Pharmacogenomics in Drug Development

When and How to Apply
  • Richard Judson
  • Arthur J. Moss
Chapter

Abstract

Pharmacogenomics research typically aims to find genetic variants that affect the pharmacokinetics or the pharmacodynamics of a drug. Pharmacokinetic effects can be very direct, and are therefore easy to understand. Genetic variants can cause loss of function for a metabolic enzyme that can in turn decrease the rate at which a drug is metabolized. This increases the amount of drug delivered to the active site, as well as the half-life of the drug in the system. There is a wider range of pharmacodynamic effects. A variant can change the binding properties of a receptor to which a drug is targeted, and can therefore affect activity. Alternatively, a variant can simply alter the level of expression of some protein that can lead to an indirect effect on drug action. Variants that cause such expression changes can be cis, meaning that a variant in the gene has a direct effect on the gene’s expression level. Alternatively, the effect can be trans, meaning that variation elsewhere in the genome indirectly affects expression levels for the gene. Genes causing such trans effects can be far removed from pathways directly involved in drug action.

Keywords

Grapefruit Juice Cardiac Safety Repolarization Reserve LQTS Mutation Clinical Trial Subject 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Barbey JT, Lazzara R, Zipes DP. Spontaneous adverse event reports of serious ventricular arrhythmias, QT prolongation, syncope, and sudden death in patients treated with cisapride. J Cardiovasc Pharmacol Ther 2002; 7:65–76.PubMedCrossRefGoogle Scholar
  2. 2.
    Haverkamp W, Martinez-Rubio A, Hief C, Lammers A, Muhlenkamp S, Wichter T et al. Efficacy and safety of d, l-sotalol in patients with ventricular tachycardia and in survivors of cardiac arrest. J Am Coll Cardiol 1997; 30:487–495.PubMedCrossRefGoogle Scholar
  3. 3.
    Lehmann MH, Hardy S, Archibald D, quart B, MacNeil DJ. Sex difference in risk of torsade de pointes with d, l-sotalol. Circulation 1996; 94:2535–2541.PubMedGoogle Scholar
  4. 4.
    Hohnloser SH. Proarrhythmia with class III antiarrhythmic drugs: types, risks, and management. Am J Cardiol 1997; 80:82G–89G.PubMedCrossRefGoogle Scholar
  5. 5.
    Fermini B, Fossa AA. The impact of drug-induced QT interval prolongation on drug discovery and development. Nat Rev Drug Discov 2003; 2:439–447.PubMedCrossRefGoogle Scholar
  6. 6.
    Shah RR. Pharmacogenetic aspects of drug-induced torsade de pointes: potential tool for improving clinical drug development and prescribing. Drug Saf 2004; 27:145–172.PubMedCrossRefGoogle Scholar
  7. 7.
    Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350:1013–1022.PubMedCrossRefGoogle Scholar
  8. 8.
    Wysowski DK, Corken A, Gallo-Torres H, Talarico L, Rodriguez EM. Postmarketing reports of QT prolongation and ventricular arrhythmia in association with cisapride and Food and Drug Administration regulatory actions. Am J Gastroenterol 2001; 96:1698–1703.PubMedCrossRefGoogle Scholar
  9. 9.
    Haverkamp W, Breithardt G, Camm AJ, Janse MJ, Rosen MR, Antzelevitch C et al. The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology. Cardiovasc Res 2000; 47:219–233.PubMedCrossRefGoogle Scholar
  10. 10.
    FDA-Psychological Drugs Advisory Committee. Briefing Document for Zeldex Capsules (ziprasidone hydrochloride). 7-19-2000.Google Scholar
  11. 11.
    Moss AJ, Schwartz PJ. Delayed repolarization (QT or QTU prolongation) and malignant ventricular arrhythmias. Mod Concepts Cardiovasc Dis 1982; 51:85–90.PubMedGoogle Scholar
  12. 12.
