A phase I study to determine the pharmacokinetics and urinary excretion of belinostat and metabolites in patients with advanced solid tumors

Bailey, Hanna; McPherson, Jordan P.; Bailey, Erin; Werner, Theresa L.; Gupta, Sumati; Batten, Julia; Reddy, Guru; Bhat, Gajanan; Sharma, Sunil; Agarwal, Neeraj

doi:10.1007/s00280-016-3167-7

Cited by 12 publications

(10 citation statements)

References 38 publications

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“…The time to plasma C max can be reached in about 30 minutes after the start of infusion (Yeo et al, 2012;Piper et al, 2014;Calvo et al, 2016). BEL is rapidly metabolized, with a plasma half-life (t 1/2 ) of 2-4 hours (Yeo et al, 2012;Piper et al, 2014;Bailey et al, 2016;Calvo et al, 2016). The plasma pharmacokinetic parameters from the previous studies in humans are presented in Table 2.…”

Section: Resultsmentioning

confidence: 99%

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

et al. 2019

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Activation of pregnane X receptor (PXR) by clinical compounds during multidrug chemotherapy results in upregulation of the expression of PXR target genes, including cytochrome p450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1), leading to chemoresistance. It is possible to overcome the PXR‐mediated chemoresistance by downregulating the upregulated PXR target genes by inhibiting the activated PXR. However, a selective and less‐toxic PXR antagonist has yet to be developed. In this regard, a clinical anticancer drug, with selective PXR antagonistic activity at its less‐toxic concentrations, would be beneficial. We sought to determine whether belinostat, a clinically‐used histone deacetylase inhibitor, inhibits the PXR target gene expression at its clinically relevant plasma concentrations (< ~100 μM) in human hepatocytes (primary hepatocytes & hepatocells) and intestinal cells (LS174T colon cancer cells). Rifampicin, an agonist of human PXR, was used to activate PXR. Cell viability and CYQUANT cell proliferation assays were performed to determine cytotoxicity and cell proliferation, respectively. Quantitative RT‐PCR assays were conducted to study the gene expression. CYP3A4 p450‐Glo and Rhodamine‐123 intracellular accumulation assays were performed to determine the function of CYP3A4 and MDR1, respectively. Belinostat, at its unbound therapeutic plasma concentrations (< ~5 μM) did not affect the viability of LS174T cells and the hepatocytes. Belinostat (1 & 3 μM) not only inhibited rifampicin‐induced gene expression of CYP3A4 and MDR1, but also attenuated rifampicin‐induced activity of CYP3A4 and MDR1. However, belinostat alone did not affect CYP3A4 or MDR1 gene expression. These results suggest that belinostat does not affect the basal expression of PXR target genes but downregulates the upregulated PXR target genes by inhibiting the ligand‐activated PXR. Notably, belinostat, at its PXR inhibiting concentrations, decreased rifampicin‐induced proliferation of LS174T cells, suggesting that belinostat suppresses PXR‐mediated proliferation of the cancer cells. Interestingly, belinostat failed to inhibit rodent PXR agonist pregnenolone‐16 alpha‐carbonitrile (PCN)‐induced expression of CYP3A1 (the rat analog of human CYP3A4) in rat primary hepatocytes, suggesting that belinostat exhibits species‐specific inhibition of PXR at unbound plasma therapeutic concentrations. Taken together, these results are consistent with the conclusion that belinostat, at its less‐toxic and clinically relevant unbound plasma concentrations, inhibits the ligand‐activated human PXR target gene expression. Future studies will determine the mechanisms of belinostat inhibition of PXR, and belinostat sensitization of the cancer cells to chemotherapy drugs with PXR agonistic activity. Support or Funding Information The authors would like to thank Drs. Coleman, Schwartz, and Tao for sharing their research facilities. This work was supported by the Auburn University Research Initiative in Cancer Grant, Animal Health and Disease Research Grant...

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Section: Resultsmentioning

confidence: 99%

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

et al. 2019

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“…HDAC inhibitors induce antitumor effects by: (1) inducing the expression of tumor suppressors including p53 and p21, promoting cell cycle arrest, and inhibiting cell proliferation (Davis et al, 2000;Richon et al, 2000;Kim et al, 2001); (2) activating extrinsic and intrinsic apoptosis by upregulating death receptors and proapoptotic proteins (Kawagoe et al, 2002;Nakata et al, 2004;Insinga et al, 2005); and (3) inhibiting angiogenesis through induction of anti-angiogenic genes and repression of pro-angiogenic genes Deroanne et al, 2002;Kwon et al, 2002). Clinical studies are being actively performed to test the effects of HDAC inhibitors in other types of cancer including glioblastoma (Galanis et al, 2009;Bailey et al, 2016;Kusaczuk et al, 2016;Choi et al, 2017;Barneh et al, 2018;Monga et al, 2018).…”

Section: Clinical Utility Of Hdac Inhibitorsmentioning

confidence: 99%

Epigenetic Regulation of Multidrug Resistance Protein 1 and Breast Cancer Resistance Protein Transporters by Histone Deacetylase Inhibition

2020

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“…Belinostat is rapidly metabolized by the liver into metabolites, which are eliminated primarily through the kidneys. [15][16][17] These resulting metabolites are inactive and not likely to be relevant to safety or tolerability. However, changes in enzyme activity and hepatic blood flow caused by liver disease can result in a reduction in hepatic metabolism and lead to increased parent belinostat exposure, potentially having a significant effect on drug-related toxicity.…”

Section: What This Study Addsmentioning

confidence: 99%

“…However, adjustments may be needed for patients with liver dysfunction. Belinostat is rapidly metabolized by the liver into metabolites, which are eliminated primarily through the kidneys . These resulting metabolites are inactive and not likely to be relevant to safety or tolerability.…”

Section: Introductionmentioning

confidence: 99%

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A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction

Takebe

Beumer

Kummar

et al. 2019

Brit J Clinical Pharma

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Aims The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. Methods We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction. Results Seventy‐two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m2/day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. Conclusion While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.

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A phase I study to determine the pharmacokinetics and urinary excretion of belinostat and metabolites in patients with advanced solid tumors

Abstract: Urinary elimination of parent belinostat was minimal, although a combined 36.7 % of belinostat metabolites were excreted in urine. Since these metabolites are primarily inactive, belinostat may not require dosage adjustment in renal dysfunction.

Cited by 12 publications

References 38 publications

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

Epigenetic Regulation of Multidrug Resistance Protein 1 and Breast Cancer Resistance Protein Transporters by Histone Deacetylase Inhibition

A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction

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