ADME and Translational Pharmacokinetics / Pharmacodynamics of Therapeutic Proteins

Applications in Drug Discovery and Development

Honghui Zhou, Frank-Peter Theil

• Publisher: Wiley
• Year: 2015
• Print ISBN: 9781118898642
• eBook ISBN: 9781118898741
• Edition: 1
• Topic: Medicine
• Subtopic: Biotechnology in Medicine

With an emphasis on the fundamental and practical aspects of ADME for therapeutic proteins, this book helps readers strategize, plan and implement translational research for biologic drugs.

•Details cutting-edge ADME (absorption, distribution, metabolism and excretion) and PKPD (pharmacokinetic / pharmacodynamics) modeling for biologic drugs
•Combines theoretical with practical aspects of ADME in biologic drug discovery and development and compares innovator biologics with biosimilar biologics and small molecules with biologics, giving a lessons-learned perspective
•Includes case studies about leveraging ADME to improve biologics drug development for monoclonal antibodies, fusion proteins, pegylated proteins, ADCs, bispecifics, and vaccines
•Presents regulatory expectations and industry perspectives for developing biologic drugs in USA, EU, and Japan
•Provides mechanistic insight into biodistribution and target-driven pharmacokinetics in important sites of action such as tumors and the brain

1
ADME FOR THERAPEUTIC BIOLOGICS: WHAT CAN WE LEVERAGE FROM GREAT WEALTH OF ADME KNOWLEDGE AND RESEARCH FOR SMALL MOLECULES

Weirong Wang¹ and Thomayant Prueksaritanont²

¹ Janssen Research and Development, LLC, Spring House, PA, USA

² Merck Research Laboratories, West Point, PA, USA

1.1 INTRODUCTION

Over the past decade, there has been increased investment to the development of biotechnologically derived drug products or biologics (including peptides, proteins, and monoclonal antibodies, mAbs, aggregately referred as large molecule (LM) drugs) in pharmaceutical companies [1, 2]. These are attributable to the reported therapeutic success of this modality thus far, together with the rapid advancement and breakthroughs in the fields of recombinant DNA biotechnology and molecular biology. However, reports on mechanistic investigation of absorption, distribution, metabolism, and excretion (ADME) processes for LMs are sparse and our current understanding of the associated mechanisms and key determinants of pharmacokinetic (PK) properties is scant [3]. Conceivably, these are related to the fact that the biopharmaceutical industry is still at an early stage, relative to the traditional pharmaceutical counterpart; the first approved LM drug product was in 1980s [4], several decades after many small molecule (SM) drugs were on the market. In addition, unlike the discovery and development of SM drugs, where the sciences and the functional role of drug metabolism and pharmacokinetics (DMPK) in studying and understanding ADME processes have been well recognized as an indispensable and integral discipline spanning from early discovery to development and postmarketing spaces [5], the function of DMPK in support of LM drug development is somewhat limited to mostly in vivo PK and/or pharmacokinetics/pharmacodynamics (PK/PD) studies, typically after candidate selection and primarily in the clinical space. Despite the intrinsic difference between SM and LM drugs, it should be of particular interest to appraise the relevance and applicability of what we have learned over the past few decades from the discovery and development of SM drugs to the same process of LMs. Thus, in this chapter, a brief historical perspective is presented on how the roles of DMPK and the key enablers for studying the ADME processes of SM drugs and their underlying mechanisms have evolved over time in order to influence internal de-risking strategy and decisions. External factors, such as changing regulatory environments and evolving LM discovery and development landscape, are briefly reviewed. Also presented is an overview of a DMPK concept analogy between SMs and LMs, as well as case examples to demonstrate the applicability of SM DMPK knowledge and experiences to LM drug discovery and development.

1.2 SM DRUG DISCOVERY AND DEVELOPMENT: HISTORICAL PERSPECTIVE

1.2.1 Evolving Role of DMPK: Paradigm Shift

It has long been well recognized that the drug discovery and development process is very expensive, largely due to a high development attrition rate and prolonged development time to meet the requirement for more extensive and complex clinical trials [1, 6–8]. In 1990s, poor human PK and bioavailability were the most significant cause of attrition for SM drugs, accounting for approximately 40% of all attrition in development. This number was dramatically reduced to approximately 8% by 2000 [7]. Such a drastic difference has been attributable primarily to a Paradigm shift in the roles of DMPK from little involvement decades before 1990 to active participation in SM drug early discovery starting in late 1980s [5]. Previously, compounds were selected mainly based on in vitro potency and in vivo efficacy in animal studies, with little attention being paid to the exposure or PK as an important measure connecting pharmacodynamics (PD)/efficacy/safety profiles, or consideration to commonly observed differences in these profiles between animals and humans. The integration of DMPK support as a key component of the overall drug discovery process helped to better understand ADME properties and filled these gaps, thus enabling proper data interpretations and rationale-based predictions of DMPK-related properties in humans [9–13]. As a result, potential liabilities of new chemical entities in humans were dialed out as early as possible, leading to increased likelihood for preclinical candidates to be developed successfully as therapeutic agents.

