Capturing the Magic Bullet: Pharmacokinetic Principles and Modeling of Antibody-Drug Conjugates
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Review Article Capturing the Magic Bullet: Pharmacokinetic Principles and Modeling of Antibody-Drug Conjugates Peiying Zuo1,2
Received 28 April 2020; accepted 23 June 2020 Abstract. Over the past two decades, antibody-drug conjugates (ADCs) have emerged as a promising class of drugs for cancer therapy and have expanded to nononcology fields such as inflammatory diseases, atherosclerosis, and bacteremia. Eight ADCs are currently approved by FDA for clinical applications, with more novel ADCs under clinical development. Compared with traditional chemotherapy, ADCs combine the target specificity of antibodies with chemotherapeutic capabilities of cytotoxic drugs. The benefits include reduced systemic toxicity and enhanced therapeutic index for patients. However, the heterogeneous structures of ADCs and their dynamic changes following administration create challenges in their development. The understanding of ADC pharmacokinetics (PK) is crucial for the optimization of clinical dosing regimens when translating from animal to human. In addition, it contributes to the optimization of dose selection and clinical monitoring with regard to safety and efficacy. This manuscript reviews the PK characteristics of ADCs and summarizes the diverse approaches for PK modeling that can be used to evaluate an ADC at the preclinical and clinical stages to support their successful development. Despite the numerous available options, fit-for-purpose modeling approaches for the PK and PD of ADCs should be critically planned and well-thought-out to adequately support the development of an ADC. KEY WORDS: ADC; antibody-drug conjugates; pharmacokinetics; modeling.
INTRODUCTION Cancer is one of the leading causes of death in humans. The seed of targeted therapy for cancer treatment was initially planted nearly a century ago by the Nobel Prize laureate Paul Ehrlich for his vision of a “magic bullet” treatment. The treatment involved a therapeutic agent carrying a destructive payload that could precisely target disease cells while sparing the healthy organs or tissues (1). It was not until 80 years later that targeted therapy in cancer became a reality thanks to the development of drugs specific to molecular targets involved in neoplastic processes. Two decades since then, targeted therapy has evolved from monoclonal antibodies (mAbs) to immune checkpoint inhibitors, and later to antibody-drug conjugates (ADCs). As a vivid representation of the “magic bullet” theory, ADCs are a Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12248-020-00475-8) contains supplementary material, which is available to authorized users. 1
Pharmacometrics US, Clinical Pharmacology & Exploratory Development, Astellas Pharma, Inc., USA, 1 Astellas Way, Northbrook, Illinois 60062, USA. 2 To whom correspondence should be addressed. (e–mail: [email protected])
class of therapeutic agents that combine the target specificity of mAbs with the chemotherapeutic activities of cytotoxic small-molecule drugs. The development of AD
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