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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.

Trichophyton tonsurans is the primary etiologic agent of fungal infections in the pediatric population. Establishing techniques that facilitate strain discrimination offer the opportunity to investigate the relationship between fungal genotype, biochemical phenotype and disease presentation in the host. In the process of expanding efforts to elucidate intra-specific genetic variability in T. tonsurans, we have identified 2 genetic polymorphisms in the ALP1 gene: a fragment length polymorphism in the 5’UTR and a single SNP (G→A) within the 3′UTR. Full sequence data revealed that the length polymorphism was constituted by a 16 bp repeat element, present in tandem from 3 to 6 times depending on the strain. Quantitative RT-PCR analysis demonstrated a clear association between the length polymorphism and ALP1 mRNA transcript levels. Not only do the sequence variations identified in this study increase our ability to discriminate T. tonsurans strains, but they also reveal the presence of a genetic variation with functional consequences at the transcript level that may play a role in regulating disease severity.

The aromatic hydrocarbon receptor (AHR) functions as a ligand-activated transcription factor that mediates responses to aromatic hydrocarbons (AHs). Induction of cytochrome P450 1A1 (CYP1A1) is the most fully characterized response and is mediated by binding of the activated AHR complex to dioxin-responsive elements (DREs) located in the 5′-flanking region of the gene. In contrast to CYP1A1 induction, several other genes including the rat male-specific constitutive hepatic CYP2C11are suppressed by AHs. Our aim was to determine whether CYP2C11suppression by AHs is mediated by the AHR via interaction with DRE-like sequences. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) suppressed CYP2C11 mRNA in primary rat hepatocytes without altering the mRNA half-life. We identified five regions in the CYP2C115′-flank containing the DRE invariant core; electrophoretic gel retardation assays showed that at least one of these DREs is a potential binding site for the AHR. To test the function of the CYP2C11-DREs, Hepa-1, BRL 5637, and HepG2 cells were transfected with reporter constructs containing regions of the CYP2C115′-flank and promoter. No decrease in luciferase activity was found following TCDD treatment. In primary rat hepatocytes, the luciferase reporter vectors were suppressed by interleukin-1β but not by TCDD. In vitro footprinting showed protein binding at several sites in the CYP2C115′-flank, but the pattern was not altered by in vivo 3-methylcholanthrene treatment. These studies imply that AHs down-regulate CYP2C11by a negative transcriptional mechanism that is not simply due to AHR binding to an identified DRE-like sequence and that is distinct from that used by inflammatory cytokines.

Cytochrome P450 2D7 (CYP2D7) has long been considered a pseudogene. A recent report described an indel polymorphism (CYP2D7138delT) that causes a frameshift generating an open reading frame and functional protein. This polymorphism was observed in 6 of 12 samples from an Indian population. Individuals with the 138delT polymorphism expressed CYP2D7 protein from a brain-specific, alternatively spliced transcript (J Biol Chem279:27383–27389, 2004). The unexpectedly high frequency of the variant allele and resulting CYP2D7expression could have important implications for brain-specific metabolism of CYP2D substrates including many psychoactive drugs. However, the 138delT variant has not been detected in other studies (Pharmacogenetics11:45–55, 2001; Biochem Biophys Res Commun336:1241–1250, 2005). Our goal was to determine the frequency of this variant in a larger, ethnically diverse population. CYP2D7138delT genotypes for 163 Caucasians, 95 East Asians, 50 Indians, 68 Hispanic Latinos, and 68 African Americans were determined by Pyrosequencing. The 138delT allele was observed at a frequency of 1.0% in East Asians and 0.74% in Hispanic Latinos. The deletion was not observed in Indians or the other ethnic populations. In addition, in each of the three samples with 138delT, the putative brain-specific transcript contains a premature stop codon that would preclude protein expression. The low frequency of the CYP2D7138delT polymorphism in our ethnically diverse sample, and particularly the absence from 50 Indian samples, is in contrast to the high frequency previously reported. Our results suggest that CYP2D7138delT is unlikely to be highly relevant for population variation of pharmacokinetics or drug response.

Cytochrome P450 2D7 (CYP2D7) has long been considered a pseudogene. A recent report described an indel polymorphism (CYP2D7 138delT) that causes a frameshift generating an open reading frame and functional protein. This polymorphism was observed in 6 of 12 samples from an Indian population. Individuals with the 138delT polymorphism expressed CYP2D7 protein from a brain-specific, alternatively spliced transcript (J Biol Chem 279:27383–27389, 2004). The unexpectedly high frequency of the variant allele and resulting CYP2D7 expression could have important implications for brain-specific metabolism of CYP2D substrates including many psychoactive drugs. However, the 138delT variant has not been detected in other studies (Pharmacogenetics 11:45–55, 2001; Biochem Biophys Res Commun 336:1241–1250, 2005). Our goal was to determine the frequency of this variant in a larger, ethnically diverse population. CYP2D7 138delT genotypes for 163 Caucasians, 95 East Asians, 50 Indians, 68 Hispanic Latinos, and 68 African Americans were determined by Pyrosequencing. The 138delT allele was observed at a frequency of 1.0% in East Asians and 0.74% in Hispanic Latinos. The deletion was not observed in Indians or the other ethnic populations. In addition, in each of the three samples with 138delT, the putative brain-specific transcript contains a premature stop codon that would preclude protein expression. The low frequency of the CYP2D7 138delT polymorphism in our ethnically diverse sample, and particularly the absence from 50 Indian samples, is in contrast to the high frequency previously reported. Our results suggest that CYP2D7 138delT is unlikely to be highly relevant for population variation of pharmacokinetics or drug response.

