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Engineered Nanoparticles for Drug Delivery in Cancer Therapy *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Tianmeng Sun, Yu Shrike Zhang, Pang Bo, Dong Choon Hyun, Miaoxin Yang, Younan Xia
Sustained release aims to deliver a drug at a predetermined rate over an extended period of time. This mode of release is critical for drugs that are rapidly metabolized and eliminated from the body after administration. The sustained release can maintain the concentration of the drug at a constant level in the plasma or target tissue by matching the rate of drug release with the rate of drug elimination. In the case of cancer therapy, maintaining the concentration of a drug within the therapeutic window is beneficial to the patient.
Regional Therapy of Liver Metastases: A Surgeon’s View
Published in Neville Willmott, John Daly, Microspheres and Regional Cancer Therapy, 2020
The susceptibility of cancer cells to chemotherapy often varies in a dose-dependent fashion. Higher drug levels often translate into higher tumor response rates. Unfortunately, high doses of chemotherapy are toxic to normal cells as well as cancer cells. Thus, systemically administered drug concentrations should remain within a narrow therapeutic window, maintaining a careful balance between therapeutic efficacy and host toxicity. The latter may preclude attaining systemic drug concentrations effective for tumor cytotoxicity. This problem can be addressed in a number of ways. Selectively increasing drug delivery to tumor cells can be performed by targeting, in which the agent is delivered directly to the liver as opposed to systemic administration. Drug delivery may be further enhanced by manipulating regional blood flow. Tumor cell drug uptake, metabolism, and release can also be altered.
Dose Ranging Studies and Dose Determination
Published in Emmanuel Lesaffre, Gianluca Baio, Bruno Boulanger, Bayesian Methods in Pharmaceutical Research, 2020
Phil Woodward, Alun Bedding, David Dejardin
Dose ranging studies are a critical part of drug development to determine the range of doses that determine the therapeutic window, defined as the difference between the minimal dose providing benefit and the maximum safe dose. The therapeutic window is determined in dose response studies. These studies will ideally model the dose response relationship to determine not only the therapeutic window but also the optimal dose for a future study. In oncology, the dose to be investigated in later phases of drug development is typically determined in dose escalation trials. These trials investigate the safety of different doses of the drug or combination of drug under investigation. The literature describes a variety of Bayesian approaches for dose ranging and dose escalation studies. In this chapter we review the Bayesian approaches for dose ranging and dose escalation trials and discuss their benefits, as well as considerations around these Bayesian methods.
Current status and prospect for future advancements of long-acting antibody formulations
Published in Expert Opinion on Drug Delivery, 2023
Puneet Tyagi, Garrett Harper, Patrick McGeehan, Shawn P Davis
With an appreciation for the potential value to our patients and the physicians’ point of view on long-acting presentation, one must now consider the technical solutions to realize this value keeping in mind the regulatory burden of evidence required. The end goal of long-acting presentations is to maximize the time for which the concentration of a medicinal molecule is above the minimum therapeutic concentration (Cmin) at the biologic target to achieve its mechanism of action. This must be balanced by maintaining the concentration below the maximum tolerable dose (Cmax) above which there is no further therapeutic benefit and may pose safety concerns due to toxicity. The concentration range between this upper and lower bound of efficacy is the therapeutic window. Long-acting presentations may extend the duration of time in the therapeutic window through multiple mechanisms, and therefore via multiple technical solutions. The rates of administration and absorption control how quickly the molecule is brought into contact with the target of interest. The rate of metabolism or clearance, which depends on the route of clearance, controls how quickly the molecule is removed from the target. The relative rates of this absorption, action, and clearance of a given dose define the pharmacokinetics (PK) of the molecule at the target and are the opportunities for tailoring dose frequency. Long-acting presentations are expected to have a lower clearance rate and thus better suited for LCM purposes in comparison to conventional or mutation-enhanced presentations.
Are PIEZO1 channels a potential therapeutic target for heart failure? Getting to the heart of the matter
Published in Expert Opinion on Therapeutic Targets, 2023
The mouse data outlined above raise the question of whether PIEZO1 antagonism could be a route to new therapies for heart failure, but more research is needed. For various reasons, genetic deletion studies do not necessarily indicate what would happen in therapeutic situations. Small-molecule, biological and depletion approaches of medical therapies usually reduce rather than completely remove the effect of a gene. Such attenuations could be advantageous here, paving the way to blunted PIEZO1 excess while sparing PIEZO1 physiological functions (Figure 1). To test such concepts experimentally, we would need to discover suitable PIEZO1 antagonists and investigate their effects in small and large animal models of different types of heart failure that incorporate risk factors and comorbidities, particularly in treatment protocols and measuring biomarkers that are relevant to clinical settings. We would then need to progress promising antagonists to human trials, guiding their design to the most relevant disease situations. A therapeutic window may need to be established through dosing studies that quantify potential adverse effects.
Rationale utilization of phospholipid excipients: a distinctive tool for progressing state of the art in research of emerging drug carriers
Published in Journal of Liposome Research, 2023
Koilpillai Jebastin, Damodharan Narayanasamy
Unfortunately, many drugs have a relatively narrow therapeutic window, which means that the therapeutic concentration isn't much lower than the toxic concentration. The use of a suitable drug carrier that affects the temporal and spatial delivery of the medication, i.e. its biodistribution and pharmacokinetics, can minimize toxicity or increase efficacy in numerous circumstances (Ambisome is a classical example of reduced toxicity). Many preclinical and clinical investigations have shown that encapsulating medications, such as anticancer agents, in lipid-based carriers reduces toxicities while increasing efficacy. Advances in LBDDS design result in improved therapeutic activity and/or reduced toxicity compared with the free drug (Mehta et al. 1994, Akbarzadeh et al. 2013).