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Effects of UGT1A1 genotype on the pharmacokinetics, pharmacodynamics, and toxicities of belinostat administered by 48-hour continuous infusion in patients with cancer.

ABSTRACT: The histone deacetylase inhibitor belinostat is eliminated through glucuronidation by UGT1A1. Polymorphisms that reduce UGT1A1 function could result in increased belinostat exposure and toxicities. We wanted to determine which single-nucleotide polymorphisms alter belinostat exposure and toxicity. In a phase 1 trial (belinostat over 48 hours in combination with cisplatin and etoposide), belinostat (400, 500, 600, or 800?mg/m(2) /24?h, 48-hour continuous infusion) was administered to patients with cancer in combination with cisplatin and etoposide (n?=?25). Patients were genotyped for UGT1A1 variants associated with reduced function: UGT1A1*6, UGT1A1*28, and UGT1A1*60. End points were associations between UGT1A1 genotype and belinostat pharmacokinetics (PK), toxicities, and global protein lysine acetylation (AcK). Belinostat AUC was increased (P?=?.003), and t1/2 increased (P?=?.0009) in UGT1A1*28 and UGT1A1*60 carriers who received more than 400?mg/m(2) /24?h. The incidence of grades 3-4 thrombocytopenia (P?=?.0081) was associated with UGT1A1 polymorphisms. The US Food and Drug Administration-approved package insert recommends dose adjustment of belinostat for UGT1A1*28. However, our data suggest dose adjustment is also necessary for UGT1A1*60. UGT1A1 polymorphisms were associated with increased systemic belinostat exposure, increased AcK, and increased incidence of toxicities, particularly at doses > 400?mg/m(2) /24?h.

SUBMITTER: Goey AK

PROVIDER: S-EPMC6361127 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Effects of UGT1A1 genotype on the pharmacokinetics, pharmacodynamics, and toxicities of belinostat administered by 48-hour continuous infusion in patients with cancer.

Goey Andrew K L AK Sissung Tristan M TM Peer Cody J CJ Trepel Jane B JB Lee Min-Jung MJ Tomita Yusuke Y Ehrlich Sheryl S Bryla Christine C Balasubramaniam Sanjeeve S Piekarz Richard R Steinberg Seth M SM Bates Susan E SE Figg William D WD

Journal of clinical pharmacology 20151109 4

The histone deacetylase inhibitor belinostat is eliminated through glucuronidation by UGT1A1. Polymorphisms that reduce UGT1A1 function could result in increased belinostat exposure and toxicities. We wanted to determine which single-nucleotide polymorphisms alter belinostat exposure and toxicity. In a phase 1 trial (belinostat over 48 hours in combination with cisplatin and etoposide), belinostat (400, 500, 600, or 800 mg/m(2) /24 h, 48-hour continuous infusion) was administered to patients wit ...[more]

PMID: 26313268

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Dataset Information

Effects of UGT1A1 genotype on the pharmacokinetics, pharmacodynamics, and toxicities of belinostat administered by 48-hour continuous infusion in patients with cancer.

Publications

Effects of UGT1A1 genotype on the pharmacokinetics, pharmacodynamics, and toxicities of belinostat administered by 48-hour continuous infusion in patients with cancer.

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