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

Federico Innocenti, Jacqueline Rami Rez, 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. FlemingAnahita Bhathena

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Objective 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 Ctrough (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.

Original languageEnglish (US)
Pages (from-to)374-381
Number of pages8
JournalPharmacogenetics and genomics
Volume23
Issue number7
DOIs
StatePublished - Jul 2013

Keywords

  • ABT-751
  • Drug Development
  • Drug Metabolism
  • Pharmacogenetics
  • Phase I
  • Sulfotransferase
  • Udp-Glucuronosyltransferase

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Innocenti, F., Rez, J. R., Obel, J., Xiong, J., Mirkov, S., Chiu, Y. L., Katz, D. A., Carr, R. A., Zhang, W., Das, S., Adjei, A., Moyer, A. M., Chen, P. X., Krivoshik, A., Medina, D., Gordon, G. B., Ratain, M. J., Sahelijo, L., Weinshilboum, R. M., ... Bhathena, A. (2013). Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: The example of the novel anticancer agent ABT-751. Pharmacogenetics and genomics, 23(7), 374-381. https://doi.org/10.1097/FPC.0b013e3283623e81