Table of Contents

Cover

Title Page

Contributors

Preface

Acknowledgement

Chapter 1: Translational Concept and Determination of Drug Absorption

1.1 Drug Absorption, Mechanism, and Its Impact on Drug Bioavailability, Drug Disposition, and Drug Safety
1.2 Effect of Physiochemical Property–Related Factors on Drug Absorption
1.3 Effect of GI-Physiological Factors and Patient Condition on Drug Absorption
1.4 Effect of food and formulation on drug absorption
1.5 Translational Approaches to Determine Drug Absorption in Clinical Studies
References

Chapter 2: Distribution: Principle, Methods, and Applications

2.1 Introduction: Drug Distribution in Relation to Drug Disposition in Humans
2.2 Influence of Drug-Related Physiochemical Factors on Drug Distribution
2.3 Influence of Physiological Factors on Drug Distribution
2.4 Plasma Protein Binding
2.5 Role of Drug Transporters in Drug Distribution
2.6 Translational Methods and Approaches in Determining Drug Distribution
2.7 Impact of Drug Distribution in Drug Disposition DDI in Clinic
References

Chapter 3: Metabolism: Principle, Methods, and Applications

3.1 Introduction: An Overview on Drug Metabolism in Relation to Clearance—Mediated by Phase I, Phase II, and Phase III Drug-Metabolizing Enzymes
3.2 Common Phase I, II, and III Drug Metabolism Reactions
3.3 Metabolic Clearance as a Critical Factor Influencing Drug Action and Safety
3.4 Species Differences in Drug Metabolism
3.5 Translational Technologies and Methodologies and Regulatory Recommendation for Drug Metabolism
References

Chapter 4: Excretion: Principle, Methods, and Applications for Better Therapy

4.1 Outline of Drug Excretion and Mechanisms
4.2 Excretion of Drugs in Humans as Function of Drug Transporters
4.3 Translational Tools to Determine the Biliary and Renal Clearance
4.4 Impairment of Drug Elimination
References

Chapter 5: Drug–Drug Interaction: From Bench to Drug Label

5.1 Introduction: The Impact of Drug–Drug Interaction on Drug Disposition and Drug Safety
5.2 DDIs Implicated with Drug-Metabolizing Enzymes (DMEs) and Drug Metabolism
5.3 Incidence of DDI Due to Drug Transporters
5.4 Clinical DDI
5.5 Conclusion
References

Chapter 6: General Toxicology: Principle, Methods, and Applications1

6.1 Introduction: The History of Toxicology
6.2 The Multifaceted Field of Toxicology
6.3 Characteristics of Toxicants, Toxins, and Exposures
6.4 Adverse Drug Reactions: Idiosyncratic and Drug-Induced Liver Injury (DILI)
6.5 In Vitro Determination of Reactive Metabolite Formation, Oxidative Stress, Mitochondrial Damage, and Nephrotoxicity
6.6 Present and Future for Assessing Toxicity in Drug Discovery and Development
References

Chapter 7: Toxicokinetics and Toxicity Testing in Drug Development1

7.1 Introduction: Toxicokinetics and Its Relationship with Pharmacokinetics and ADME in Preclinical Development
7.2 Types of Preclinical Dosing that Support Toxicokinetics
7.3 Pharmacokinetic Parameters in Support of Toxicokinetic Assessments
7.4 Genotoxicity, Oncogenicity, Reproductive Toxicity versus Toxicogenomics and Biomarkers in Preclinical Species
7.5 Drug Metabolism and Drug Related-Toxicities
References

Chapter 8: PBPK Modeling and In Silico Prediction for ADME and Drug–Drug Interaction

8.1 Introduction: Computational Assessment of ADME and Drug–Drug Interaction (DDI) within Pharmaceutical R&D Paradigm
8.2 PBPK Models for ADMET and DDI
8.3 In Silico Prediction of ADMET
8.4 Applications of In Silico Models in ADME, DDI, and Drug Toxicity
References

Chapter 9: Translational Tools toward Better Drug Therapy in Human Populations

9.1 Introduction: Translational ADMET and Its Therapeutic Value
9.2 Translational Bioinformatics and Biomarkers: Utilization for Better Drug Therapy
9.3 Genomics and Pharmacogenomics in Translational ADMET
9.4 Translational ADMET, Approaches and Tools
9.5 Scaling of PK in Prediction of Human PK and Dosing
References

Chapter 10: Phase 1–Phase 3 Clinical Studies, Procedures, Responsibilities, and Documentation

