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Research ArticleArticle

Pharmacokinetic and Drug Metabolism Properties of Novel Therapeutic Modalities

Brooke M. Rock and Robert S. Foti
Drug Metabolism and Disposition October 2019, 47 (10) 1097-1099; DOI: https://doi.org/10.1124/dmd.119.088708
Brooke M. Rock
Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (B.M.R.) and Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F.)
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  • For correspondence: brooke@amgen.com
Robert S. Foti
Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (B.M.R.) and Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F.)
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Abstract

The discovery and development of novel pharmaceutical therapies is rapidly transitioning from a small molecule–dominated focus to a more balanced portfolio consisting of small molecules, monoclonal antibodies, engineered proteins (modified endogenous proteins, bispecific antibodies, and fusion proteins), oligonucleotides, and gene-based therapies. This commentary, and the special issue as a whole, aims to highlight these emerging modalities and the efforts underway to better understand their unique pharmacokinetic and absorption, disposition, metabolism, and excretion (ADME) properties. The articles highlighted herein can be broadly grouped into those focusing on the ADME properties of novel therapeutics, those exploring targeted-delivery strategies, and finally, those discussing oligonucleotide therapies. It is also evident that whereas the field in general continues to progress toward new and more complex molecules, a significant amount of effort is still being placed on antibody-drug conjugates. As therapeutic molecules become increasingly complex, a parallel demand for advancements in experimental and analytical tools will become increasingly evident, both to increase the speed and efficiency of identifying safe and efficacious molecules and simultaneously decreasing our dependence on in vivo studies in preclinical species. The research and commentary included in this special issue will provide researchers, clinicians, and the patients we serve more options in the ongoing fight against grievous illnesses and unmet medical needs.

SIGNIFICANCE STATEMENT Recent trends in drug discovery and development suggest a shift away from a small molecule–dominated approach to a more balanced portfolio that includes small molecules, monoclonal antibodies, engineered proteins, and gene therapies. The research presented in this special issue of Drug Metabolism and Disposition will serve to highlight advancements in the understanding of the mechanisms that govern the pharmacokinetic and drug metabolism properties of the novel therapeutic modalities.

Introduction

The speed at which science is evolving has unveiled new biologic pathways and novel drug targets (Santos et al., 2017). In many cases, modulating new targets can require exploring their pharmacology beyond classic small molecule-target interactions, leading to an influx of new therapeutic modalities. A look at the new drugs approved by the U.S. Food and Drug Administration since 1980 illustrates a rapidly emerging change from approvals dominated by small molecules (prior to 2000) to a more balanced portfolio of small molecules and “non–small molecule” drugs such as monoclonal antibodies, engineered proteins, oligonucleotides, and vaccines (Fig. 1A) (Reichert, 2003; Mullard, 2018; Morrison, 2019). Likewise, in the last 10 years, the list of top-selling drugs in North America has swung from being dominated by small molecules to now including eight protein therapeutics among the ten top-selling drugs in the United States (Quan et al., 2018; Wineinger et al., 2019). Indeed, an analysis of the total sales of the top ten drugs in each year from 2010 to present shows a decreasing dependence on small-molecule revenue and a rapid shift toward sales of monoclonal antibodies and engineered proteins (Fig. 1B) (https://www.pharmacytimes.com; https://www.drugs.com/top200; Philippidis, 2019).

Fig. 1.
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Fig. 1.

Recent drug approvals by the U.S. Food and Drug Administration (A) and sales of the top ten best-selling drugs in each year point toward a more balanced therapeutic portfolio (B). Prior to 2000, FDA drug approvals consisted mainly of small-molecule (SM) therapeutics, though recent trends suggest a more equal distribution between small-molecule and biologic approvals (A). Likewise, prior to 2010, the top ten selling drugs in a given year consisted primarily of small molecules, with revenue in recent years being more heavily weighted toward monoclonal antibodies (mAb) and engineered proteins (B).

