© Geriatric Times. All rights reserved.
CVD, Pharmacogenomics and Tailored Medical Therapy
by Debabrata Mukherjee, M.D.
Geriatric Times May/June 2003 Vol. IV Issue 3
Individuals respond very differently to medications in terms of both efficacy and safety. There are significant inter-individual differences in drug absorption, metabolism and excretion that are related to genetic polymorphisms. Pharmacogenomics is the study of these polymorphisms that has the ultimate objective of tailoring individual drug therapy to optimize safety and efficacy. The concept of an individualized approach to drug therapy is extremely promising and has significant health and economic implications. Each year, approximately 2.1 million hospitalized patients suffer from an adverse reaction to a prescribed medication, and more than 100,000 deaths are caused by an adverse reaction (Lazarou et al., 1998).
Inherited differences in drug metabolizing enzymes are usually monogenic traits. The overall clinical effect of most drugs is, however, not monogenic, but influenced by multiple genes involved in pathways of drug absorption, metabolism, disposition and target receptor (Evans and Johnson, 2001). For a single drug, therefore, one gene may determine the extent of drug activation, a second one may affect drug excretion, and yet a third one may determine receptor sensitivity. The overall effect of this drug may then be influenced by polymorphisms in any of these genes. This article addresses the currently known polymorphisms affecting cardiovascular drug responses and discusses the potential application of pharmacogenomics in improving drug safety and efficacy.
Pharmacogenomics evolved from the older, more established field of pharmacogenetics, which studies individual ability to metabolize a drug. Pharmacogenomics has a broader scope and is a comprehensive study of the genetic basis of a drug's absorption, distribution, metabolism, excretion and receptor-target affinity. The cytochrome P450 (CYP) enzyme family plays an important role in the metabolism of numerous drugs, including antidepressants, antipsychotics and cardiovascular agents. The understanding of the molecular basis of the CYP genetic polymorphisms began with the characterization of the drug-metabolizing enzyme debrisoquine hydroxylase (CYP 2D6) (Gonzalez et al., 1988). The ability to metabolize debrisoquine is bimodally distributed as extensive metabolizers and poor metabolizers and is inherited in an autosomal recessive pattern (Mahgoub et al., 1977). An important aspect of the debrisoquine/sparteine-related CYP 2D6 polymorphism is the large number of drugs metabolized differentially on the same basis, including ß-blockers and others of cardiovascular significance.
Mibefradil (Posicor), a tetralol derivative, was a long-acting calcium antagonist used for the treatment of patients with hypertension and chronic stable angina pectoris. This drug was virtually completely metabolized via two parallel pathways, an esterase-catalyzed hydrolysis and CYP 3A4-mediated oxidation. Oral, multiple-dose administration of mibefradil 50 mg or 100 mg once daily was associated with inhibition of the CYP 3A4 pathway of metabolism, increasing the half-life and bioavailability of the parent compound (Welker et al., 1998). The inhibition of CYP resulted in numerous clinically relevant drug interactions, which ultimately resulted in mibefradil's withdrawal from the market (Welker et al., 1998).
There have been a number of recent advances in understanding the implications of polymorphisms in various cardiovascular diseases (Table). (Due to copyright concerns, this table cannot be reproduced online. Please see p14 of the print edition--Ed.) The identification of the molecular mechanisms of blood pressure variation has implications for the development and use of antihypertensive treatments. Thiazide diuretics inhibit the Na-Cl cotransporter of the distal convoluted tubule (Lifton et al., 2001). A polymorphism of the gene for cytoskeletal protein, adducin, which is linked to hypertension, sodium sensitivity and blood pressure response to diuretic therapy, has been identified (Ferrari, 1998). A new antihypertensive compound that could be selectively used in patients with this polymorphism has also been identified.
The clinical course of the congenital long QT syndrome (LQTS), a hereditary malignant arrhythmic disorder, can be predicted through genotypic analysis (Zareba et al., 1998). These researchers observed increased mortality in patients with SCN5A mutation, which suggested the need for aggressive therapy in those individuals. The primary defect with the SCN5A mutation is in the late opening sodium channels, and a gene-specific therapy with class Ib sodium channel blockers is very effective in these patients (Rosero et al., 1997). Similarly, in patients with LQTS due to abnormal potassium channel function, therapies directed at altering the function of the abnormal channels to create outward current might be effective (Emilien et al., 2000).
Platelet glycoprotein IIb/IIIa, a membrane receptor for fibrinogen and von Willebrand factor, plays an important role in platelet aggregation and pathogenesis of acute coronary syndromes. A high frequency of a polymorphism of PlA2 of the gene encoding glycoprotein IIIa has been associated with a higher prevalence of premature myocardial infarction (Weiss et al., 1996). In 1997, Walter et al. reported a fivefold increased risk in stent thrombosis in patients with the PlA2 genotype, and, in 1996, Weiss et al. reported a twofold increased risk of myocardial infarction in patients with the PlA2 polymorphism. The PlA2 polymorphism has been associated with increased fibrinogen binding with adenosine diphosphate (ADP) (Goodall et al., 1999), suggesting that dual antiplatelet therapy using ADP antagonists such as clopidogrel (Plavix) may be more effective in patients with this polymorhism (Topol, 2000).
Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce mortality in patients with both symptomatic and asymptomatic left ventricular dysfunction and after an acute myocardial infarction. An insertion/deletion polymorphism (consisting of a 287-bp alu repeat sequence) in intron 16 of the DCP1 gene that encodes ACE is associated with significant variation in serum level among patients (Rigat et al., 1990). Individuals homozygous for the deletion allele (DD) have twice the serum levels compared to those homozygous for the insertion allele (II), and heterozygous (ID) people have intermediate levels (Rioux, 2000). In patients with systolic dysfunction, the ACE D allele was associated with a significantly poorer transplant-free survival (McNamara et al., 2001). This effect was primarily seen in patients who were not on ß-blockers and suggests a potential pharmacogenetic interaction between the ACE D/I polymorphism and therapy with ß-blockers in the treatment of heart failure. Thus, knowledge of the ACE genotype may help segregate patients into potential responders and nonresponders and determine overall prognosis.
There are significant economic issues related to pharmacogenomics. Bringing a new drug to the market currently costs approximately $500 million, making it economically unattractive for pharmaceutical companies to target small patient populations based on pharmacogenomics (Mancinelli et al., 2000). In order to make tailored drug therapy feasible, regulatory agencies would have to offer economic incentives to companies in the form of shortened approval times and fewer regulatory hurdles. The U.S. Food and Drug Administration does support pharmacogenetic testing throughout drug development (Bullock, 1999). A number of drugs have been withdrawn from the market, such as mibefradil and troglitazone (Rezulin) (Biswas et al., 2001; Welker et al., 1998), resulting in a significant economic loss for the pharmaceutical companies. This type of loss possibly could have been avoided by pharmacokinetic testing incorporating pharmacogenomics. The initial economic cost of genotyping may eventually be offset by smaller clinical trials, fewer adverse effects, improved survival rates and accelerated drug approval.
The anticipated benefits of pharmacogenomics include safer, more effective medications that can be administered in the optimum dose in an individual patient. Single nucleotide polymorphism analysis is likely to be incorporated in future clinical trials (Grant, 1999), and results of such studies may then be used to design subsequent trials incorporating genetic prescreening. Practicing clinicians can then avoid the usual trial and error approach with drugs and use predictive genetic testing for optimal therapy. This is likely to substantially reduce adverse reactions and result in significant savings to the health care system in the future.
Dr. Mukherjee is director of the Peripheral Vascular Interventions program and assistant professor of cardiology at the University of Michigan. His research interests include genomics, vascular diseases and acute coronary syndromes.
References
Biswas P, Wilton LV, Shakir SA (2001), Troglitazone and liver function abnormalities: lessons from a prescription event monitoring study and spontaneous reporting. Drug Saf 24(2):149-154.
Bullock PL (1999), Viewpoint: pharmacogenetics and its impact on drug development. Drug Benefit Trends 11(1):53-54.
Emilien G, Ponchon M, Caldas C et al. (2000), Impact of genomics on drug discovery and clinical medicine. QJM 93(7):391-423.
Evans WE, Johnson JA (2001), Pharmacogenomics: the inherited basis for interindividual differences in drug response. Annu Rev Genomics Hum Genet 2:9-39.
Ferrari P (1998), Pharmacogenomics: a new approach to individual therapy of hypertension? Curr Opin Nephrol Hypertens 7(2):217-222.
Gonzalez FJ, Skoda RC, Kimura S et al. (1988), Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331(6155):442-446.
Goodall AH, Curzen N, Panesar M et al. (1999), Increased binding of fibrinogen to glycoprotein IIIa-proline33 (HPA-Ib, PlA2, Zwb) positive platelets in patients with cardiovascular disease. Eur Heart J 20(10):742-747 [see comment].
Grant DM (1999), Pharmacogenomics and the changing face of clinical pharmacology. Can J Clin Pharmacol 6:131-132.
Lazarou J, Pomeranz BH, Corey PN (1998), Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279(15):1200-1205 [see comments].
Lifton RP, Gharavi AG, Geller DS (2001), Molecular mechanisms of human hypertension. Cell 104(4):545-556.
Mahgoub A, Idle JR, Dring LG et al. (1977), Polymorphic hydroxylation of Debrisoquine in man. Lancet 2(8038):584-586.
Mancinelli L, Cronin M, Sadee W (2000), Pharmacogenomics: the promise of personalized medicine. AAPS Pharmsci 2(1):E4.
McNamara DM, Holubkov R, Janosko K et al. (2001), Pharmacogenetic interactions between beta-blocker therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. Circulation 103(12):1644-1648 [see comment].
Mukherjee D, Topol EJ (2002), Pharmacogenomics in cardiovascular diseases. Prog Cardiovasc Dis 44(6):479-498.
Rigat B, Hubert C, Alhenc-Gelas F et al. (1990), An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86(4):1343-1346.
Rioux PP (2000), Clinical trials in pharmacogenetics and pharmacogenomics: methods and applications. Am J Health Syst Pharm 57(9):887-898; quiz 899-901.
Rosero SZ, Zareba W, Robinson JL, Moss AL (1997), Gene-specific therapy for long QT syndrome: QT shortening with lidocaine and tocainide in patients with mutation of the sodium-channel gene. Ann Noninvasive Electrocardiol 2:274-278.
Topol EJ (2000), The future of antiplatelet therapy: optimizing management in patients with acute coronary syndrome. Clin Cardiol 23(suppl 6):VI-23-28.
Walter DH, Schachinger V, Elsner M et al. (1997), Platelet glycoprotein IIIa polymorphisms and risk of coronary stent thrombosis. Lancet 350(9086):1217-1219 [see comments].
Weiss EJ, Bray PF, Tayback M et al. (1996), A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 334(17):1090-1094 [see comments].
Welker HA, Wiltshire H, Bullingham R (1998), Clinical pharmacokinetics of mibefradil. Clin Pharmacokinet 35(6):405-423.
Zareba W, Moss AJ, Schwartz PJ et al. (1998), Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med 339(4):960-965.