10.1 Introduction: What Is Clinical Investigation? Goals, Utility, and Processes of Four Phases in Clinical Drug Development
10.2 General Clinical Study Design: Enrollment, Responsibilities, and Documentation
10.3 Integration of Clinical Trials with Preclinical Absorption, Distribution, Metabolism, and Excretion (ADME), Drug–Drug Interaction (DDI), and Pharmacogenomics in Investigating
10.4 Clinical Pharmacology Studies of Special Populations
References

Chapter 11: Regulatory Submission: MIST and Drug Safety Assessment

11.1 Drug Development and Approval Processes According to the Food and Drug Administration (FDA), European Medicines Agency (EMA), and Other Regulatory Authorities
11.2 Studies Required for IND and NDA
11.3 Drug Labeling and Black Box Warning
References

Index

End User License Agreement

List of Illustrations

Chapter 1: Translational Concept and Determination of Drug Absorption

Figure 1.1 Oral drug disposition indicating the bioavailability as a function of intestinal absorption $c1-math-0028$ , the fraction escaping intestinal metabolism $c1-math-0029$ , and the fraction escaping hepatic extraction $c1-math-0030$ , along with plasma drug bioavailability, the product of these three parameters.
Figure 1.2 The possible mechanisms of drug absorption across the intestinal epithelia monolayers, such as transepithelial passive diffusion (TC-PD), paracellular passive diffusion (PC-PD), and active transport by uptake (PepT1) and efflux transporters (P-gp, BCRP, MRP). Furthermore, the Figure indicates the interplay between drug transporters and DMEs such as CYP3A that influence the drug absorption and bioavailability.
Figure 1.3 Intestinal epithelial cell (enterocyte) indicating the tight junctions and the apical surface with microvilli at the lumen givinb the appearance of a brush border. As seen, the presence of microvilli greatly increases the available absorptive surface area for the enterocyte. Adapted from Ref [72] with permission.

Chapter 2: Distribution: Principle, Methods, and Applications

Figure 2.1 Methods to determine plasma protein binding. (A) Equilibrium dialysis, (B) ultracentrifugation, and (C) ultrafiltration.
Figure 2.2 Determination of $c2-math-0073$ from in vivo data. (A) One-compartment model with well-perfused central compartment, and (B) two-compartment model with central and peripheral compartments. K1, K2, and Ke are rate constants.

Chapter 3: Metabolism: Principle, Methods, and Applications

Figure 3.1 Role of drug metabolism by phase I/II DME at endoplasmic reticulum (ER) and by phase III mediated by membrane-bound drug transporters (efflux or uptake functions) in the disposition and elimination of drugs in bile and urine.
Figure 3.2 Contribution of metabolism, P450, CYP3A to metabolism relative to other elimination pathways, other enzymes, and pther P450s of hundreds of drugs on the market (data listed in various publications). (D) represents the % of each P450 enzyme to total P450 protein content in hepatocytes.
Figure 3.3 Examples of reactions catalyzed by cytochrome P450-mediated phase I. The metabolism is via NADPH-mediated oxidative and reductive reactions covering various classes of drugs and structures such as (A) aliphatic, (B) olephinic, and (C) aromatic.
Figure 3.4 Examples of P450-mediated reactions for known drugs and probe substrates catalyzed by CYP1A2, CYP3A4, CYP2A6, CYP2C9, CYP2C19, CYP2E1, and CYP2D6.
Figure 3.5 N-oxidation reaction of phase I mediated by several enzymes including P450s, such as CYP3A4 and FMOs. Antifungal drug voriconazole N-oxidation reaction is catalyzed by CYP2C9, CYP2C19, CYP3A4, and FMO3/FMO1.
Figure 3.6 Examples of function group that can be subject to methylation-mediated phase II conjugation reactions.
Figure 3.7 Examples of function group that can be subject to glucuronidation reactions catalyzed by phase II, UGTs.

