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Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751.

AbstractOBJECTIVE:
ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751.
METHODS:
UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes.
RESULTS:
UGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (>2) was associated with an average 34% increase in ABT-751 clearance (P=0.044), an 18% reduction in ABT-751 AUC (P=0.045), and a 50% increase in sulfation metabolic ratios (P=0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P=0.022), and UGT1A4*2 was associated with a 65% decrease in ABT-751 C trough (P=0.009).
CONCLUSION:
These results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability.
AuthorsFederico Innocenti, Jacqueline Ramírez, Jennifer Obel, Julia Xiong, Snezana Mirkov, Yi-Lin Chiu, David A Katz, Robert A Carr, Wei Zhang, Soma Das, Araba Adjei, Ann M Moyer, Pei Xian Chen, Andrew Krivoshik, Diane Medina, Gary B Gordon, Mark J Ratain, Leonardo Sahelijo, Richard M Weinshilboum, Gini F Fleming, Anahita Bhathena
JournalPharmacogenetics and genomics (Pharmacogenet Genomics) Vol. 23 Issue 7 Pg. 374-81 (Jul 2013) ISSN: 1744-6880 [Electronic] United States
PMID23670235 (Publication Type: Clinical Trial, Phase I, Journal Article)
Chemical References
  • ABT751
  • Antineoplastic Agents
  • Sulfonamides
  • Tubulin Modulators
  • bilirubin glucuronoside glucuronosyltransferase
  • Glucuronosyltransferase
  • Sulfotransferases
  • Arylsulfotransferase
  • SULT1A1 protein, human
Topics
  • Adult
  • Aged
  • Antineoplastic Agents (pharmacokinetics)
  • Arylsulfotransferase (genetics)
  • Female
  • Gene Dosage
  • Genetic Variation
  • Glucuronosyltransferase (genetics, metabolism)
  • Humans
  • Male
  • Middle Aged
  • Sulfonamides (pharmacokinetics)
  • Sulfotransferases (genetics, metabolism)
  • Tubulin Modulators (pharmacokinetics)

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