    Roden DM. Taking the “idio” out of “idiosyncratic”: predicting torsades de pointes. Pacing Clin Electrophysiol 1998; 21:1029–1034.PubMedCrossRefGoogle Scholar
  13. 13.
    Bednar MM, Harrigan EP, Anziano RJ, Camm AJ, Ruskin JN. The QT interval. Prog Cardiovasc Dis 2001; 43:1–45.PubMedGoogle Scholar
  14. 14.
    CPMP-Committee for Proprietary Medicinal Products. Points to Consider: The assessment of the potential for QT prolongation by non-cardiovascular medicinal products. 1997. London. Ref Type: ReportGoogle Scholar
  15. 15.
    Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999; 99:529–533.PubMedGoogle Scholar
  16. 16.
    Priori SG, Napolitano C. Genetic defects of cardiac ion channels. The hidden substrate for torsades de pointes. Cardiovasc Drugs Ther 2002; 16:89–92.PubMedCrossRefGoogle Scholar
  17. 17.
    Stephens JC, Schneider JA, Tanguay DA, Choi J, Acharya T, Stanley SE et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science 2001; 293:489–493.PubMedCrossRefGoogle Scholar
  18. 18.
    Marchini J, Cardon LR, Phillips MS, Donnelly P. The effects of human population structure on large genetic association studies. Nat Genet 2004.Google Scholar
  19. 19.
    Pitman EJG. Significance tests which may be applied to samples from any populations. Journal of the Royal Statistical Society (Series B) 1937; 4:119–130.Google Scholar
  20. 20.
    Brown CC, Fears TR. Exact significance levels for multiple binomial testing with application to carcinogenicity screens. Biometrics 1981; 37:763–774.PubMedCrossRefGoogle Scholar
  21. 21.
    Heyse J, Rom D. Adjusting for multiplicity of statistical tests in the analysis of carcinogenicity studies. Biometric Journal 1988; 30:883–896.CrossRefGoogle Scholar
  22. 22.
    Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A 2000; 97:10483–10488.PubMedCrossRefGoogle Scholar
  23. 23.
    Judson R, Stephens JC, Windemuth A. The predictive power of haplotypes in clinical response. Pharmacogenomics 2000; 1:15–26.PubMedCrossRefGoogle Scholar
  24. 24.
    Seebohm G, Chen J, Strutz N, Culberson C, Lerche C, Sanguinetti MC. Molecular determinants of KCNQ1 channel block by a benzodiazepine. Mol Pharmacol 2003; 64:70–77.PubMedCrossRefGoogle Scholar
  25. 25.
    Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC et al. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 2002; 105:1943–1948.PubMedCrossRefGoogle Scholar
  26. 26.
    Donger C, Denjoy I, Berthet M, Neyroud N, Cruaud C, Bennaceur M et al. KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation 1997; 96:2778–2781.PubMedGoogle Scholar
  27. 27.
    Napolitano C, Schwartz PJ, Brown AM, Ronchetti E, Bianchi L, Pinnavaia A et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J Cardiovasc Electrophysiol 2000; 11:691–696.PubMedCrossRefGoogle Scholar
  28. 28.
    Roden DM, Woosley RL, Primm RK. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am Heart J 1986; 111:1088–1093.PubMedCrossRefGoogle Scholar
  29. 29.
    Zehender M, Hohnloser S, Just H. QT-interval prolonging drugs: mechanisms and clinical relevance of their arrhythmogenic hazards. Cardiovasc Drugs Ther 1991; 5:515–530.PubMedCrossRefGoogle Scholar
  30. 30.
    Sesti F, Abbott GW, Wei J, Murray KT, Saksena S, Schwartz PJ et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci USA 2000; 97:10613–10618.PubMedCrossRefGoogle Scholar
  31. 31.
    Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW et al. MiRP1 forms IKr potassium channels with hERG and is associated with cardiac arrhythmia. Cell 1999; 97:175–187.PubMedCrossRefGoogle Scholar
  32. 32.