Chapter 4: Excretion: Principle, Methods, and Applications for Better Therapy

Figure 4.1 Drug transporters at the AP and BL side of hepatocytes and proximal tubular cells. From Ref [3] with permission.
Figure 4.2 Roles for bile acid transporters in enterohepatic and systemic circulations. Figure presented by Ref [18].
Figure 4.3 Sandwich-cultured hepatocytes, an in vitro model for hepatobiliary disposition.
Figure 4.4 In vitro extrapolation of hepatobiliary disposition.
Figure 4.5 The comparison between PTC and DTC in efflux of statin drug rosuvastatin. PTC or DTC model grown in Transwell format. Efflux of MRP2-mediated rosuvastatin vs. passively diffused marker mannitol. Ja-b is the value for flux from apical side to basolateral side across the cell monolayer grown on semipermeable membrane in Transwell format, while Jb-a is the flux from basolateral to apical side. Ref [52] with permission.
Figure 4.6 The validation of drug transporter efflux function of PTC model grown in Transwell format. Efflux of MRP2-mediated rosuvastatin vs. passively diffused marker mannitol. Ja-b is the value for flux from apical side to basolateral side across the cell monolayer grown on semipermeable membrane in Transwell format, while Jb-a is the flux from basolateral to apical side. Ref [52] with permission.
Figure 4.7 Schematic presentation of potential synergy between MRP2 and MRP3 during cholestasis events. Ref [3] with permission.

Chapter 5: Drug–Drug Interaction: From Bench to Drug Label

Figure 5.1 Effect of DDI on the disposition of victim target drug.
Figure 5.2 (A) Example of mechanism-based inhibition by CYP2D6 and CYP2C19. (B) Mechanism-based inhibition by CYP3A4 implicated in liver toxicity and injury.
Figure 5.3 Relationship between $c5-math-0075$ and [I]. Adapted from Ref [50] with permission.
Figure 5.4 Drug transporters, localizations, and functions in major body organs influencing drug disposition. Adapted from Ref [90, 91] with permission.
Figure 5.5 Possible clinical DDI study design objective drug (O) and precipitant drug (P) in relation to pharmacokinetic sampling (PK) and wash period (Washout). Adapted from Ref [148, 149] with permission.

Chapter 6: General Toxicology: Principle, Methods, and Applications1

Figure 6.1 Pathway of drugs that undergo safe disposition mediated by metabolism vs. pathway of drug associated with DILI.
Figure 6.2 Preparation of in vitro model to study and predict the renal drug disposition and toxicity (A) and screening strategy (B) for nephrotoxicity using human PTCM and rat PTCM prior to in vivo animal screening and human clinical trials.
Figure 6.3 Integrated testing strategy as recommended by National Research Council using tiered testing approach employing QSAR and high throughput in vitro testing, medium throughput testing (MTP) using alternative species, and targeted mammalian testing.
Figure 6.4 Adverse outcome pathway (AOP) structure. An AOP begins with a chemical interaction leading to a molecular initiating event, then through a series of key events (KE) leading to an adverse outcome (AO).

Chapter 7: Toxicokinetics and Toxicity Testing in Drug Development1

Figure 7.1 Oral bioavailability is a function of intestinal absorption (F_a), the fraction escaping intestinal metabolism (F_G), and the fraction escaping hepatic extraction (F_H).
Figure 7.2 Schematic presentation of decisions for risk assessment and safety testing of human excretory (A) and circulating (B) metabolites. Ref [24] with permission.

Chapter 8: PBPK Modeling and In Silico Prediction for ADME and Drug–Drug Interaction

Figure 8.1 A PBPK model for the whole body.

Chapter 9: Translational Tools toward Better Drug Therapy in Human Populations

Figure 9.1 Why is drug development still failing? (A) Due to poor ADME/PK, (B) failure reduced due to advancement of predicting human ADME/PK, and (C) failure in Phase 3 due to poor efficacy and safety reasons. Adapted from Ref [2] with permission.
Figure 9.2 Factors implicated in selection of dosing regimen (exposure) and to ensure therapeutic response.
Figure 9.3 Tau-selective imaging agents, including a number of promising compounds (arylquinoline derivatives [THK-5105]; pyridoindole derivatives [T-807]; phenyl- or pyridinyl-butadienyl-benzothiazoles [PBB-3], the new heterocyclic compounds as imaging probes: aminothienopyridazines (ATPZs).
Figure 9.4 Translational tools and strategy for better design of a clinical study and its outcome.
Figure 9.5 Metabolism of codeine.
Figure 9.6 Metabolism of tamoxifen by CYP2D6 and formation of active metabolite endoxifen.
Figure 9.7 Translational path: from bedside to bench.
Figure 9.8 Pediatric estimated dose of antifungal drugs based on body weight ratio of pediatrics and adults compared to dose estimated from actual clearance value in pediatrics.

Chapter 10: Phase 1–Phase 3 Clinical Studies, Procedures, Responsibilities, and Documentation

Figure 10.1 Sequential procedures in establishing and completing clinical investigations.
Figure 10.2 Clinical drug development, phases, timeline, and regulatory submission timeline.
Figure 10.3 General reaction for the conversion of testosterone to estradiol catalyzed by aromatase. The enzyme aromatase (P450 19) converts the ring A to aromatic form (A) by the detailed reaction in (B).