As molecular biology and genetic techniques continue to evolve, modalities beyond typical small and large molecules are rapidly finding their way into the drug discovery pipeline. This evolution is requiring drug metabolism and pharmacokinetic researchers to develop new tools to understand the absorption, disposition, metabolism, and excretion (ADME) of these new chemical entities, as described in the review by cite (Datta-Mannan, 2019) included in this issue. The fact that many of these analytical and experimental tools were developed to characterize monoclonal antibodies is a particular challenge, as emerging research suggests that many of the newer, highly-engineered therapeutic proteins may not be subject to the same disposition mechanisms as unmodified antibodies (Vugmeyster et al., 2012; Ueda, 2014). In this issue of Drug Metabolism and Disposition a series of primary research articles and review articles are presented to highlight the importance of understanding new modalities from an ADME scientist’s perspective. This issue focuses on the following three areas: 1) biodistribution and pharmacokinetic considerations of new modalities, 2) targeted drug delivery, and 3) oligonucleotide therapeutics. In addition, this issue contains a review article with a focus on different mechanisms that influence the disposition of peptides and monoclonal antibodies (Datta-Mannan, 2019).

Biodistribution and Pharmacokinetic Considerations of New Modalities

Establishing a pharmacokinetic-pharmacodynamic (PK-PD) relationship with small and large molecules has traditionally been performed by measuring drug concentration from the blood compartment and linking that concentration to a response (Bueters et al., 2013; Singh et al., 2015; Glassman and Balthasar, 2016). However, new technologies in targeted delivery have required ADME scientists to think beyond the blood compartment for drug and pharmacodynamic measurements to aid in the development of translational models, especially for pharmacological targets expressed outside of the vasculature (Shah, 2015; Glassman and Balthasar, 2016; Tibbitts et al., 2016). For many new modalities, understanding the biodistribution and exposure to the active form of the molecule at the therapeutic site of action is critical to establishing a PK-PD relationship (Lin, 2009; Shah and Betts, 2013; Conner et al., 2014; Glassman et al., 2015). In vitro assays that can provide information on the in vivo pharmacokinetic behavior of a molecule prior to conducting in vivo studies are crucial to informing the design of new modalities and can increase the speed at which new modalities reach clinical trials (Xu and Vugmeyster, 2012; Pearson and Rock, 2015). One such assay described in this issue is a novel in vitro assay by Foti et al. that informs how new chemical entities such as peptide-antibody conjugates will behave in vivo and provides a basis on which to prioritize molecules for in vivo studies (Foti et al., 2019). Advancements in the sensitivities of bioanalytical techniques have also enhanced the ability to measure drug at the site of action (Foti et al., 2015). To that end, the article by Zhang et al. (2019c) describes the importance of measuring drug concentration in the correct tissue compartment (e.g., site of action) along with the implications of asymmetric drug distribution. Looked at from a wholistic viewpoint, integrating the results of in vitro and in vivo biodistribution experiments will lead to a stronger translational understanding of new modalities but will also require advancements in many of our current modeling approaches. The article by Li et al. (2019) defines a mathematical model for understanding PK-PD in a mouse tumor model with different antibody fragments. As such, it serves as a good example of a parameterized model that can help identify the required amount of drug needed at the site of action to achieve efficacy.

Targeted Drug Delivery

The aim of a targeted drug delivery approach is to concentrate the active drug at the site of action while reducing exposure to other regions of the body (Iqbal et al., 2017; Srinivasarao and Low, 2017). The hallmark examples of targeted drug delivery are antibody-drug conjugates (ADCs), in which a cytotoxin (e.g., small molecule) is covalently attached to a monoclonal antibody targeting the tissue of interest and ultimately increasing the efficacy and therapeutic index of the cytotoxin. There are numerous publications on the ADME properties of ADCs that affect both their biodistribution and efficacy (Bornstein, 2015; Hamblett et al., 2016; Kraynov et al., 2016). For therapies that are designed to directly deliver to the site of action it is also important to understand the blood stability as well as the rate of delivery, as many such molecules use linker strategies that may be susceptible to degradation by proteases found in circulation (Tsuchikama and An, 2018). Two articles by Zhang et al. (2019a,b) define different linkages to either peptides or antibodies that enable the effective delivery of the warhead. These authors also point out elements to consider when measuring drug stability either in vitro or in vivo. Directed drug delivery has also enabled the success of oligonucleotides as therapeutics (Zimmermann et al., 2017).

