Free Drug Theory – No Longer Just a Hypothesis?

Summerfield, Scott; Yates, James; Fairman, David

doi:10.1007/s11095-022-03172-7

Cited by 41 publications

(34 citation statements)

References 57 publications

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“…Second, the Free Drug Hypothesis is generally taken prima facie when translating drug PD from in vitro systems into living organisms [5], [8]. This draws from the assumption that drug nonspecifically bound to circulating plasma protein or extracellular parenchymal protein is unable to interact with its intended target -in this case, the intracellular kinase domain of HER2.…”

Section: Discussionmentioning

confidence: 99%

“…This draws from the assumption that drug nonspecifically bound to circulating plasma protein or extracellular parenchymal protein is unable to interact with its intended target -in this case, the intracellular kinase domain of HER2. Violations of the free drug hypothesis are generally driven by mechanisms that disturb steady state equilibria assumptions, such as drug transport proteins like P-glycoprotein (Pgp) or high tissue clearance rates relative to diffusion [8]. While lapatinib is a substrate for Pgp and breast cancer resistance protein (BCRP) [33], the direction of its transport is extracellular, such that intracellular lapatinib concentrations are unlikely to be higher than what one would expect from free plasma concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…Free drug concentrations were simulated to inform tumor concentrations based on the Free Drug Hypothesis [8]. Prior to PK/PD simulation, we used the following equation to estimate the average unbound steady-state concentrations of alpelisib (PI3Kα), abemaciclib (CDK4/6), palbociclib (CDK4/6), ribociclib (CDK4/6), lapatinib (HER1/2), and neratinib (HER1/2/4):…”

Section: Variability In Systemic Drug Exposurementioning

confidence: 99%

“…For lapatinib, the reported PPB of "> 99%" was estimated as 99.5%. The following values were used for each As it is generally thought that only free drug is available to interact with pharmacologically relevant targets in vivo [8], [9],…”

Section: Variability In Systemic Drug Exposurementioning

confidence: 99%

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Dissecting sources of variability in patient response to targeted therapy: anti-HER2 therapies as a case study

Cao

2022

Preprint

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Background and Purpose: Despite their use to treat cancers with specific genetic aberrations, targeted therapies elicit heterogeneous responses. Sources of variability are critical to targeted therapy drug development, yet there exists no method to discern their relative contribution to response heterogeneity. Experimental Approach: We use HER2-amplified breast cancer and two agents, neratinib and lapatinib, to develop a platform for dissecting sources of variability in patient response. The platform comprises four components: pharmacokinetics, tumor burden and growth kinetics, clonal composition, and sensitivity to treatment. Pharmacokinetics are simulated using population models to capture variable systemic exposure. Tumor burden and growth kinetics are derived from clinical data comprising over 800,000 women. The fraction of sensitive and resistant tumor cells is informed by HER2 immunohistochemistry. Growth rate-corrected drug potency is used to predict response. We integrate these factors and simulate clinical outcomes for virtual patients. The relative contribution of these factors to response heterogeneity are compared. Key Results: The platform was verified with clinical data, including response rate and progression-free survival (PFS). For both neratinib and lapatinib, the growth rate of resistant clones influenced PFS to a higher degree than systemic drug exposure. Variability in exposure at labeled doses did not significantly influence response. Drug potency strongly influenced responses to neratinib. Variability in patient HER2 immunohistochemistry scores influenced responses to lapatinib. Exploratory twice daily dosing improved PFS for neratinib but not lapatinib. Conclusion and Implications: The platform can dissect sources of variability in response to target therapy, which may facilitate decision-making during drug development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Variability In Systemic Drug Exposurementioning

confidence: 99%

Section: Variability In Systemic Drug Exposurementioning

confidence: 99%

See 2 more Smart Citations

Dissecting sources of variability in patient response to targeted therapy: anti-HER2 therapies as a case study

Cao

2022

Preprint

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“…10 Furthermore, the free-drug hypothesis suggests that high levels of protein binding also prohibit on-target pharmacological effects, because circulating, protein-bound drug remains inactive. 11 Considering that most agents are highly protein-bound, 12 measuring total drug concentration in tumor tissue provides little insight into the pharmacologically active free fraction available capable of targeted inhibition. Even so-called brain-penetrant therapeutics may not have been evaluated for their ability to enter intact brain tissue, because their preclinical evaluation usually is limited to use of an experimental model of glioblastoma in which a tumor is implanted in the brain of a rodent.…”

mentioning

confidence: 99%

A Window of Opportunity to Overcome Therapeutic Failure in Neuro-Oncology

Vogelbaum

Heimberger

et al. 2022

American Society of Clinical Oncology Educational Book

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Glioblastoma is the most common primary malignant brain neoplasm and it remains one of the most difficult-to-treat human cancers despite decades of discovery and translational and clinical research. Many advances have been made in our understanding of the genetics and epigenetics of gliomas in general; yet, there remains an urgent need to develop novel agents that will improve the survival of patients with this deadly disease. What sets glioblastoma apart from all other cancers is that it develops and spreads within an organ that renders tumor cells inaccessible to most systemically administered agents because of the presence of the blood-brain barrier. Inadequate drug penetration into the central nervous system is often cited as the most common cause of trial failure in neuro-oncology, and even so-called brain-penetrant therapeutics may not reach biologically relevant concentrations in tumor cells. Evaluation of the pharmacokinetics and pharmacodynamics of a novel therapy is a cornerstone of drug development, but few trials for glioma therapeutics have incorporated these basic elements in an organ-specific manner. Window-of-opportunity clinical trial designs can provide early insight into the biological plausibility of a novel therapeutic strategy in the clinical setting. A variety of window-of-opportunity trial designs, which take into account the limited access to treated tissue and the challenges with obtaining pretreatment control tissues, have been used for the initial development of traditional and targeted small-molecule drugs and biologic therapies, including immunotherapies and oncolytic viral therapies. Early-stage development of glioma therapeutics should include a window-of-opportunity component whenever feasible.

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Atypical applications of transverse diffusion of laminar flow profiles methodology for in‐capillary reactions in capillary electrophoresis

Bržezická,

Kohútová,

Glatz

2024

J of Separation Science

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Capillary electrophoresis (CE) is a powerful separation technique offering quick and efficient analyses in various fields of bioanalytical chemistry. It is characterized by many well‐known advantages, but one, which is perhaps the most important for this application field, is somewhat overlooked. It is the possibility to perform chemical and biochemical reactions at the nL scale inside the separation capillary. There are two basic formats applicable for this purpose, heterogeneous and homogeneous. In the former, one reactant is immobilized onto a particle or monolithic support or directly on the capillary wall, and the other is injected. In the latter, the reactant mixing inside a capillary is based on electromigration or diffusion. One of the diffusion‐based methodologies, termed Transverse Diffusion of Laminar Flow Profiles, is the subject of this review. Since most studies utilizing in‐capillary reactions in CE focus on enzymes, which are being continuously and exhaustively reviewed, this review covers the atypical applications of this methodology, but still in the bioanalytical field. As can be seen from the demonstrated applications, they are not limited to reactions, but can also be utilized for other biochemical systems.

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Free Drug Theory – No Longer Just a Hypothesis?

Cited by 41 publications

References 57 publications

Dissecting sources of variability in patient response to targeted therapy: anti-HER2 therapies as a case study

Dissecting sources of variability in patient response to targeted therapy: anti-HER2 therapies as a case study

A Window of Opportunity to Overcome Therapeutic Failure in Neuro-Oncology

Atypical applications of transverse diffusion of laminar flow profiles methodology for in‐capillary reactions in capillary electrophoresis

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