Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development

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.

Race, Gender, and Genetic Polymorphism Contribute to Variability in Acetaminophen Pharmacokinetics, Metabolism, and Protein-Adduct Concentrations in Healthy African-American and European-American Volunteers

“…Although all of these failed to show a significant influence of this gene variant, none of the studies measured the sulfation metabolites directly. A more recent study evaluated the association of four different SULT1A1 gene variants with plasma pharmacokinetics of ABT-751, an experimental cancer treatment (Innocenti et al, 2013). Although they found no association of SULT1A1*2 with ABT-751 pharmacokinetics, they did find a significant association of a SULT1A1 gene copy number variant (CNV) with increased ABT-751 clearance and ABT-751 sulfate-to-ABT-751 AUC ratios.…”

UGT1A and UGT2B Genetic Variation Alters Nicotine and Nitrosamine Glucuronidation in European and African American Smokers

“…Genotyping for the UGT1A9 indels, rs45625337 and rs10538910, was performed using the in-house GeneScan (PCR-Sizing) assays run on ABI 3700 as described previously (58). Genotyping for UGT1A4 _135498 C>A (rs6755571) and UGT1A4 _135876 T>C (rs12468274) was performed using a SNaPshot (Applied Biosystems, Life Technologies, Carlsbad, CA) single base extension 2-plex assay as described (59). The extension products were run on an ABI 3130xl (Applied Biosystems), and the data analyzed by the GeneMapper software (Applied Biosystems).…”

Pharmacogenetics of Sult1A1

“…In cancer patients treated with ABT-751, those with greater than two copies of SULT1A1 experienced an average 34% increase in ABT-751 clearance (p = 0.044), an 18% reduction in ABT-751 area under the plasma concentration-time curve (p = 0.045), and a 50% increase in sulfation metabolic ratios (p = 0.025). They also observed a gene–dose effect of increasing metabolic ratios with increasing copies of SULT1A1 [25]. These data concordantly suggest a decrease in active ABT-751 bioavailability with higher SULT1A1 gene copies, implying that patients receiving this drug may have to have the dose adjusted based on individual genetic profiles of phase II enzymes.…”

“…Like Innocenti et al . [25], data generated in preclinical trials can be used to prequalify candidate genes and therefore guide future pharmacogenetic studies.…”