    Jongbloed R, Marcelis C, Velter C, Doevendans P, Geraedts J, Smeets H. DHPLC analysis of potassium ion channel genes in congenital long QT syndrome. Hum Mutat 2002; 20:382–391.PubMedCrossRefGoogle Scholar
  33. 33.
    Makita N, Horie M, Nakamura T, Ai T, Sasaki K, Yokoi H et al. Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation. Circulation 2002; 106:1269–1274.PubMedCrossRefGoogle Scholar
  34. 34.
    Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC. A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci U S A 2000; 97:12329–12333.PubMedCrossRefGoogle Scholar
  35. 35.
    Mitcheson JS, Chen J, Sanguinetti MC. Trapping of a methanesulfonanilide by closure of the hERG potassium channel activation gate. J Gen Physiol 2000; 115:229–240.PubMedCrossRefGoogle Scholar
  36. 36.
    Ficker E, Obejero-Paz CA, Zhao S, Brown AM. The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (hERG) mutations. J Biol Chem 2002; 277:4989–4998.PubMedCrossRefGoogle Scholar
  37. 37.
    Lees-Miller JP, Duan Y, Teng GQ, Duff HJ. Molecular determinant of high-affinity dofetilide binding to hERG1 expressed in Xenopus oocytes: involvement of S6 sites. Mol Pharmacol 2000; 57:367–374.PubMedGoogle Scholar
  38. 38.
    Abitbol I, Peretz A, Lerche C, Busch AE, Attali B. Stilbenes and fenamates rescue the loss of I(KS) channel function induced by an LQT5 mutation and other IsK mutants. EMBO J 1999; 18:4137–4148.PubMedCrossRefGoogle Scholar
  39. 39.
    Roti EC, Myers CD, Ayers RA, Boatman DE, Delfosse SA, Chan EK et al. Interaction with GM130 during hERG ion channel trafficking. Disruption by type 2 congenital long QT syndrome mutations. Human Ether-a-go-go-Related Gene. J Biol Chem 2002; 277:47779–47785.PubMedCrossRefGoogle Scholar
  40. 40.
    Valdivia CR, Tester DJ, Rok BA, Porter CB, Munger TM, Jahangir A et al. A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs. Cardiovasc Res 2004; 62:53–62.PubMedCrossRefGoogle Scholar
  41. 41.
    El Sherif N, Caref EB, Yin H, Restivo M. The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome. Tridimensional mapping of activation and recovery patterns. Circ Res 1996; 79:474–492.PubMedGoogle Scholar
  42. 42.
    Akar FG, Yan GX, Antzelevitch C, Rosenbaum DS. Unique topographical distribution of M cells underlies reentrant mechanism of torsade de pointes in the long-QT syndrome. Circulation 2002; 105:1247–1253.PubMedCrossRefGoogle Scholar
  43. 43.
    Shimizu W, McMahon B, Antzelevitch C. Sodium pentobarbital reduces transmural dispersion of repolarization and prevents torsades de Pointes in models of acquired and congenital long QT syndrome. J Cardiovasc Electrophysiol 1999; 10:154–164.PubMedCrossRefGoogle Scholar
  44. 44.
    Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 2001; 104:569–580.PubMedCrossRefGoogle Scholar
  45. 45.
    Liu DW, Antzelevitch C. Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell. Circ Res 1995; 76:351–365.PubMedGoogle Scholar
  46. 46.
    Houltz B, Darpo B, Edvardsson N, Blomstrom P, Brachmann J, Crijns HJ et al. Electrocardiographic and clinical predictors of torsades de pointes induced by almokalant infusion in patients with chronic atrial fibrillation or flutter: a prospective study. Pacing Clin Electrophysiol 1998; 21:1044–1057.PubMedCrossRefGoogle Scholar
  47. 47.
    Ackerman MJ, Tester DJ, Jones GS, Will ML, Burrow CR, Curran ME. Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. Mayo Clin Proc 2003; 78:1479–1487.PubMedGoogle Scholar
  48. 48.
