Pharmacokinetic and Drug Metabolism Properties of Novel Therapeutic Modalities

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.

Study on In Vitro Metabolism and In Vivo Pharmacokinetics of Beauvericin

“…As a cyclic peptide compound, BEA can be incubated with biological matrices to evaluate their stability [ 26 , 38 , 39 ]. A variety of in vitro systems derived from the human liver can be used to investigate potential drug interactions, such as subcellular human liver tissue components, recombinant CYP enzymes, and human liver tissue [ 40 ]. In this study, human liver microsomes were used to investigate the inhibitory effect of BEA on CYP enzyme.…”

Alpinetin: A Review of Its Pharmacology and Pharmacokinetics

“…Pharmacokinetics is mainly to quantitatively estimate the absorption, distribution, metabolism and excretion properties of drugs, which provide essential information for clinical research (Rock and Foti, 2019;Wang et al, 2021). Recently, the pharmacokinetic profiles of alpinetin have been investigated by ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) (Ye et al, 2018), ultraperformance liquid chromatography tandem mass spectrometry method with electrospray ionisation (UHPLC-ESI-MS/MS) (Chen et al, 2015), and ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) primary in rats (Qiu et al, 2019) (Table 3).…”

RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges

“…Therapeutic drugs act on corresponding molecular targets, biological pathways, or cellular processes to elicit pharmacological effects for the treatment of human diseases. Small-molecule compounds and proteins/antibodies remain as the major forms of medications for medical use and the preferred modalities in drug development, acting mainly on protein targets such as enzymes, receptors, ion channels, transporters, and kinases (Santos et al, 2017;Usmani et al, 2017;Rock and Foti, 2019;Yin and Rogge, 2019). With unique physicochemical and pharmacological characteristics complementary to traditional protein-targeted small-molecule and protein drugs (Table 1), RNA molecules, such as aptamers, antisense oligonucleotides (ASO), small interfering RNAs (siRNA), and guide RNAs (gRNA), have emerged as a new class of modalities in clinical practice and are under active development (Crooke et al, 2018;Yin and Rogge, 2019;Yu et al, 2019); RNA molecules may act not only on conventional proteome but also on previously undrugged transcriptome, including mRNAs to be translated into proteins and functional noncoding RNAs (ncRNAs) which largely outnumber mRNAs (Mattick, 2004;Djebali et al, 2012), as well as the genome.…”