Chapter 11: Regulatory Submission: MIST and Drug Safety Assessment

Figure 11.1 Drug development processes: from preclinical to market.

List of Tables

Chapter 1: Translational Concept and Determination of Drug Absorption

Table 1.1 Log D Values and Impact in Drug Permeability and Oral Absorption
Table 1.2 Physiological Parameters of GI Tract Regions
Table 1.3 pH of the Gastrointestinal tract under Fed vs. Fasted State

Chapter 2: Distribution: Principle, Methods, and Applications

Table 2.1 pK_a of Some Acids and Base
Table 2.2 Comparison between the Distribution of Strong Acid and Base in Body Compartments with Different pH. Values are listed in [12]
Table 2.3 Blood Flow, Perfusion Rate, and Relative Size of Different Organs and Tissues in Standard 70-kg Human
Table 2.4 Physiological and Medical Conditions Associated with Altered Plasma Albumin and AAG
Table 2.6 Values of Volume of Distribution for Selected Drugs

Chapter 3: Metabolism: Principle, Methods, and Applications

Table 3.1 Phase I oxidative Reactions and Reductions
Table 3.2 Phase II Conjugative Reactions and Hydrolysis
Table 3.3 Major Drug Metabolism Reactions and Localizations in Subcellular Compartments
Table 3.4 Strategic Applications of in vitro Models in Drug Metabolism and its Mechanisms

Chapter 4: Excretion: Principle, Methods, and Applications for Better Therapy

Table 4.1 List of Established Models Used in Vitro to Determine Kidney Excretion, Mechanisms, and Nephrotoxicity
Table 4.2 Alteration of PK of Drugs Influenced by DMEs and Transporters in Patients with CKD Compared to Normal adapted data (from Table 2 of [86])
Table 4.3 Epidemiological Studies Linking Uric Acid to Chronic Kidney Disease (CKD). Adapted from Ref [89] with permission

Chapter 5: Drug–Drug Interaction: From Bench to Drug Label

Table 5.1 Relationship Between I/K_i for CYP Inhibition by an Object Drug and DDI Risk Based on Fold Increase in Systemic Exposure of an Orally Administered Object Drug Whose Clearance Depends on the Metabolism of Inhibited Enzyme
Table 5.2 Adverse Drug Reactions of Selected Drugs in Association with Drug Transporter Function
Table 5.3 Drug transporter, substrates, and in vitro/in vivo inhibitors with corresponding IC₅₀/K_i values

Chapter 6: General Toxicology: Principle, Methods, and Applications1

Table 6.1 Example of Drugs Associated with DILI and the Degulatory Actions, Withdrawals, Warnings, or Second on line to Withdrawal or Warnings
Table 6.2 Fold Changes in Biomarker Data Shown as the Fold Difference for the Average Biomarker Values of Two Dose Groups and Time Point When Compared to Control (vesicle) Data at Day 29

Chapter 8: PBPK Modeling and In Silico Prediction for ADME and Drug–Drug Interaction

Table 8.1 Physiological Parameters for Humans and Small Animal Toxicity Species used in Constructing PBPK Models

Chapter 9: Translational Tools toward Better Drug Therapy in Human Populations

Table 9.1 Allele Combination of Diplotypes in Prediction of CYP2D6 Phenotypes
Table 9.2 CYP2D6 Phenotypes, Frequency, and Corresponding Genotypes and Diplotypes
Table 9.3 Frequencies of CYP2D6 Alleles among Various Ethnic Groups
Table 9.4 Translational of Growth Classification from Animal Species to Human

Chapter 10: Phase 1–Phase 3 Clinical Studies, Procedures, Responsibilities, and Documentation

Table 10.1 Summary of Clinical Stages in Drug Development
Table 10.2(A) Studies Conducted in Phase 1 Clinical Studies

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Translational ADMET for drug therapy : principles, methods, and pharmaceutical applications
/ Souzan Yanni.

[DNLM: 1. Drug Evaluation, Preclinical. 2. Pharmacokinetics. 3. Drug-Related Side Effects and Adverse Reactions. 4. Pharmaceutical Preparations–metabolism. QV 771]

Preface

Drug disposition implicated by absorption, distribution, metabolism, and excretion (ADME) and by toxicity (T) are always two of the most critical issues that pharmaceutical scientists and regulatory authorities focus on during the discovery and development of a new medicine for any target disease and the human population. Pharmaceutical companies spend 20–30% of their R&D budget to assess compound behavior with respect to ADMET, the factor that subsequently affects the pharmacological response and safety of any given drug in target patient populations. Preclinical and clinical tools and technologies that support the prediction of pharmacokinetics (PK) and pharmacodynamics (PD) in relation to toxicokinetics (TK) and toxicodynamics (TD) are continuously under development and improvement to reduce the cost and to increase the precision in developing a new medicine that ensures efficacy and safety of target human populations.

