Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations

Receptor Theory 86 3.3.3 PK/PD Models Accommodating Delayed Pharmacological Response 89 3.3.4 PK/PD Models Accommodating Functional Adaptation Leading to Nonlinearity in Pharmacological Response with Respect to Time 96 3.3.5 PK/Efficacy Modeling 97 3.3.6 Translation of PK/PD and PK/Efficacy Modeling to Human 100 3.3.7 Average, Minimum, and Maximum Steady-State Concentrations 104 3.3.8 Estimation of Biologically Effective Dose in Human 107 3.3.9 Therapeutic Window 109 3.3.10 Static Models for Drug Interactions 109 3.4 Physiologically Based Pharmacokinetic (PBPK) Modeling and Its Integration with Pharmacodynamics and Efficacy Models 112 3.4.1 PK Modeling Compartmental vs PBPK 112 3.4.2 PK Variability: Population PK (popPK) Modeling vs PBPK 114 3.4.3 Integration of PBPK with PD, Quantitative Systems Pharmacology (QSP) Models or Quantitative Systems Toxicologyand Safety (QSTS) 114 3.4.4 PBPK Models to Evaluate Drug-Drug Interactions 115 3.4.5 DDI Risk Assessment with PBPK vs Static Models 118 Keywords 123 References 125 4 Physiological Model For Absorption 129 4.1 Introduction 130 4.2 Drug Absorption and Gut Bioavailability 130 4.2.1 Solubility and Dissolution Rate 130 4.2.2 Permeability: Transcellular, Paracellular, and Carrier-Mediated Pathways 136 4.2.3 Barriers to Membrane Transport - Luminal Degradation, Efflux, and Gut Metabolism 138 4.3 Factors Affecting Drug Absorption and Gut Bioavailability 140 4.3.1 Physiological Factors Affecting Oral Drug Absorption and Species Differences in Physiology 140 4.3.2 Compound-Dependent Factors 144 4.3.3 Formulation-Dependent Factors 144 4.4 In Silico Predictions of Passive Permeability and Solubility 147 4.4.1 In Silico Models for Permeability 147 4.4.2 In Silico Models for Solubility 147 4.5 Measurement of Permeability, Solubility, Luminal Stability, Efflux, Intestinal Metabolism 148 4.5.1 In Vitro, In Situ, and In Vivo Models for Effective Permeability 148 4.5.2 Measurement of Thermodynamic or Equilibrium Solubility 153 4.5.3 Luminal Stability 154 4.5.4 Efflux 154 4.5.5 In Vitro Models for Gut Metabolism and Estimation of Fraction Escaping Gut Metabolism 155 4.6 Absorption Modeling 156 Keywords 162 References 163 5 Physiological Model For Distribution 169 5.1 Introduction 170 5.2 Factors Affecting Tissue Distribution of Xenobiotics 170 5.2.1 Physiological Factors and Species Differences in Physiology 171 5.2.2 Compound-Dependent Factors 176 5.3 In Silico Models of Tissue Partition Coefficients 176 5.4 Measurement of Parameters Representing the Rate and Extent of Tissue Distribution 181 5.4.1 Assessment of Rate and Extent of Brain Penetration 181 5.5 Physiological Model for Drug Distribution 186 5.6 Drug Concentrations at the Site of Action 187 Keywords 189 References 189 6 Physiological Models For Drug Metabolism And Excretion 193 6.1 Introduction 193 6.2 Factors Affecting Drug Metabolism and Excretion of Xenobiotics 194 6.3 Models for Hepatobiliary and Renal Excretion 197 6.3.1 In Silico Models 197 6.3.2 In Vitro Models for Hepatic Metabolism 197 6.3.3 In Vitro Models for Transporters 200 6.4 Physiological Models 203 6.4.1 Hepato-Biliary Elimination of Parent Drug and Metabolites 205 6.4.2 Renal Excretion 208 References 211 7 Generic Whole-Body Physiologically Based Pharmacokinetic Modeling 217 7.1 Introduction 217 7.2 Structure of a Generic Physiologically-Based Pharmacokinetic (PBPK) Model 218 7.3 Somatic Compartments 220 7.3.1 Lungs (LU) 220 7.3.2 Arterial Blood (ART) 220 7.3.3 