1.2.2 Key Enablers to Successful DMPK Support

The aforementioned successful DMPK support would not have been possible without numerous advances over the past few decades in drug metabolism sciences and technologies, which have provided powerful tools to enable DMPK scientists to shape SM drug metabolism research. Of special note are two key enablers, signifying game changers within the time period of interest (late-1980s to late-1990s): (i) rapid advancement of cytochrome P450 (CYP) science and (ii) availability of liquid chromatography–mass spectrometry (LC–MS). As will be described in later sections, these elements and associated wealth of information generated over the last few decades can be leveraged and applied to support LM drug development.

The CYP enzymes play central roles in the metabolism of SMs; it is estimated that more than 70% of marketed SM drugs were eliminated primarily by CYPs [13]. CYP enzymes were discovered in 1958, and research on their structure, function, regulation, and tissue expression levels, as well as their role in drug metabolism, was rapidly expanded in the 1980–1990s [14–16]. Such rapid advancement provided fundamental concepts and important tools that helped leverage preclinical/in vitro results as a bridge to clinical outcomes, consequently enabling one to predict, understand, and manage clinical findings, particularly with respect to human clearance and PK variability due to factors such as CYP-mediated drug–drug interaction (DDI) or CYP polymorphism [13, 16–18]. Specifically, for compounds with CYPs as the major or sole contributor to their metabolism, human metabolic clearance can be reasonably predicted based simply on in vitro metabolism studies with recombinant CYP isoforms, corrected for relative expression levels of each isoform in tissues [19]. In addition, the knowledge of CYP substrate specificity, multiplicity, and responses to factors, such as inducers and inhibitors, has provided a means to quantitatively predict, based on in vitro studies with specific CYP marker substrates or inhibitors/inducers, the magnitude of DDI, thus enabling a selection of candidates at discovery stage that do not bear considerable liability to serious clinical DDIs, either as perpetrators or victims [16–18, 20]. The DDI prediction results have also been used (and accepted by regulatory agencies) to inform inclusion and exclusion criteria for clinical programs, decide whether a clinical DDI study is needed, and inform product labeling with respect to dosage adjustment and warning/contraindication when used with other medications [21, 22]. Collectively, advances in understanding CYPs, the primary determinant for clearance mechanism of majority of SM drugs, has helped reduce drug development failure rate due to undesirable human PK properties.

In the area of tools and technologies, the successful coupling of high performance liquid chromatography with mass spectrometry (MS) has provided unprecedented sensitivity, selectivity, and high throughput that has facilitated the rapid assessment of ADME properties and the multiplicity of their governing factors for SM candidates in animals and humans [23–26]. Capitalizing on chromatographic separation and mass selectivity, the LC–MS technology enables the quantitation of coeluting or overlapping analytes, which otherwise would be constrained by chromatographic resolution. A dramatic outcome of this feature is the various in vivo and in vitro cassette studies in which more than one compounds were administered or incubated for the screening of DMPK properties, including metabolic stability, DDI liability, and plasma protein binding [23–25]. Along with the accelerated method development similarly attributed to the extraordinary selectivity and sensitivity of LC–MS, this practice has tremendously facilitated the speed and throughput of analyses of samples of low concentrations or of small volumes. Likewise, LC–MS technology has reshaped the business of metabolite characterization, allowing rapid detection and identification of major metabolites of drug candidates so that the result can be fed back into the cycle in time to influence the synthetic chemistry effort. Together, this powerful technology has enabled informed decisions to be made rapidly on a large number of candidates, each available in a small quantity, during the discovery stage. It has also enabled other in-depth mechanistic investigations into the governing factors of ADME processes, as well as detailed and accurate characterization of ADME properties of development candidates required for risk mitigation and regulatory submission [5, 10, 26]. With the recent advent of new chromatographic techniques, such as ultraperformance liquid chromatography, and more sophisticated MS, such as high resolution MS [27], this technology will continue to be the most powerful tool for drug discovery and development for SMs, and potentially for LMs alike.