Because human population can vary depending on age, race, gender, disease, environment, and so forth, drug dose has to be adjusted. Updated in vitro and in vivo as well as in silico tools are developed and validated to be used in improving drug design toward the selection of the most effective and safe drug candidate. Regulatory organizations like the Food and Drug Administration and European Medicines Agency through updated guidance are reaching out to pharmaceutical companies, biotech, and contract research organizations (CROs) in order to support the research and development efforts by listing the most acceptable tools and approaches that scientists can employ to strategically design preclinical and clinical investigations. These efforts can aid in distinguishing the drug candidates that might be developed to become new therapeutic agents from those that are not and that will fail fast and fail cheap. Predictive ADMET tools such as in vitro, in vivo, and in silico models, such as physiologically based pharmacokinetic models, are tools that have the potential to enhance the selection of lead compounds, to facilitate the understanding of mechanisms underlying the disposition of drugs, to determine pharmacokinetic parameters, and to select the drug dose for first in human (FIH) investigations.

In vitro, in vivo, and in silico correlation that could translate data generated from bench to bedside or from bedside to bench is now a frequently used approach to reveal hidden adverse events, adverse drug reaction, and drug–drug interactions (DDIs) and to elucidate the mechanism of drug disposition, thus optimizing drug dose in human. Furthermore, the current in vitro and in silico technologies can now be used to predict plasma and tissue concentrations of drugs, select animal model by extrapolating across species, provide preclinical dosing regimen, assess the variability among human populations, and predict the potential DDI, thus ensuring the selection of preclinical toxicity species and drug therapy in all human populations regardless of age, gender, race, or disease.

These predictive tools have been used to calculate drug clearance. The accurate determination of drug clearance has warranted extensive translational research efforts, thus improving our ability to estimate safe and efficacious doses in different human populations, sometimes from retrospective clinical studies (from one population to other) toward the design of prospective clinical investigations in a target population.

The broad and current coverage of translational ADMET from drug discovery to drug development will serve as a handbook for scientists and managers from multidisciplinary functions within biotechnology and pharmaceutical companies and CROs to assist in designing and executing drug discovery and development programs that are conducted in compliance with regulatory guidelines. This book focuses on the most critical and emerging points that emphasize the translational ADME, also mapping the most effective approaches and technologies that are currently used to investigate ADME, PK, and toxicology prior to setup of clinical studies. The book can also be a textbook for senior graduate and medical students to be utilized as a hands-on manual in conducting in vitro, in silico, and preclinical in vivo ADMET studies.

Several case studies from drug discovery and drug development of drug candidates from varies therapeutic areas including, study design, possible data interpretations and decision-making tactics will be illustrated. These studies will demonstrate the integration of in vitro, in vivo, and in silico data to address human PK/PD/TK/TD and hence to select the safe and therapeutic dose in human and to support the design of clinical studies, investigational new drug, and new drug application submissions. Furthermore, the book will also demonstrate the strategy in translating ADME properties retrospectively from bedside to bench and from bench to bedside toward the design of a safe and effective medicine in special human populations, for example, pediatrics.

The unique features of this book will support the pharmaceutical professionals who are interested in becoming pharmaceutical managers and leaders with ADMET.

SOUZAN B. YANNI

Acknowledgement

The author likes to thank Wiley Editor team especially, Jonathan Rose who presented to her the opportunity of writing this book and who provided her with access to Wiley publications and resources. Also like to thank the rest of the editorial team, specifically Ms. Sarah Brown and Ms. Kiruthika Balasubramanian for their excellent effort in revising the contents of the book and completing the process in timely fashion.

Furthermore, the author likes to thank the scientists and post doc who contributed in the writing of chapter 6 and chapter 7 of this book. Finally, the author needs to express her gratitude to all her pharmaceutical industry colleagues, mentors, and leaders who indirectly supported this book through their excellent publications, training, and guide. Lastly but not least, the author likes to thank her family that provided continuous encouragement and support towards the completion of the book, especially her husband, Professor Adel Hanna, and sons Attorney Mr. Peter Hanna and Hani Hanna.

Translational Admet For Drug Therapy

Principles, Methods, and Pharmaceutical Applications

Contributors

Preface

Acknowledgement