A population pharmacokinetic/toxicity model for the reduction of platelets during a 48-h continuous intravenous infusion of the histone deacetylase inhibitor belinostat

Peer, Cody J.; Hall, O. Morgan; Sissung, Tristan M.; Piekarz, Richard; Balasubramaniam, Sanjeeve; Bates, Susan E.; Figg, William D.

doi:10.1007/s00280-018-3631-7

Cited by 9 publications

(4 citation statements)

References 16 publications

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“…UGT1A1 IMs or PMs receiving larger belinostat doses also had increased incidences of higher-grade neutropenia and thrombocytopenia. A pharmacokinetic model of 48-h continuous infusion belinostat did not find an effect of UGT1A1 genotype status on platelet reductions, though the authors hypothesized that the data sets used had insufficient observations to predict differences [ 74 ].…”

Section: Resultsmentioning

confidence: 99%

UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

Nelson

Seligson

Bottiglieri

et al. 2021

Cancers

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Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments.

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Section: Resultsmentioning

confidence: 99%

UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

Nelson

Seligson

Bottiglieri

et al. 2021

Cancers

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“…This has the capacity to be exploited to achieve large-scale in vitro PLT preparation to meet clinical resource needs. 83 Use of certain HDAC inhibitors, such as abexinostat, 84 panobinostat, 85 and belinostat, 86 as well as HDM inhibitors like INCB059872, may be followed by drug-induced thrombocytopenia resulting from dysregulated megakaryopoiesis. Therefore, further exploration of the specific mechanisms by which histone modification affects PLT generation will provide insights regarding the rational use of inhibitor drugs in clinical practice.…”

Section: Epigenetics Modulation Of Megakaryopoiesis and Plt Formation...mentioning

confidence: 99%

Epigenetic regulation of megakaryopoiesis and platelet formation

Xu,

Ye,

Wen

et al. 2024

haematol

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Platelets, produced by megakaryocytes, play unique roles in physiological processes, such as hemostasis, coagulation, and immune regulation, while also contributing to various clinical diseases. During megakaryocyte differentiation, the morphology and function of cells undergo significant changes due to the programmed expression of a series of genes. Epigenetic changes modify gene expression without altering the DNA base sequence, effectively impacting the inner workings of the cell at different stages of growth, proliferation, differentiation, and apoptosis. These modifications also play an important role in megakaryocyte development and platelet biogenesis. However, the specific mechanisms underlying epigenetic processes or the vast epigenetic regulatory network formed by their interactions remain unclear. In this review, we systematically summarize the key roles played by epigenetics in megakaryocyte development and platelet formation, including DNA methylation, histone modification, and non-coding RNA regulation. We expect our review to provide a deeper understanding of the biological processes underlying megakaryocyte development and platelet formation and to inform the development of new clinical interventions aimed at addressing platelet-related diseases and improving patient prognoses.

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“…Gut dysbiosis and increased gut permeability can also heighten TLR activation, which alters the synthesis of the proadhesive hepatic factor von Willebrand factor, thereby modulating the coagulation pathways [167]. Of note, HDAC inhibition can decrease the levels and activity of platelets in preclinical models [168], suggesting that gut dysbiosis associated with reduced butyrate levels may act to potentiate the role of platelets and coagulation factors in MS. Also, HDAC inhibitors, such as butyrate, increase tPA levels, thereby increasing the conversion of plasminogen to plasmin, which breaks down fibrin [169]. This highlights the potential roles of gut-microbiome-derived butyrate in the regulation of increased platelet and coagulation factors in MS, with relevance to core central processes and wider comorbidities in MS pathophysiology, which requires investigation in MS patients.…”

Section: Integrating Ms Pathophysiologymentioning

confidence: 99%

Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells

Anderson¹,

Rodriguez

Reíter

2019

IJMS

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Recent data highlight the important roles of the gut microbiome, gut permeability, and alterations in mitochondria functioning in the pathophysiology of multiple sclerosis (MS). This article reviews such data, indicating two important aspects of alterations in the gut in the modulation of mitochondria: (1) Gut permeability increases toll-like receptor (TLR) activators, viz circulating lipopolysaccharide (LPS), and exosomal high-mobility group box (HMGB)1. LPS and HMGB1 increase inducible nitric oxide synthase and superoxide, leading to peroxynitrite-driven acidic sphingomyelinase and ceramide. Ceramide is a major driver of MS pathophysiology via its impacts on glia mitochondria functioning; (2) Gut dysbiosis lowers production of the short-chain fatty acid, butyrate. Butyrate is a significant positive regulator of mitochondrial function, as well as suppressing the levels and effects of ceramide. Ceramide acts to suppress the circadian optimizers of mitochondria functioning, viz daytime orexin and night-time melatonin. Orexin, melatonin, and butyrate increase mitochondria oxidative phosphorylation partly via the disinhibition of the pyruvate dehydrogenase complex, leading to an increase in acetyl-coenzyme A (CoA). Acetyl-CoA is a necessary co-substrate for activation of the mitochondria melatonergic pathway, allowing melatonin to optimize mitochondrial function. Data would indicate that gut-driven alterations in ceramide and mitochondrial function, particularly in glia and immune cells, underpin MS pathophysiology. Aryl hydrocarbon receptor (AhR) activators, such as stress-induced kynurenine and air pollutants, may interact with the mitochondrial melatonergic pathway via AhR-induced cytochrome P450 (CYP)1b1, which backward converts melatonin to N-acetylserotonin (NAS). The loss of mitochnodria melatonin coupled with increased NAS has implications for altered mitochondrial function in many cell types that are relevant to MS pathophysiology. NAS is increased in secondary progressive MS, indicating a role for changes in the mitochondria melatonergic pathway in the progression of MS symptomatology. This provides a framework for the integration of diverse bodies of data on MS pathophysiology, with a number of readily applicable treatment interventions, including the utilization of sodium butyrate.

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A population pharmacokinetic/toxicity model for the reduction of platelets during a 48-h continuous intravenous infusion of the histone deacetylase inhibitor belinostat

Abstract: This model suggests a q3week schedule allows for sufficient platelet recovery before the next belinostat infusion is optimal.

Cited by 9 publications

References 16 publications

UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

Epigenetic regulation of megakaryopoiesis and platelet formation

Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells

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