Chyla: Abbvie, Inc: Employment, Other: Stock or options. Popovic:AbbVie: Employment, Other: Stock or options. Lu:AbbVie: Employment, Other: Stock or options. Dunbar:AbbVie: Employment, Other: Stock or options. Quarless:AbbVie: Employment, Other: Stock or options. Robinson:AbbVie: Employment, Other: Stock or options. Warder:AbbVie: Employment, Other: Stock or options. Jacobson:AbbVie: Employment, Other: Stock or options. Zhou:AbbVie: Employment, Other: Stock or options. Souers:AbbVie: Employment, Other: Stock or options. Waring:AbbVie: Employment, Other: Stock or options. Bhathena:AbbVie: Employment, Other: Stock or options. Leverson:AbbVie Inc: Employment, Other: Stock or options. Kim:AbbVie: Employment, Other: Stock or options.

Background:Venetoclax (VEN) monotherapy in patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) has been efficacious with a complete remission rate of 16% and also durable with median time to progression of 33.2 months (Roberts et al., 2019). Despite these responses, many pts eventually relapse. To investigate possible mechanisms of resistance to VEN monotherapy, we performed a genome-wide CRISPR screen to identify genes whose loss of expression leads to reduction in drug sensitivity. To determine whether similar genomic alterations occur in pts treated with VEN, we analyzed the DNA and RNA of pre- and post-therapy specimens from CLL pts enrolled in two VEN monotherapy trials (NCT01328626 and NCT01889186).

Mathew: AbbVie Inc.: Employment. Haribhai:AbbVie Inc.: Employment. Kohlhapp:AbbVie Inc.: Employment. Duggan:AbbVie Inc.: Employment. Ellis:AbbVie Inc.: Employment. Riehm:AbbVie Inc.: Employment. Robinson:AbbVie Inc.: Employment. Shi:AbbVie Inc.: Employment. Bhathena:AbbVie Inc.: Employment. Leverson:AbbVie Inc: Employment, Equity Ownership, Patents & Royalties. Pappano:AbbVie Inc.: Employment. Donawho:AbbVie Inc.: Employment. Uziel:AbbVie Inc.: Employment.

Introduction and objectives:

Chyla: AbbVie Inc.: Employment, Other: may own stock. Popovic:AbbVie Inc.: Employment, Other: may own stock. Potluri:AbbVie Inc.: Employment, Other: may own stock. Hayslip:AbbVie Inc.: Employment, Other: May own stock. Huang:AbbVie Inc.: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Mabry:AbbVie Inc.: Employment, Other: May own stock. Bhathena:AbbVie Inc.: Employment, Other: may own stock.

Background:We recently reported encouraging antileukemic activity of venetoclax, an orally available selective BCL-2 inhibitor, in combination with hypomethylating agents (HMA; NCT02203773) or low dose cytarabine (LDAC; NCT02287233) in patients aged ≥65 years with treatment-naive acute myeloid leukemia (AML) who are not fit for standard induction therapy [Pollyea et al, ASCO 2016 (abstract 7009); Lin et al, ASCO 2016 (abstract 7007)]. Here we present the genetic and molecular markers observed in this patient population, and their correlation with responses.

Ross: AbbVie: Employment, Equity Ownership. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Chyla:AbbVie: Employment, Equity Ownership. Roberts-Rapp:AbbVie: Employment, Equity Ownership. Goswami:AbbVie: Employment, Equity Ownership. Yan:AbbVie: Employment, Equity Ownership. Huang:AbbVie: Employment, Equity Ownership. Bhathena:AbbVie: Employment, Equity Ownership. Enschede:AbbVie: Employment, Equity Ownership. Maciag:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. McKeegan:AbbVie: Employment, Equity Ownership.

Introduction:Multiple myeloma (MM) tumor cell survival is largely dependent on a complex network of interactions between pro-survival (BCL-2, BCL-XL, MCL-1) and pro-death (BIM, NOXA, BID, BAD, BAK, BAX) BCL-2 family members. Venetoclax (VEN) is a potent, selective, orally bioavailable small-molecule BCL-2 inhibitor. Bortezomib (BTZ) is a proteasome inhibitor that can impede MCL-1 activity by increasing the MCL-1 antagonist NOXA. The addition of VEN has been shown to enhance the activity of BTZ in MM cell line and xenograft models. Chromosomal abnormalities (immunoglobulin heavy chain translocations, amplification, deletions) can also influence sensitivity of MM cells to treatment. Results presented herein describe retrospective biomarker analysis in a subset of dose-escalation patients (pts) from an ongoing phase 1b study of VEN in combination with BTZ and dexamethasone in relapsed/refractory (R/R) MM.

Pharmacogenetics is the study of relationships between genetic variation and inter‐individual differences with respect to drug response. As the field has matured over the past 15 years, a remarkable diversity of pathways, variation types, and mechanisms have been found to be relevant pharmacogenetic factors. Today, pharmacogenetics is becoming more important in pharmacology for target validation, lead optimization, and understanding of idiosyncratic toxicity. This unit provides an overview of the history of pharmacogenetics and current research applications in drug discovery, as well as a discussion of research quality issues relevant for human subjects research in the pharmacogenetics laboratory. Curr. Protoc. Hum. Genet. 60:9.19.1‐9.19.23. © 2009 by John Wiley & Sons, Inc.