Venous Blood (VEN) 220 7.3.4 Stomach (ST) 220 7.3.5 Gut (GU) 220 7.4 Model Assumptions 221 7.5 PBPK Software 221 References 223 8 Pbpk Modeling Of Biotherapeutics 225 8.1 Introduction 226 8.2 Therapeutic Proteins 226 8.2.1 Peptides and Proteins 226 8.2.2 Antibodies and Antibody-Based Therapies 227 8.3 Pharmacokinetics of Therapeutic Proteins 234 8.3.1 Absorption 234 8.3.2 Renal Elimination 235 8.3.3 Immunogenicity 235 8.3.4 PEGylation 239 8.3.5 Transport by Convective and Transcytotic Extravasation 239 8.3.6 Catabolic Elimination (Proteolysis) 239 8.3.7 FcRn-Mediated Protection of IgGs Against Catabolism in FcRn-Rich Cells 241 8.3.8 Distribution and lymphatic elimination 242 8.3.9 Target-Mediated Drug Disposition and Receptor-Mediated Endocytosis 243 8.4 PBPK Modeling of Monoclonal Antibodies 244 8.4.1 Full PBPK Model for Monoclonal Antibodies 244 8.4.2 Minimal PBPK Model for Monoclonal Antibodies 253 8.5 Applications of PBPK Modeling of Monoclonal Antibodies 253 8.5.1 Pharmacokinetic Scaling 253 8.5.2 PBPK Integration with Pharmacodynamics of Monoclonal Antibodies 255 Keywords 156 References 258 9 Uncertainty And Population Variability 263 9.1 Introduction 264 9.2 Distinguishing Uncertainty and Variability 264 9.3 Sources of Uncertainty in Drug-related Parameters 264 9.4 Sources of Variability in System Parameters 266 9.5 Handling Population Variability 269 9.5.1 A POSTERIORI and A PRIORI Approaches to Handling Population Variability 269 9.5.2 Correlations Between Parameters 271 9.6 Uncertainty and Sensitivity Analysis 272 9.6.1 Local Sensitivity Analysis (One-at-a-time (OAT) and Derivative-based Methods) 272 9.6.2 Parameter Interactions and Global Sensitivity Analysis (GSA) 275 9.6.3 Global Sensitivity Analysis for Correlated Parameters (cGSA) 278 9.6.4 Applications of Sensitivity Analysis for PBPK Models 280 9.6.5 Limitations of Global Sensitivity Analysis 281 9.7 Uncertainty and Population Variability in Clinical Efficacy and Safety 282 Keywords 285 References 285 10 Nonclinical, Clinical, and Model-Informed Drug Development 293 10.1 Introduction: An Overview of Different Phases of Drug Development 294 10.2 Nonclinical Development 295 10.2.1 Preclinical Pharmacology, PK/PD Modeling, and Human Dose Prediction 297 10.2.2 Safety and Toxicology Studies 297 10.2.3 Studies with Radiolabeled Compound 298 10.3 Clinical Pharmacology Studies 302 10.3.1 First-in-Human, Single, and Multiple Ascending Dose Studies 302 10.3.2 Biopharmaceutics - Absolute Oral Bioavailability and Bioequivalence Study 304 10.3.3 Food Effect Study 304 10.3.4 Organ (Hepatic and Renal) Impairment Study 305 10.3.5 Pediatric Assessment 306 10.3.6 Mass Balance Study 307 10.3.7 Drug Interaction Study 307 10.3.8 Pharmacogenomics Study 308 10.3.9 Thorough QT (TQT) and Concentration QT (C-QT) Study 308 10.3.10 Immunogenicity Assays and Comparability Study for Biologics 309 10.3.11 Drug Labelling 309 10.4 Clinical Development in Oncology 310 10.5 Fast Track Routes to Address Unmet Medical Need in the Treatment of Serious Conditions 311 10.6 Model-Informed Drug Development 312 10.7 Physiologically Based Pharmacokinetic Models Complementing Clinical Pharmacology Studies 314 10.8 PBPK in Oncology 315 Regulatory Guidelines 316 References 319 Section II. Applications In The Pharmaceutical Industry 323 11 Overview Of Pbpk Applications 325 11.1 Introduction 325 11.2 PBPK Applications for Internal Decisions 326 11.3 PBPK Applications for Regulatory Filing 328 11.4 PBPK Modeling and Simulations Along the Value Chain 332 References 335 12 