Drug Targeting Organ-Specific Strategies

Contents XXV
12.8. Tissue Slices from Other Organs . . . . . . . . . . . . . . . . . . . . . . . . . 327
12.9 Summary and Future Possibilities . . . . . . . . . . . . . . . . . . . . . . . . . 327
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
13 Pharmacokinetic/Pharmacodynamic Modelling in Drug Targeting
Johannes H. Proost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
13.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
13.1.1 Drug Targeting and Effectiveness: The Role of Pharmacokinetics . . 333
13.1.2 Pro-drugs and Drug–Carrier Conjugates . . . . . . . . . . . . . . . . 334
13.1.3 Scope of this Chapter . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
13.2 Pharmacokinetics and Pharmacodynamics, Modelling, Simulation, and
Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
13.2.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
13.2.1.1 Pharmacokinetic Processes . . . . . . . . . . . . . . . . . . 335
13.2.1.2 Transport Mechanisms . . . . . . . . . . . . . . . . . . . . . 336
13.2.1.3 Perfusion and Permeability . . . . . . . . . . . . . . . . . . 336
13.2.1.4 Plasma Protein Binding and Tissue Binding . . . . . . . . . 337
13.2.2 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
13.2.3 Model and Modelling . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
13.2.4 Pharmacokinetic Models . . . . . . . . . . . . . . . . . . . . . . . . . 338
13.2.4.1 Compartmental Models . . . . . . . . . . . . . . . . . . . . 338
13.2.4.2 Physiologically-based Pharmacokinetic (PB-PK) Models . 340
13.2.4.3 Compartmental Models Versus Physiologically-based
Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
13.2.4.4 Principles of Modelling . . . . . . . . . . . . . . . . . . . . 343
13.2.5 Pharmacodynamic Models . . . . . . . . . . . . . . . . . . . . . . . . 344
13.2.5.1 Sigmoid E max Model . . . . . . . . . . . . . . . . . . . . . . 344
13.2.5.2 Growth/Kill Models . . . . . . . . . . . . . . . . . . . . . . 344
13.2.5.3 Empirical PK/PD Relationships . . . . . . . . . . . . . . . 345
13.2.6 Pharmacokinetic/Pharmacodynamic (PK/PD) Models . . . . . . . . 345
13.2.7 Simulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
13.2.8 Data Analysis by Modelling . . . . . . . . . . . . . . . . . . . . . . . 346
13.2.8.1 Model Building . . . . . . . . . . . . . . . . . . . . . . . . . 346
13.2.8.2 Defining the Objective Function . . . . . . . . . . . . . . . 347
13.2.8.3 Searching the Best-fitting Set of Parameters . . . . . . . . . 348
13.2.8.4 Identification of Model Parameters . . . . . . . . . . . . . . 348
13.2.8.5 Goodness-of-Fit . . . . . . . . . . . . . . . . . . . . . . . . . 349
13.2.8.6 Model Selection . . . . . . . . . . . . . . . . . . . . . . . . 350
13.3 Pharmacokinetic Models for Drug Targeting . . . . . . . . . . . . . . . . . . 351
13.3.1 Model of Stella and Himmelstein . . . . . . . . . . . . . . . . . . . . 351
13.3.1.1 Disposition of DC . . . . . . . . . . . . . . . . . . . . . . . 352
13.3.1.2 Delivery of the DC to the Target Site . . . . . . . . . . . . . 353