducers of Drug Metabolism Based on In Vitro Data, 340</p>
<p>17.3 Surrogate In Vivo Values for the Unbound Concentration of the Perpetrator at the Site of Action, 345</p>
<p>17.4 Models Used to Predict DDIs In Vivo, 347</p>
<p>17.5 Predictive Models for Transporter–Based DDIs, 359</p>
<p>17.6 Application of Physiologically Based Pharmacokinetic Models to DDI Prediction: The Dynamic Approach, 362</p>
<p>17.7 Conclusion, 362</p>
<p>Problems, 363</p>
<p>References, 364</p>
<p>18 Introduction to Physiologically Based Pharmacokinetic Modeling 367<br />Sara E. Rosenbaum</p>
<p>18.1 Introduction, 368</p>
<p>18.2 Components of PBPK Models, 369</p>
<p>18.3 Equations for PBPK Models, 369</p>
<p>18.4 Building a PBPK Model, 373</p>
<p>18.5 Simulations, 377</p>
<p>18.6 Estimation of Human Drug–Specific Parameters, 378</p>
<p>18.7 More Detailed PBPK Models, 381</p>
<p>18.8 Application of PBPK Models, 387</p>
<p>References, 388</p>
<p>19 Introduction to Pharmacodynamic Models and Integrated Pharmacokinetic Pharmacodynamic Models 391<br />Drs. Diane Mould and Paul Hutson</p>
<p>19.1 Introduction, 392</p>
<p>19.2 Classic Pharmacodynamic Models Based on Receptor Theory, 393</p>
<p>19.3 Direct Effect Pharmacodynamic Models, 402</p>
<p>19.4 Integrated PK PD Models: Intravenous Bolus Injection in the One–Compartment Mode and the Sigmoidal Emax Model, 406</p>
<p>19.5 Pharmacodynamic Drug Drug Interactions, 410</p>
<p>Problems, 411</p>
<p>References, 412</p>
<p>20 Semimechanistic Pharmacokinetic Pharmacodynamic Models 413<br />Drs. Diane Mould and Paul Hutson</p>
<p>20.1 Introduction, 414</p>
<p>20.2 Hysteresis and the Effect Compartment, 416</p>
<p>20.3 Physiological Turnover Models and Their Characteristics, 419</p>
<p>20.4 Indirect Effect Models, 422</p>
<p>20.5 Other Indirect Effect Models, 432</p>
<p>20.6 Models of Tolerance, 442</p>
<p>20.7 Irreversible Drug Effects, 450</p>
<p>20.8 Disease Progression Models, 452</p>
<p>Problems, 459</p>
<p>References, 465</p>
<p>Appendix A Review of Exponents and Logarithms 469<br />Sara E. Rosenbaum</p>
<p>A.1 Exponents, 469</p>
<p>A.2 Logarithms: Log and Ln, 470</p>
<p>A.3 Performing Calculations in the Logarithmic Domain, 471</p>
<p>A.4 Calculations Using Exponential Expressions and Logarithms, 472</p>
<p>A.5 Decay Function: e kt, 474</p>
<p>A.6 Growth Function: 1 e kt, 475</p>
<p>A.7 Decay Function in Pharmacokinetics, 475</p>
<p>Problems, 476</p>
<p>Appendix B Rates of Processes 479<br />Sara E. Rosenbaum</p>
<p>B.1 Introduction, 479</p>
<p>B.2 Order of a Rate Process, 480</p>
<p>B.3 Zero–Order Processes, 480</p>
<p>B.4 First–Order Processes, 482</p>
<p>B.5 Comparison of Zero– and First–Order Processes, 484</p>
<p>B.6 Detailed Example of First–Order Decay in Pharmacokinetics, 484</p>
<p>B.7 Examples of the Application of First–Order Kinetics to Pharmacokinetics, 487</p>
<p>Appendix C Creation of Excel Worksheets for Pharmacokinetic Analysis 489<br />Sara E. Rosenbaum</p>
<p>C.1 Measurement of AUC and Clearance, 489</p>
<p>C.2 Analysis of Data from an Intravenous Bolus Injection in a One–Compartment Model, 494</p>
<p>C.3 Analysis of Data from an Intravenous Bolus Injection in a Two–Compartment Model, 496</p>
<p>C.4 Analysis of Oral Data in a One–Compartment Model, 498</p>
<p>C.5 Noncompartmental Analysis of Oral Data, 501</p>
<p>Appendix D Derivation of Equations for Multiple Intravenous Bolus Injections 505<br />Sara E. Rosenbaum</p>
<p>D.1 Assumptions, 505</p>
<p>D.2 Basic Equation for Plasma Concentration After Multiple Intravenous Bolus Injections, 505</p>
<p>D.3 Steady–State Equations, 508</p>
<p>Appendix E Enzyme Kinetics: Michaelis Menten Equation and Models for Inhibitors and Inducers of Drug Metabolism 509<br />Sara E. Rosenbaum and Roberta S. King</p>
<p>E.1 Kinetics of Drug Metabolism: The Michaelis Menten Model, 510</p>
<p>E.2 Effect of Perpetrators of DDI on Enzyme Kinetics and Intrinsic Clearance, 515</p>
<p>References, 526</p>
<p>Appendix F Summary of the Properties of the Fictitious Drugs Used in the Text 527<br />Sara E. Rosenbaum</p>
<p>Appendix G Computer Simulation Models 529<br />Sara E. Rosenbaum</p>
<p>Glossary of Terms 531</p>
<p>Index 537</p>
