Factors affecting the pharmacokinetic profile of MS-275, a novel histone deacetylase inhibitor, in patients with cancer

Acharya, Milin; Karp, Judith E.; Sausville, Edward A.; Hwang, Karam; Ryan, Qin; Gojo, Ivana; Venitz, Jürgen; Figg, William D.; Sparreboom, Alex

doi:10.1007/s10637-005-5707-6

Cited by 18 publications

(14 citation statements)

References 27 publications

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“…CV is 62% (n = 11) for the 1000 mg/m 2 dose level (qd and bid cohorts) whereas CVs are 39% (n = 4), 45% (n = 5), and 71% (n = 3) for the 1500, 1750, and 2000 mg groups, respectively. This indicates that dosing by body surface area does not eliminate variance in clearance for belinostat, similar to reported findings for MS-275 [15]. The reason for the variation in clearance has not been identified in this small study but correction for the patients' surface area may not be required for oral dosing of belinostat…”

Section: Discussionsupporting

confidence: 74%

Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101)

Steele

Plumb

Vidal

et al. 2010

Cancer Chemother Pharmacol

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PurposeThe primary objective of this sub-study, undertaken as an extension to the previously reported phase I study, was to explore the feasibility, tolerability and pharmacokinetics (PK) of belinostat when administered by the oral route. Preliminary PD studies were also performed to enable comparison of the biologic effects of the oral and intravenous formulations. Patients and MethodsOral belinostat was administered in a range of doses and schedules (once, twice, or thrice daily), on either day 1 or days 1 -5, of the second or a subsequent treatment cycle in 15 patients who were included in the phase I trial of intravenous belinostat.Serial blood samples were collected for pharmacokinetic and pharmacodynamic (histone acetylation) analyses, and the results compared with corresponding analyses following intravenous administration. ResultsA total mean daily AUC of 2767 1453 ng hr/ml (8.7 4.6 M hr) resulted from a dose of 1000 mg/m 2 once daily (qd). There was no clear evidence of drug accumulation on twice daily dosing (bid) however a trend towards accumulation was apparent when belinostat was given three times daily (tid). Mean half life (T½) of a single dose of 1000 mg/m 2 was 1.5 hr ( 0.3 hr) and peak levels were reached in an average of 1.9hrs ( 0.3 hr). The half life was found to be independent of dose, but a trend towards increasing half life following multiple dosing was observed. Histone H4 4 hyperacetylation in PBMCs estimated after oral dosing was comparable to that achieved after intravenous administration. ConclusionsHigh doses of oral belinostat, up to 1000 mg/m 2 bid for 5 consecutive days, have been tolerated in this small study. An oral formulation could lead to enhanced drug exposure and, more importantly, prolonged effects on the intended drug target. Future trials are required to establish the optimal dose and schedule of oral administration of belinostat.

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Section: Discussionsupporting

confidence: 74%

Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101)

Steele

Plumb

Vidal

et al. 2010

Cancer Chemother Pharmacol

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“…Favorable aspects of depsipeptide, such as its tolerability and long half-life, makes this HDACi a suitable candidate for further clinical studies (reviewed in [32]). Moreover, benzamides such as CI-994 (Nacetyldinaline) and MS-275 are currently in clinical trials for their ability to arrest tumor cell growth [33,34]. Aberrant activities of HDACs and HATs have been observed in a number of central nervous system tumors [35,36] and neurological disorders (reviewed in [37]), providing support for chemical manipulation of these enzymes as a treatment for such conditions.…”

Section: Hdac Inhibitors and Neurodegenerative Diseasesmentioning

confidence: 99%

Histone deacetylases: Focus on the nervous system

Morrison

Majdzadeh

D’Mello

2007

Cell. Mol. Life Sci.

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Neurodegenerative disease strikes millions worldwide and there is mounting evidence suggesting that underlying the onset and progression of these debilitating diseases is inappropriate neuronal apoptosis. Recent reports have implicated a family of proteins known as histone deacetylases (HDACs) in various neuronal processes including the neuronal death program. Initial headway in this field has been made largely through the use of broad-spectrum HDAC inhibitors. In fact, pharmacological inhibition of HDAC activity has been shown to protect neurons in several models of neurodegeneration. The observation that HDAC inhibitors can have opposing effects in different paradigms of neurodegeneration suggests that individual members of the HDAC protein family may play distinct roles that could depend on the specific cell type under study. The purpose of this review is to detail work involving the use of HDAC inhibitors within the context of neurodegeneration and examine the roles of individual HDAC members in the nervous system with specific focus on neuronal cell death.

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“…59 MS-275 is a potent orally available inhibitor, and is undergoing evaluation in several clinical trials. 60,61 Electrophilic ketones, such as trapoxin and 2-amino-8-oxo-9, are a new and growing class of HDAC inhibitors. These agents include various trifl uoromethyl ketones.…”

Section: Development Of Histone Deacetylase Inhibitorsmentioning

confidence: 99%

Recent advances in histone deacetylase targeted cancer therapy

Hoshino

Matsubara

2010

Surg Today

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Epigenetic regulators such as histone acetyltransferases (HATs) and histone deacetylases (HDACs) are known to play an important role in gene expression. Of these enzymes, HDACs have been shown to be commonly associated with many types of cancers and to affect cancer development. Consequently, HDACs have been considered as promising targets for cancer therapy. In addition, the inhibition of HDACs by histone deacetylase inhibitors (HDACIs) shifts the balance between the deacetylating activity of HDACs and the acetylating activity of HATs in the regulation of gene expression. Therefore, HDACIs are an exciting new addition in cancer therapies. Numerous HDACIs have been identified and some have recently been used in clinical trials for cancer treatment, although the mechanisms underlying the anticancer effects of HDACIs remain unclear. In this review, we examine the most recent developments in HDACIs and various aspects of HDAC-targeted cancer treatment.

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Factors affecting the pharmacokinetic profile of MS-275, a novel histone deacetylase inhibitor, in patients with cancer

Abstract: The current analysis has eliminated a number of candidate covariates from further consideration as important determinants of MS-275 absorption and disposition. Furthermore, MS-275 can be added to the list of cancer drugs where BSA-based dosing is not more accurate than fixed dosing.

Cited by 18 publications

References 27 publications

Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101)

Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101)

Histone deacetylases: Focus on the nervous system

Recent advances in histone deacetylase targeted cancer therapy

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