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 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

7 Citations (Scopus)

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

Fingerprint

Pharmacogenetics
Genetic Association Studies
Antineoplastic Agents
Glucuronides
Pharmacokinetics
Sulfates
ABT751
Genes
Sulfotransferases
Glucuronosyltransferase
Area Under Curve

Keywords

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

ASJC Scopus subject areas

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

Cite this

Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development : The example of the novel anticancer agent ABT-751. / Innocenti, Federico; Rez, Jacqueline Rami; Obel, Jennifer; Xiong, Julia; Mirkov, Snezana; Chiu, Yi Lin; Katz, David A.; Carr, Robert A.; Zhang, Wei; Das, Soma; Adjei, Araba; Moyer, Ann; Chen, Pei Xian; Krivoshik, Andrew; Medina, Diane; Gordon, Gary B.; Ratain, Mark J.; Sahelijo, Leonardo; Weinshilboum, Richard M; Fleming, Gini F.; Bhathena, Anahita.

In: Pharmacogenetics and Genomics, Vol. 23, No. 7, 07.2013, p. 374-381.

Research output: Contribution to journalArticle

Innocenti, F, Rez, JR, Obel, J, Xiong, J, Mirkov, S, Chiu, YL, Katz, DA, Carr, RA, Zhang, W, Das, S, Adjei, A, Moyer, A, Chen, PX, Krivoshik, A, Medina, D, Gordon, GB, Ratain, MJ, Sahelijo, L, Weinshilboum, RM, Fleming, GF & 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, vol. 23, no. 7, pp. 374-381. https://doi.org/10.1097/FPC.0b013e3283623e81
Innocenti, Federico ; Rez, Jacqueline Rami ; Obel, Jennifer ; Xiong, Julia ; Mirkov, Snezana ; Chiu, Yi Lin ; Katz, David A. ; Carr, Robert A. ; Zhang, Wei ; Das, Soma ; Adjei, Araba ; Moyer, Ann ; Chen, Pei Xian ; Krivoshik, Andrew ; Medina, Diane ; Gordon, Gary B. ; Ratain, Mark J. ; Sahelijo, Leonardo ; Weinshilboum, Richard M ; Fleming, Gini F. ; Bhathena, Anahita. / Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development : The example of the novel anticancer agent ABT-751. In: Pharmacogenetics and Genomics. 2013 ; Vol. 23, No. 7. pp. 374-381.
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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.",
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T1 - Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development

T2 - The example of the novel anticancer agent ABT-751

AU - Innocenti, Federico

AU - Rez, Jacqueline Rami

AU - Obel, Jennifer

AU - Xiong, Julia

AU - Mirkov, Snezana

AU - Chiu, Yi Lin

AU - Katz, David A.

AU - Carr, Robert A.

AU - Zhang, Wei

AU - Das, Soma

AU - Adjei, Araba

AU - Moyer, Ann

AU - Chen, Pei Xian

AU - Krivoshik, Andrew

AU - Medina, Diane

AU - Gordon, Gary B.

AU - Ratain, Mark J.

AU - Sahelijo, Leonardo

AU - Weinshilboum, Richard M

AU - Fleming, Gini F.

AU - Bhathena, Anahita

PY - 2013/7

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N2 - 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.

AB - 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.

KW - ABT-751

KW - Drug Development

KW - Drug Metabolism

KW - Pharmacogenetics

KW - Phase I

KW - Sulfotransferase

KW - Udp-Glucuronosyltransferase

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