Browsing by Author "Desta, Z."

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects
    (NPG - Nature Publishing Group, 2013-10-29) Henry, N. L.; Chan, H-P; Dantzer, J.; Goswami, C. P.; Li, L.; Skaar, Todd C.; Rae, J. M.; Desta, Z.; Khouri, N.; Pinsky, R.; Oesterreich, S.; Zhou, C.; Hadjiiski, L.; Philips, S.; Robarge, J.; Nguyen, A. T.; Storniolo, A. M.; Flockhart, D. A.; Hayes, D. F.; Helvie, M. A.; Stearns, V.; Department of Medicine, School of Medicine
    Background: Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy. Methods: Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment. Results: Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ⩾20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed. Conclusion: Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes.
  • Thumbnail Image
    Item
    Cytochrome P450 2D6 activity predicts discontinuation of tamoxifen therapy in breast cancer patients
    (Springer Nature, 2009-08) Rae, J. M.; Sikora, M. J.; Henry, N. L.; Li, L.; Kim, S.; Oesterreich, S.; Skaar, Todd C.; Nguyen, A. T.; Desta, Z.; Storniolo, A. M.; Flockhart, David A.; Hayes, D. F.; Stearns, V.
    The selective estrogen receptor modulator tamoxifen is routinely used for treatment and prevention of estrogen-receptor-positive breast cancer. Studies of tamoxifen adherence suggest that over half of patients discontinue treatment before the recommended 5 years. We hypothesized that polymorphisms in CYP2D6, the enzyme responsible for tamoxifen activation, predict for tamoxifen discontinuation. Tamoxifen-treated women (n=297) were genotyped for CYP2D6 variants and assigned a ‘score’ based on predicted allele activities from 0 (no activity) to 2 (high activity). Correlation between CYP2D6 score and discontinuation rates at 4 months was tested. We observed a strong nonlinear correlation between higher CYP2D6 score and increased rates of discontinuation (r2=0.935, P=0.018). These data suggest that presence of active CYP2D6 alleles may predict for higher likelihood of tamoxifen discontinuation. Therefore, patients who may be most likely to benefit from tamoxifen may paradoxically be most likely to discontinue treatment prematurely.
  • Thumbnail Image
    Item
    Estrogen receptor genotypes, menopausal status, and the effects of tamoxifen on lipid levels: revised and updated results.
    (Clinical pharmacology and therapeutics, 2010-11) Hayes, D.F.; Skaar, Todd C.; Rae, J.M.; Henry, N.L.; Nguyen, A.T.; Stearns, V.; Li, L.; Philips, S.; Desta, Z.; Flockhart, D.A.
    We previously reported that the ESR1 XbaI genotypes were associated with baseline and tamoxifen-induced serum lipid profiles. The analysis in that study was carried out by PCR followed by restriction-enzyme digestion. After reanalysis using more robust TaqMan assays, the findings related to ~10% of the genotypes for the ESR1 XbaI single-nucleotide polymorphism (SNP) were revised. For the other genotypes (i.e., ESR1 PvuII, ESR2, and CYP2D6), the results were nearly identical to those in the previous study. Upon reanalysis, previously reported associations between the ESR1 Xba1 genotypes and baseline triglyceride and low-density lipoprotein (LDL) cholesterol levels were no longer observed. Previously reported associations between the ESR1 XbaI genotypes and tamoxifen-induced changes in levels of total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were also no longer observed. However, the following observations from the original report did not change: (i) the levels of circulating lipids are lower in women taking tamoxifen; (ii) there is an association between the ESR2-02 genotypes and changes in triglyceride levels; and (iii) neither ESR1 PvuII nor CYP2D6 is associated with any changes in serum lipid concentrations in patients receiving treatment with tamoxifen.
  • Thumbnail Image
    Item
    Identification and Mechanistic Investigation of Drug-Drug Interactions Associated With Myopathy: A Translational Approach
    (Wiley Blackwell (John Wiley & Sons), 2015-09) Han, X.; Quinney, S. K.; Wang, Z.; Zhang, P.; Duke, J.; Desta, Z.; Elmendorf, J. S.; Flockhart, D. A.; Li, L.; Department of Medical & Molecular Genetics, IU School of Medicine
    Myopathy is a group of muscle diseases that can be induced or exacerbated by drug-drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine-simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System.
  • Thumbnail Image
    Item
    Implementation of a pharmacogenomics consult service to support the INGENIOUS trial
    (Wiley, 2016-07) Eadon, M.T.; Desta, Z.; Levy, K.D.; Decker, B.S.; Pierson, R.C.; Pratt, V.M.; Callaghan, J.T.; Rosenman, M.B.; Carpenter, J.S.; Holmes, A.M.; McDonald, C.A.; Benson, E.A.; Patil, A.S.; Vuppalanchi, R.; Gufford, B.T.; Dave, N.; Robarge, J.D.; Hyder, M.A.; Haas, D.M.; Kreutz, R.P.; Dexter, P.R.; Skaar, Todd C.; Flockhart, D.A.; Medicine, School of Medicine
    Hospital systems increasingly utilize pharmacogenomic testing to inform clinical prescribing. Successful implementation efforts have been modeled at many academic centers. In contrast, this report provides insights into the formation of a pharmacogenomics consultation service at a safety-net hospital, which predominantly serves low-income, uninsured, and vulnerable populations. The report describes the INdiana GENomics Implementation: an Opportunity for the UnderServed (INGENIOUS) trial and addresses concerns of adjudication, credentialing, and funding.
  • Thumbnail Image
    Item
    Population pharmacogenetic-based pharmacokinetic modeling of efavirenz, 7-hydroxy- and 8-hydroxyefavirenz
    (Wiley, 2014-01) Abdelhady, A.M.; Desta, Z.; Jiang, F.; Yeo, C.W.; Shin, J.; Overholser, B.R.; Department of Medicine, IU School of Medicine
    The purpose of this study was to determine the demographic and pharmacogenetic covariates that influence the disposition of efavirenz (EFV) and its major metabolites. A population pharmacokinetic (PK) model was developed from a randomized, cross-over, drug-interaction study in healthy male Korean subjects (n = 17). Plasma concentrations of EFV and its hydroxy-metabolites (0-120 hours) were measured by LC/MS/MS. Genomic DNA was genotyped for variants in the cytochrome P450 (CYP) 2A6, 2B6, 3A5, and MDR1 genes. A PK model was built in a stepwise procedure using nonlinear mixed effect modeling in NONMEM 7. The covariate model was built using the generalized additive modeling and forward selection-backward elimination. Model-based simulations were performed to predict EFV steady-state concentrations following 200, 400, and 600 mg daily oral dose among different CYP2B6 genotypes. The final model included only CYP2B6 genotype as a covariate that predicts EFV clearance through the formation of 8-OH EFV that represented 65% to 80% of EFV clearance. The total clearance of EFV in CYP2B6*6/*6 genotype was ∼30% lower than CYP2B6*1/*1 or CYP2B6*1/*6 alleles (P < .001). Clopidogrel reduced both formation and elimination clearances of 8-OH EFV by 22% and 19%, respectively (P = .033 and .041). Other demographics and genotype of accessory CYP pathways did not predict EFV or metabolites PK. CYP2B6 genotype was the only significant predictor of EFV disposition. The developed model may serve as the foundation for further exploration of pharmacogenetic-based dosing of EFV.