Applications Of Hypothesis Generation And Testing With Pbpk Models 337 12.1 Introduction 338 12.2 Hypothesis Generation and Testing with PBPK Models 338 12.2.1 Parameter Estimation from Intravenous Pharmacokinetic Profiles 338 12.2.2 Simulation of Oral PK Profile 341 12.2.3 Sensitivity Analysis 342 12.2.4 Verification of Hypotheses 346 12.2.5 Auto-inhibition of Drug-Metabolizing Enzymes, Uptake and Efflux Transporters 347 12.3 Hypothesis Generation and Testing Along the Value Chain 348 12.4 Conclusions 351 References 351 13 Applications of Physiologically Based Pharmacokinetic Models Integrated With Drug Effect Models (Pbpk/Pd) 353 13.1 Introduction: Integration of PBPK with Drug Effect Models 354 13.2 Dosing in Specific Populations 355 13.3 PBPK/PD for Bottom-Up Prediction of Inter-Patient Variability in Drug Response 357 13.4 PBPK/PD for Predicting the Inter-Patient Variability in Response to Prodrugs and Active Metabolites 358 13.5 PBPK/PD When Systemic Concentrations are not the Driver forDrug Response 359 13.5.1 Pre-Systemic Drug Target 359 13.5.2 Effect-Site Drug Concentration Different from Systemic Concentration 360 13.6 PBPK/PD for Monoclonal Antibodies 362 13.7 PBPK Models Linked to Quantitative Systems Pharmacology and Toxicology Models 363 13.7.1 PBPK-QST Models to Predict Drug-Induced Liver Injury 363 13.7.2 PBPK-QST Models to Predict Drug-Induced Cardiotoxicity 367 13.8 Conclusions 371 References 371 14 Pbpk Modeling and Simulations to Evaluate Clinical Drug-Drug Interactions 375 14.1 Introduction 376 14.2 Clinical DDI Studies and Modeling Approaches to Address Key Questions Related to Drug-Drug Interactions 376 14.2.1 Dedicated Clinical DDI Studies 378 14.2.2 Investigation of Phenotypic Effects for NMEs Predominantly Cleared by Polymorphic Enzyme or Transporter 379 14.2.3 Prospective Nested DDI Study 380 14.2.4 Cocktail DDI Study 381 14.2.5 PBPK Modeling and Simulations 381 14.2.6 Claims Relating to Results of DDI Studies 381 14.2.7 Impact on Label 382 14.3 PBPK Modeling of Different Types of Drug Interactions 382 14.3.1 PBPK Modeling Strategy: New Molecular Entity as Victim of CYP-Based Drug Interactions 382 14.3.2 PBPK Modeling Strategy: New Molecular Entity as Perpetrator of CYP-Based Drug Interactions 383 14.3.3 Non-CYP Based Drug Interactions 384 14.3.4 Transporter-Mediated Drug Interactions 385 14.4 DDI Predictions with PBPK Modeling and Simulations in Clinical Drug Development and Regulatory Submissions 387 14.4.1 DDI Predictions Along the Value Chain (Figure 14.5) 387 14.4.2 Possible Regulatory Outcomes, Based on the Predictions from a Verified and Validated PBPK Model 389 14.4.3 Regulatory Acceptance of PBPK Analyses Included in Regulatory Submissions 390 14.4.4 Predictive Performance of PBPK Models 391 14.5 Comparison of DDI Prediction Using Static and Dynamic Models 392 14.6 Conclusions 393 References 394 15 Dose Extrapolation Across Populations (Healthy Adult Caucasian To Pediatric, Pregnant Women, Different Ethnicities, Geriatric, Smokers And Obese Populations) 397 15.1 Introduction 398 15.2 PBPK Modeling Strategy for Dose Extrapolation to Specific Populations 398 15.3 Potential Benefits of PBPK Modeling for Dose Extrapolations to Specific Populations 399 15.4 Dose Extrapolations to Specific populations 404 15.4.1 Pediatric Starting Dose Selection 404 15.4.2 Pregnancy 406 15.4.3 Ethnicity - Japanese Population 407 15.4.4 Geriatric Population 408 15.4.5 Obese 409 15.4.6 Smokers 410 15.5 Conclusions 410 References 411 16 Dose Extrapolation Across Populations: