A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction
| العنوان: | A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction |
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| المؤلفون: | Laura K. Fogli, Geraldine O'Sullivan Coyne, William R. Schelman, Richard D. Kim, Nancy Moore, Bassel F. El-Rayes, Chandra P. Belani, Naoko Takebe, Heinz-Josef Lenz, James H. Doroshow, Cindy L. O'Bryant, Sanjay Goel, Jan H. Beumer, Alice P. Chen, Larry Rubinstein, Richard Piekarz, Brian F. Kiesel, Afshin Dowlati, Vincent Chung, Shivaani Kummar, Ulka N. Vaishampayan, Joseph Tuscano |
| المصدر: | British Journal of Clinical Pharmacology |
| بيانات النشر: | John Wiley and Sons Inc., 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, drug safety, Hydroxamic Acids, 030226 pharmacology & pharmacy, Gastroenterology, Severity of Illness Index, Liver disease, chemistry.chemical_compound, 0302 clinical medicine, Neoplasms, Pharmacology (medical), 030212 general & internal medicine, Infusions, Intravenous, Sulfonamides, Liver Diseases, Histone deacetylase inhibitor, Middle Aged, 3. Good health, Liver, Toxicity, Original Article, Female, liver disease, Adult, medicine.medical_specialty, Maximum Tolerated Dose, medicine.drug_class, Metabolic Clearance Rate, Drug Administration Schedule, 03 medical and health sciences, Pharmacokinetics, Internal medicine, medicine, Humans, Dosing, histone deacetylase inhibitor, Aged, Neoplasm Staging, Pharmacology, Dose-Response Relationship, Drug, business.industry, Original Articles, medicine.disease, drug metabolism, Histone Deacetylase Inhibitors, anticancer drugs, chemistry, Liver function, business, Belinostat, Drug metabolism |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 1365-2125 0306-5251 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::da699f2f14408ad5cd5706ebb3ca7d05Test http://europepmc.org/articles/PMC6848909Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....da699f2f14408ad5cd5706ebb3ca7d05 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13652125 03065251 |
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