Abstract |
Belinostat is a second-generation zinc-binding histone deacetylase inhibitor that is approved for peripheral T-cell lymphoma and is currently being studied in small cell lung cancer and other advanced carcinomas as a 48-hour continuous intravenous infusion. Belinostat is predominantly metabolized by UGT1A1, which is polymorphic. Preliminary analyses revealed a difference in belinostat clearance based on UGT1A1 genotype. A 2-compartment population pharmacokinetic (PK) model was developed and validated that incorporated the UGT1A1 genotype, albumin, and creatinine clearance on the clearance parameter; body weight was a significant covariate on volume. Simulated doses of 600 and 400 mg/m(2) /24 h given to patients considered extensive or impaired metabolizers, respectively, provided equivalent AUCs. This model and subsequent simulations supported additional PK/toxicity and pharmacogenomics/toxicity analyses to suggest a UGT1A1 genotype-based dose adjustment to normalize belinostat exposure and allow for more tolerable therapy. In addition, global protein lysine acetylation was modeled with PK and demonstrated a reversible belinostat exposure/response relationship, consistent with previous reports.
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Authors | Cody J Peer, Andrew K L Goey, Tristan M Sissung, Sheryl Erlich, Min-Jung Lee, Yusuke Tomita, Jane B Trepel, Richard Piekarz, Sanjeeve Balasubramaniam, Susan E Bates, William D Figg |
Journal | Journal of clinical pharmacology
(J Clin Pharmacol)
Vol. 56
Issue 4
Pg. 450-60
(Apr 2016)
ISSN: 1552-4604 [Electronic] England |
PMID | 26637161
(Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Intramural)
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Copyright | © 2015, The American College of Clinical Pharmacology. |
Chemical References |
- Albumins
- Antineoplastic Agents
- Hydroxamic Acids
- Sulfonamides
- Creatinine
- UGT1A1 enzyme
- Glucuronosyltransferase
- belinostat
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Topics |
- Adult
- Aged
- Albumins
(metabolism)
- Antineoplastic Agents
(administration & dosage, pharmacokinetics)
- Creatinine
(metabolism)
- Female
- Genotype
- Glucuronosyltransferase
(genetics)
- Humans
- Hydroxamic Acids
(administration & dosage, pharmacokinetics)
- Kinetics
- Male
- Middle Aged
- Models, Biological
- Neoplasms
(drug therapy, genetics, metabolism)
- Pharmacogenetics
(methods)
- Sulfonamides
(administration & dosage, pharmacokinetics)
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