    Bezzina CR, Verkerk AO, Busjahn A, Jeron A, Erdmann J, Koopmann TT et al. A common polymorphism in KCNH2 (hERG) hastens cardiac repolarization. Cardiovasc Res 2003; 59:27–36.PubMedCrossRefGoogle Scholar
  49. 49.
    Splawski I, Timothy KW, Tateyama M, Clancy CE, Malhotra A, Beggs AH et al. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 2002; 297:1333–1336.PubMedCrossRefGoogle Scholar
  50. 50.
    Kanki H, Yang P, Xie HG, Kim RB, George AL, Jr., Roden DM. Polymorphisms in beta-adrenergic receptor genes in the acquired long QT syndrome. J Cardiovasc Electrophysiol 2002; 13:252–256.PubMedCrossRefGoogle Scholar
  51. 51.
    Marx SO, Kurokawa J, Reiken S, Motoike H, D’Armiento J, Marks AR et al. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science 2002; 295:496–499.PubMedCrossRefGoogle Scholar
  52. 52.
    Piippo K, Swan H, Pasternack M, Chapman H, Paavonen K, Viitasalo M et al. A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics. J Am Coll Cardiol 2001; 37:562–568.PubMedCrossRefGoogle Scholar
  53. 53.
    Hara M, Danilo P, Jr., Rosen MR. Effects of gonadal steroids on ventricular repolarization and on the response to E 4031. J Pharmacol Exp Ther 1998; 285:1068–1072.PubMedGoogle Scholar
  54. 54.
    Rodriguez I, Kilborn MJ, Liu XK, Pezzullo JC, Woosley RL. Drug-induced QT prolongation in women during the menstrual cycle. JAMA 2001; 285:1322–1326.PubMedCrossRefGoogle Scholar
  55. 55.
    Stramba-Badiale M, Locati EH, Martinelli A, Courville J, Schwartz PJ. Gender and the relationship between ventricular repolarization and cardiac cycle length during 24-h Holter recordings. Eur Heart J 1997; 18:1000–1006.PubMedGoogle Scholar
  56. 56.
    Burke JH, Goldberger JJ, Ehlert FA, Kruse JT, Parker MA, Kadish AH. Gender differences in heart rate before and after autonomic blockade: evidence against an intrinsic gender effect. Am J Med 1996; 100:537–543.PubMedCrossRefGoogle Scholar
  57. 57.
    Rashba EJ, Zareba W, Moss AJ, Hall WJ, Robinson J, Locati EH et al. Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome. LQTS Investigators. Circulation 1998; 97:451–456.PubMedGoogle Scholar
  58. 58.
    Drici MD, Burklow TR, Haridasse V, Glazer RI, Woosley RL. Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart. Circulation 1996; 94:1471–1474.PubMedGoogle Scholar
  59. 59.
    Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR, Jr. Torsades de pointes occurring in association with terfenadine use. JAMA 1990; 264:2788–2790.PubMedCrossRefGoogle Scholar
  60. 60.
    Garte S, Gaspari L, Alexandrie AK, Ambrosone C, Autrup H, Autrup JL et al. Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol Biomarkers Prev 2001; 10:1239–1248.PubMedGoogle Scholar
  61. 61.
    Nakamura K, Goto F, Ray WA, McAllister CB, Jacqz E, Wilkinson GR et al. Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 1985; 38:402–408.PubMedCrossRefGoogle Scholar
  62. 62.
    Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 1998; 38:389–430.PubMedCrossRefGoogle Scholar
  63. 63.
    Tirona RG, Lee W, Leake BF, Lan LB, Cline CB, Lamba V et al. The orphan nuclear receptor HNF4alpha determines PXR-and CAR-mediated xenobiotic induction of CYP3A4. Nat Med 2003; 9:220–224.PubMedCrossRefGoogle Scholar
  64. 64.
    Curtis LH, Ostbye T, Sendersky V, Hutchison S, Allen LaPointe NM, Al Khatib SM et al. Prescription of QT-prolonging drugs in a cohort of about 5 million outpatients. Am J Med 2003; 114:135–141.PubMedCrossRefGoogle Scholar
  65. 65.