Oligonucleotide Therapeutics

Oligonucleotide (ON) therapeutics use a biologic process known as RNA interference (RNAi), in which short interfering RNA molecules (siRNAs) or antisense oligonucleotides (ASOs) neutralize a target mRNA sequence to prevent subsequent protein translation (Nair et al., 2017; Andersson et al., 2018). Although the potential applications of ASOs and siRNAs to the field of therapeutics is vast, understanding the underlying delivery efficiency and relative tissue distribution remain significant challenges. It is well established in the ON field that sensitive bioanalytical assays are required to study the ADME properties of ONs (Humphreys et al., 2019a; Thayer et al., 2019). Presented herein is an overview by Post et al. (2019) of ADME properties of an ASO from preclinical species to clinical outcomes. In addition to the need to understand the translation of ON therapeutics, there remains only limited information on the potential for drug-drug interactions, or the potential effects of protein binding, topics addressed herein by Ramsden et al. (2019) and Humphreys et al. (2019b), respectively. The therapeutic potential of ON therapeutics is rapidly increasing with the development of new delivery techniques, as evidenced by the multitude of ongoing clinical trials (Titze-de-Almeida et al., 2017; Zimmermann et al., 2017; Saw and Song, 2019). As the field continues to evolve, ADME scientists will have the opportunity to inform the design of newer-generation molecules, specifically for the kinetics of drug delivery and impact of comedications on therapeutic treatments.

Conclusion

In the past decade the expansion of biology and genetics has increased the need for ADME scientists to expand the tools available to underwrite the absorption, disposition, metabolism, and excretion of new therapeutic modalities. It is vital to understand and characterize the ADME properties of a new chemical entity that ultimately lead to a safe and efficacious dose (e.g., acceptable therapeutic index). The articles presented herein underscore the importance of integrating in vitro and in vivo experiments in the assessment of novel modalities. Perhaps one of the greatest challenges in drug discovery is the generation of knowledge required to design and develop new modalities and the novel experimental approaches needed to characterize such modalities. ADME scientists across industry and academia are now faced with a unique opportunity and responsibility to continue exploring and discovering new approaches to keep up with and advance the ever-changing face of therapeutic modalities. This special issue of Drug Metabolism and Disposition on the Pharmacokinetic and Drug Metabolism Properties of Novel Therapeutic Modalities will serve to highlight some of these emerging tools that will be critical in transforming today’s experimental molecules into tomorrow’s successful therapeutics.

Authorship Contributions

Wrote or contributed to the writing of the manuscript: Rock, Foti.

Footnotes

    • Received July 10, 2019.
    • Accepted July 26, 2019.
  • https://doi.org/10.1124/dmd.119.088708.

Abbreviations

ADME
absorption, disposition, metabolism, and excretion
ASO
antisense oligonucleotide
ON
oligonucleotide
PK-PD
pharmacokinetic-pharmacodynamic
  • Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics

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Drug Metabolism and Disposition: 47 (10)
Drug Metabolism and Disposition
Vol. 47, Issue 10
1 Oct 2019
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PK Properties of Novel Therapeutic Modalities

Brooke M. Rock and Robert S. Foti
Drug Metabolism and Disposition October 1, 2019, 47 (10) 1097-1099; DOI: https://doi.org/10.1124/dmd.119.088708

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PK Properties of Novel Therapeutic Modalities

Brooke M. Rock and Robert S. Foti
Drug Metabolism and Disposition October 1, 2019, 47 (10) 1097-1099; DOI: https://doi.org/10.1124/dmd.119.088708
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    • Biodistribution and Pharmacokinetic Considerations of New Modalities
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ISSN 1521-009X (Online)

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