1.2.3 Regulatory Considerations

Successful development of a drug candidate requires the right set of high quality data to help inform decisions not only internally, but also decisions by regulatory authorities. In-depth industry analysis by PhRMA has attributed much of the increasing R&D costs to the extending development times in clinical phases (10–15 years), greatly influenced by the increased regulatory demands in today’s low risk, low tolerance environment, and stemmed primarily from the withdrawal of several prominent prescription drugs from the market over the past decades for safety reasons. Of special note was the withdrawal of the drugs from the U.S. market in 1990s, half of which due to serious and unmanageable safety issues as a result of PK and/or PD DDIs. These occurrences prompted the FDA to publish guidance documents for industry to encourage the characterization of DDI potential for a new molecular entity early in the drug development process [21]. The first two guidance documents: one on in vitro DDI, published in 1997, and the other on in vivo DDI, published in 1999, focused on metabolic DDI due to CYPs, and was based primarily on considerable advances in our understanding of roles of the CYP family at the time. In the latest draft DDI guidance recently issued [22], there are recommendations to conduct many additional drug transporters, and drug interaction studies for LMs have been included for the first time. Given the current status and understanding of drug transporter sciences relative to the CYPs [28], the inclusion of drug transporters in the latest guidance suggested that the FDA has become more proactive in embracing evolving sciences in their decision making. Likewise, much less is known about LM drugs in their DMPK properties and underlying DDI mechanisms in comparison with SM drugs. Consistent with this, the time span between the first approved LM drug in 1986 and the anticipated DDI guidance is much shorter than the corresponding time span of many decades for SM drugs. This apparently speedy process for LMs may be attributable to the decision of the 2003 FDA...

Table of contents

• COVER
• TITLE PAGE
• TABLE OF CONTENTS
• LIST OF CONTRIBUTORS
• FOREWORD
• 1 ADME FOR THERAPEUTIC BIOLOGICS
• 2 PROTEIN ENGINEERING
• 3 THERAPEUTIC ANTIBODIES—PROTEIN ENGINEERING TO INFLUENCE ADME, PK, AND EFFICACY
• 4 ADME FOR THERAPEUTIC BIOLOGICS
• 5 OVERVIEW OF ADME AND PK/PD OF ADCs
• 6 ROLE OF LYMPHATIC SYSTEM IN SUBCUTANEOUS ABSORPTION OF THERAPEUTIC PROTEINS
• 7 BIODISTRIBUTION OF THERAPEUTIC BIOLOGICS
• 8 PREDICTION OF HUMAN PHARMACOKINETICS FOR PROTEIN-BASED BIOLOGIC THERAPEUTICS
• 9 FIXED DOSING VERSUS BODY-SIZE-BASED DOSING FOR THERAPEUTIC BIOLOGICS—A CLINICAL PHARMACOLOGY STRATEGY
• 10 IMPACT OF DISEASES, COMORBIDITY, AND TARGET PHYSIOLOGY ON ADME, PK, AND PK/PD OF THERAPEUTIC BIOLOGICS
• 11 IMMUNOGENICITY: ITS IMPACT ON ADME OF THERAPEUTIC BIOLOGICS
• 12 MECHANISTIC PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS IN DEVELOPMENT OF THERAPEUTIC MONOCLONAL ANTIBODIES
• 13 INTEGRATED QUANTITATION OF BIOTHERAPEUTIC DRUG–TARGET BINDING, BIOMARKERS, AND CLINICAL RESPONSE TO SUPPORT RATIONAL DOSE REGIMEN SELECTION
• 14 TARGET-DRIVEN PHARMACOKINETICS OF BIOTHERAPEUTICS
• 15 TARGET-DRIVEN PHARMACOKINETICS OF BIOTHERAPEUTICS
• 16 TUMOR EFFECT-SITE PHARMACOKINETICS
• 17 BRAIN EFFECT SITE PHARMACOKINETICS
• 18 MOLECULAR PATHOLOGY TECHNIQUES IN THE PRECLINICAL DEVELOPMENT OF THERAPEUTIC BIOLOGICS
• 19 LABELING AND IMAGING TECHNIQUES FOR QUANTIFICATION OF THERAPEUTIC BIOLOGICS
• 20 KNOWLEDGE OF ADME OF THERAPEUTIC PROTEINS IN ADULTS FACILITATES PEDIATRIC DEVELOPMENT
• 21 LC/MS VERSUS IMMUNE-BASED BIOANALYTICAL METHODS IN QUANTITATION OF THERAPEUTIC BIOLOGICS IN BIOLOGICAL MATRICES
• 22 BIOSIMILAR DEVELOPMENT: NONCLINICAL AND CLINICAL STRATEGIES AND CHALLENGES WITH A FOCUS ON THE ROLE OF PK/PD ASSESSMENTS
• 23 ADME PROCESSES IN VACCINES AND PK/PD APPROACHES FOR VACCINATION OPTIMIZATION
• 24 DRUG DEVELOPMENT STRATEGIES FOR THERAPEUTIC BIOLOGICS: INDUSTRY PERSPECTIVES
• 25 REVIEW: THE CRITICAL ROLE OF CLINICAL PHARMACOLOGY IN THE DEVELOPMENT OF BIOLOGICS
• 26 INVESTIGATING THE NONCLINICAL ADME AND PK/PD OF AN ANTIBODY–DRUG CONJUGATE: A CASE STUDY OF ADO-TRASTUZUMAB EMTANSINE (T-DM1)
• 27 USE OF PK/PD KNOWLEDGE IN GUIDING BISPECIFIC BIOLOGICS RESEARCH AND DEVELOPMENT
• INDEX
• END USER LICENSE AGREEMENT