    Roe CM, Odell KW, Henderson RR. Concomitant use of antipsychotics and drugs that may prolong the QT interval. J Clin Psychopharmacol 2003; 23:197–200.PubMedCrossRefGoogle Scholar
  66. 66.
    Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs 2002; 62:1649–1671.PubMedCrossRefGoogle Scholar
  67. 67.
    Paulussen AD, Gilissen RA, Armstrong M, Doevendans PA, Verhasselt P, Smeets HJ et al. Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. J Mol Med 2004; 82:182–188.PubMedCrossRefGoogle Scholar
  68. 68.
    Swan H, Viitasalo M, Piippo K, Laitinen P, Kontula K, Toivonen L. Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and hERG potassium channel defects. J Am Coll Cardiol 1999; 34:823–829.PubMedCrossRefGoogle Scholar
  69. 69.
    Ficker E, Jarolimek W, Kiehn J, Baumann A, Brown AM. Molecular determinants of dofetilide block of hERG K+ channels. Circ Res 1998; 82:386–395.PubMedGoogle Scholar
  70. 70.
    Chen J, Seebohm G, Sanguinetti MC. Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of hERG and eag potassium channels. Proc Natl Acad Sci U S A 2002; 99:12461–12466.PubMedCrossRefGoogle Scholar
  71. 71.
    Kubota T, Shimizu W, Kamakura S, Horie M. Hypokalemia-induced long QT syndrome with an underlying novel missense mutation in S4-S5 linker of KCNQ1. J Cardiovasc Electrophysiol 2000; 11:1048–1054.PubMedCrossRefGoogle Scholar
  72. 72.
    Seebohm G, Scherer CR, Busch AE, Lerche C. Identification of specific pore residues mediating KCNQ1 inactivation. A novel mechanism for long QT syndrome. J Biol Chem 2001; 276:13600–13605.PubMedGoogle Scholar
  73. 73.
    Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996; 12:17–23.PubMedCrossRefGoogle Scholar
  74. 74.
    Shalaby FY, Levesque PC, Yang WP, Little WA, Conder ML, Jenkins-West T et al. Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. Circulation 1997; 96:1733–1736.PubMedGoogle Scholar
  75. 75.
    Splawski I, Shen J, Timothy KW, Vincent GM, Lehmann MH, Keating MT. Genomic structure of three long QT syndrome genes: KVLQT1, hERG, and KCNE1. Genomics 1998; 51:86–97.PubMedCrossRefGoogle Scholar
  76. 76.
    Ackerman MJ, Schroeder JJ, Berry R, Schaid DJ, Porter CJ, Michels VV et al. A novel mutation in KVLQT1 is the molecular basis of inherited long QT syndrome in a near-drowning patient’s family. Pediatr Res 1998; 44:148–153.PubMedCrossRefGoogle Scholar
  77. 77.
    Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, hERG, SCN5A, KCNE1, and KCNE2. Circulation 2000; 102:1178–1185.PubMedGoogle Scholar
  78. 78.
    Liu H, Tateyama M, Clancy CE, Abriel H, Kass RS. Channel openings are necessary but not sufficient for use-dependent block of cardiac Na(+) channels by flecainide: evidence from the analysis of diseaselinked mutations. J Gen Physiol 2002; 120:39–51.PubMedCrossRefGoogle Scholar
  79. 79.
    Abriel H, Wehrens XH, Benhorin J, Kerem B, Kass RS. Molecular pharmacology of the sodium channel mutation D1790G linked to the long-QT syndrome. Circulation 2000; 102:921–925.PubMedGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2005

Authors and Affiliations

  • Richard Judson
    • 1
  • Arthur J. Moss
    • 2
  1. 1.Research & Development, Genaissance PharmaceuticalsNew HavenUSA
  2. 2.University of Rochester Medical CenterRochesterUSA

Personalised recommendations