Healthy Adult To Hepatic And Renal Impairment Populations 417 16.1 Introduction 418 16.2 Pathophysiological Changes in Organ Impairment 419 16.2.1 Hepatic Impairment 419 16.2.2 Renal Impairment 420 16.3 PBPK Modeling Strategy: Model Development, Verification, Validation, and Application 420 16.4 Benefits of Applying Validated PBPK Models to Organ-Impaired Populations 421 16.4.1 Enhancing Regulatory Confidence in the Application of PBPK Modeling for the Prediction of Exposure in the Organ-Impaired Population 421 16.4.2 Contribution of PBPK to the Totality of Evidence in Evaluating the Effect of Renal Impairment on Drug Exposure to Inform Labelling 424 16.5 Conclusions 425 References 426 17 Absorption-Related Applications Of Pbpk Modeling 429 17.1 Introduction 429 17.2 In Vitro - In Vivo Disconnect, Parameter Non-Identifiability and the Importance of Identifying Factors Limiting Absorption Through a Deconvolution of the Mechanisms Contributing to Gut Bioavailability 431 17.3 Non-Regulatory Internal Applications of PBPK Modeling and Simulations 433 17.3.1 Prediction of Fraction Absorbed 433 17.3.2 Oral Formulation Development 433 17.4 Regulatory Applications of PBPK Modeling and Simulations 438 17.4.1 Food-Drug Interactions 438 17.4.2 Interactions of a Poorly Soluble Weak Base with Acid Reducing Agents (ARAs) 444 17.4.3 In Vitro - In Vivo Correlations (IVIVCs) to Serve as Surrogate for Bioequivalence Testing (Case Study 12) 445 17.4.4 Biowaivers Based on Virtual Bioequivalence 449 17.4.5 Virtual Bioequivalence of Locally Acting Products (LAPs) 450 17.5 Conclusions 450 References 452 18 Regulatory Guidelines On The Reporting Of Physiologically Based Pharmacokinetic (Pbpk) Modeling Analysis 457 18.1 Introduction 457 18.2 Food and Drug Administration (FDA) Guidelines 458 18.3 European Medicines Agency (EMA) Guidelines 459 18.4 Comparison of FDA and EMA Guidelines 461 18.5 Risk-Informed Evidentiary Framework to Assess PBPK Model Credibility 463 18.6 Drug Model Verification of Locally Acting Products (LAPs) 464 References 466 19 Resolving The Challenges To Establishing Confidence In Pbpk Models 469 19.1 Introduction 470 19.2 Requirements for Developing Mechanistically Credible PBPK Models for the Three Broad Categories of Applications 470 19.3 Challenges to Developing Mechanistically Credible PBPK Models and Consequences 473 19.3.1 Model Building 473 19.3.2 Model Verification of Predicted Exposure and Validation of Predictive Performance 476 19.4 Resolving the Challenges to Developing Mechanistically Credible PBPK Models 476 19.5 Totality of Evidence 478 19.6 Conclusions 480 References 481 20 Epilogue 483 20.1 PBPK Modeling Successes 483 20.2 Challenges 484 20.2.1 Drug Model Parameterization 484 20.2.2 Knowledge Gaps in Physiological Parameters 485 20.2.3 Prospective Validation of Prediction Performance 485 20.3 Meeting the Challenges 485 20.4 Future Directions for PBPK Modeling 486 References 488 Section III. Case Studies Of Pbpk Applications In The Pharmaceutical Industry 491 Case Study 1 Hypothesis Testing (Solubility) 493 Case Study 2 Hypothesis Testing (Gastric Emptying) 499 Case Study 3 Hypothesis Testing (Intestinal Loss) 505 Case Study 4 Pbpk/Pd 509 Case Study 5 Drug-Drug Interaction (Inhibition) 515 Case Study 6 Drug-Drug Interaction (Induction) 521 Case Study 7 Genetic Polymorphism 527 Case Study 8 Pediatric Extrapolation 535 Case Study 9 Pregnancy 541 Case Study 10 Hepatic Impairment 547 Case Study 11 Renal Impairment 555 Case Study 12 Absorption - Ivivc 561 Appendices 567 Index 579