Key factors influencing ADME properties of therapeutic proteins: A need for ADME characterization in drug discovery and development

Keywords:intradermal subcutaneous therapeutic proteins PBPK modeling reactive oxygen species proteolysis oxidation lymphatic system a b s t r a c tThe intradermal (ID) and subcutaneous (SC) routes are commonly used for therapeutic proteins (TPs) and vaccines; however, the bioavailability of TPs is typically less than small molecule drugs given via the same routes. Proteolytic enzymes in the dermal, SC, and lymphatic tissues may be responsible for the loss of TPs. In addition, the TPs may be exposed to reactive oxygen species generated in the SC tissue and the lymphatic system in response to injection-related trauma and impurities within the formulation. The reactive oxygen species can oxidize TPs to alter their efficacy and immunogenicity potential. Mechanistic understandings of the dominant proteolysis and oxidative routes are useful in the drug discovery process, formulation development, and to assess the potential for immunogenicity and altered pharmacokinetics (PK). Furthermore, in vitro tools representing the ID or SC and lymphatic system can be used to evaluate the extent of proteolysis of the TPs after the injection and before systemic entry. The in vitro clearance data may be included in physiologically based pharmacokinetic models for improved PK predictions. In this review, we have summarized various physiological factors responsible for proteolysis and oxidation of TPs after ID and SC administration.

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“…However, rates of proteolysis of TPs are generally higher in lower animal species as compared to humans. 91…”

Section: Effect Of Animal Species On Pk Of Tpsmentioning

confidence: 99%

Proteolysis and Oxidation of Therapeutic Proteins After Intradermal or Subcutaneous Administration

Varkhede

Bommana

Schöneich

et al. 2020

Journal of Pharmaceutical Sciences

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“…The development of drug candidates involves the assessment of several parameters, such as absorption, distribution, metabolism, and excretion (ADME), because of the risk of unwanted adverse effects or poor bioavailability when assayed in vivo . This is one of the main reasons for the frequent failure to develop drug candidates .…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Molecular Modeling, and Evaluation of Novel Sulfonylhydrazones as Acetylcholinesterase Inhibitors for Alzheimer's Disease

Fernandes

Cunha

Sakata

et al. 2017

Archiv der Pharmazie

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Alzheimer's disease (AD) is the most common type of dementia and related to the degeneration of hippocampal cholinergic neurons, which dramatically affects cognitive ability. Acetylcholinesterase (AChE) inhibitors are employed as drugs for AD therapy. Three series of sulfonylhydrazone compounds were designed, and their ability to inhibit AChE was evaluated. Fifteen compounds were synthesized and twelve of them had IC values of 0.64-51.09 μM. The preliminary structure-activity relationships indicated that the methylcatechol moiety and arylsulfonyl substituents generated better compounds than both the benzodioxole and alkylsulfonyl chains. Molecular dynamics studies of compound 6d showed that the interaction with the peripheral binding site of AChE was similar to donepezil, which may explain its low IC (0.64 μM). Furthermore, the drug-likeness of 6d suggests that the compound may have appropriate oral absorption and brain penetration. Compound 6d also presented antiradical activity and was not cytotoxic to LL24 cells, suggesting that this compound might be considered safe. Our findings indicate that arylsulfonylhydrazones may be a promising scaffold for the design of new drug candidates for the treatment of AD.

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“…The absorption, distribution, metabolism and excretion (ADME) of therapeutics are governed by molecular size, charge and post‐translational modifications (for protein therapeutics). The site or route of administration is also critical, with the ECM largely influential on entry into the circulation, or tissue admission and retention (Tibbitts et al, ). Once in the circulation, the enhanced permeability of fenestrated neovasculature allows drugs of an appropriate size to enter and remain within tissues, whereas usually they would be retained in the circulation (Maeda et al, ).…”

Section: Extending Drug Half‐life To Increase Efficacy and Targetingmentioning

confidence: 99%

Targeting the extracellular matrix for delivery of bioactive molecules to sites of arthritis

Schultz

2018

British J Pharmacology

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Modifications to the extracellular matrix (ECM) can be either causal or consequential of disease processes including arthritis and cancer. In arthritis, the cartilage ECM is adversely affected by the aberrant behaviours of inflammatory cells, synoviocytes and chondrocytes, which secrete a plethora of cytokines and degradative proteases. In cancer, the ECM and stromal cells are linked to disease severity, and metalloproteinases are implicated in metastasis. There have been some successes in the field of targeted therapies, but efficacy depends upon the type and stage of disease. ECM targets are becoming increasingly attractive for drug delivery, owing to changes in ECM structure and composition in the diseased state, and the long in vivo half‐life of its components. This review will highlight various strategies for targeting therapeutics to arthritic joints, including antibody and peptide‐mediated drug delivery platforms to aid delivery to the ECM and retention at disease sites. Linked Articles This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc

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Key factors influencing ADME properties of therapeutic proteins: A need for ADME characterization in drug discovery and development

Cited by 158 publications

References 147 publications

Proteolysis and Oxidation of Therapeutic Proteins After Intradermal or Subcutaneous Administration

Proteolysis and Oxidation of Therapeutic Proteins After Intradermal or Subcutaneous Administration

Synthesis, Molecular Modeling, and Evaluation of Novel Sulfonylhydrazones as Acetylcholinesterase Inhibitors for Alzheimer's Disease

Targeting the extracellular matrix for delivery of bioactive molecules to sites of arthritis

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