By: Neal Shah
The focus of pharmacy is rapidly shifting from simple filling and dispensing of prescriptions to preventative medicine and efficient clinical practice. The field of genetics has been incorporated in many defining therapies and will continue to shape how we treat our patients. Examples discussed here are the roles of human leukocyte antigen presence in fatal rashes, correct therapeutic management of HIV, and CYP2C9 polymorphisms in specific populations.
HIV enters our CD4+ cells via two receptors: CCR5 and CXCR4. Generally, HIV uses CCR5 more during the initial years of the infection, however, as therapy is administered, a shift to using CXCR4 occurs.1 This means that therapy should be tailored to inhibit these receptors, since using a CCR5-specific inhibitor in the presence of dual/mixed CCR5/CXCR4 or CXCR4-only strains would be futile. One such antiviral drug for HIV targets the virus that specifically uses the CCR5 receptor to enter CD4+ cells: maraviroc. Maraviroc (Selzentry®, ViiV) is approved solely for use in CCR5-trophic HIV strains that are resistant to other drugs.2 A study by Symons et al. earlier this year confirmed that in the presence of dual/mixed CCR5/CXCR4, maraviroc successfully inhibited growth of CCR5-dependent HIV, but was not able to decrease CXCR4 growth.3 However, maraviroc remains controversial in clinical use because of conflicting reports of overall efficacy from studies. There is an ongoing trial to combine maraviroc and an integrase inhibitor, raltegravir, in treatment-naïve patients.4 Interestingly, maraviroc also has been shown to be effective in novel situations such as organ transplantation,5 and the CCR5 receptor has also been shown to reduce cardiovascular risks and decrease atherogenicity.6
Another HIV medication that has genetic sensitivities is a nucleoside reverse transcriptase inhibitor (NRTI) called abacavir (Ziagen®, GlaxoSmithKline; abbreviated as ABC). Although efficacious in lowering viral load, due to a potentially fatal hypersensitivity reaction characterized by a rash, patients must be screened for a specific human leukocyte antigen (HLA-B*5701) prior to initiating abacavir therapies.7 This well-documented reaction gained a Black Box Warning onto the package insert of abacavir and many rapid tests that detect the HLA-B*5701 allele. A paper earlier this year published positive results of using simple and effective polymerase chain reaction (PCR) via a blood sample.8 Last month, another paper determined that 100% reproducibility of the PCR results were attained by using non-invasive buccal or salivary swabs.9
Abacavir is not the only drug to show hypersensitivity based on human leukocyte antigens. Carbamazepine (Tegretol®, Novartis; abbreviated as CBZ) is an anti-epileptic drug (AED) that, like other AEDs, has various therapeutic purposes. Carbamazepine has been linked to lethal skin reactions known as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).10,11 These reactions to carbamazepine originate from the expression of the HLA-B*1503 allele. This allele is expressed more in Asian patients, whereas Caucasian and African patients are considered low-risk. Interestingly, within the Asian population, Japanese and Koreans show lower risks compared to South Asian Indians, Chinese, Indonesian, and Taiwanese populations.12-15 Japanese patients with the HLA-B*1511 allele expression are at greater risk for the cutaneous reactions.16,17 Another interesting note is that if a patient tests positive for this allele, both carbamazepine and phenytoin (Dilantin®, Pfizer) should be avoided, as potential cross-reactivity exists.18,19 This is most likely due to the structural similarities of phenytoin and carbamazepine.20 Since AEDs (and especially carbamazepine and phenytoin) are more commonly used and dispensed compared to antiretroviral drugs, allele testing for at-risk patient groups is encouraged.
The cytochrome P450 (CYP450) enzyme system is one of the most important routes of metabolism of exogenous substances. Polymorphisms of CYP450 subsets can cause increased toxic metabolites, decreased drug efficacy, or overdose-like effects from medications. Additionally, CYP450 interactions are the most common sources of drug interactions in clinical practice; and managing therapies, while balancing these interactions, is of utmost importance. For instance, increased CYP2E1 will cause acetaminophen (Tylenol®, McNeil) to be metabolized to hepatotoxic intermediates.21,22 Decreased drug efficacy is commonly seen when CYP450 is used to activate prodrugs in patients with insufficient enzymes; such an example is discussed below. Overdose-like effects occur when active molecules cannot be metabolized to inactive metabolites, and therefore exert effects for a longer time, necessitating a decreased dose or prolonged dosing interval.
CYP450 polymorphisms are also divided racially: deficiencies in CYP2C9 are common in Asian patients23,24, which can cause an overdose-like effect of drugs such as warfarin (Coumadin®, Bristol-Myers Squibb), which can lead to bleeding. On the other hand, some drugs use CYP2C9 to convert from a prodrug form to active substances. A specific pharmacogenetic example that inspired this article were reports that Asian patients with deficient levels of CYP2C9 had subtherapeutic efficacy from clopidogrel (Plavix®, Bristol-Myers Squibb).25-27 Clopidogrel is administered orally as a prodrug that requires CYP2C9—among other CYP450 enzymes—to exert its actions.28 This can potentially be fatal since clopidogrel acts as an inhibitor of platelet aggregation used to prevent clotting, and if the drug is not activated, clots may develop even while on therapy. These reports were effective enough to require a Black Box Warning update of clopidogrel by the FDA in 2010.29
Genetics may also determine pharmaceutical therapy as a whole. Chemotherapy agents such as imatinib (Gleevec®, Novartis), nilotnib (Tasigna®, Novartis), and dasatinib (Sprycel®, Bristol-Myers Squibb) are specifically indicated when the patient is Philadelphia chromosome positive in chronic myelogenous leukemia (CML).30-32
Overall, this trend of tailoring therapies based on genotyping will not be limited to the above-mentioned conditions. Chronic diseases, like Type 1 and Type 2 diabetes mellitus, will eventually become foci for future research. As pharmacogenetic research grows, it will provide us with greater insight into preventative medicine and efficient clinical practice.
- Bleul C, Wu L, Hoxie et al. The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T-lymphocytes. Proc Natl Acad Sci U S A. 1997 March 4; 94(5): 1925–1930.
- Selzentry® [package insert]. Pfizer, Inc. New York.
- Symons J, van Lelyveld SF, Hoepelman A et al. Maraviroc is able to inhibit dual-R5 viruses in a dual/mixed HIV-1-infected patient. J Antimicrob Chemother. 2011 Apr;66(4):890-5.
- U.S. National Institutes of Health. Pilot Study of Maraviroc/Raltegravir for Naive HIV-1 Patients (NNNB). http://clinicaltrials.gov/ct2/show/NCT01291459; accessed October 21, 2011.
- Gilliam BL, Riedel DJ, Redfield RR. Clinical use of CCR5 inhibitors in HIV and beyond. J Transl Med. 2011 Jan 27;9 Suppl 1:S9.
- Jones KL, Maguire JJ, Davenport AP. Chemokine receptor CCR5: from AIDS to atherosclerosis. Br J Pharmacol. 2011 Apr;162(7):1453-69.
- Chaponda M, Pirmohamed M. Hypersensitivity reactions to HIV therapy. Br J Clin Pharmacol. 2011 May;71(5):659-71.
- Dello Russo C, Lisi L, Lofaro A et al. Novel sensitive, specific and rapid pharmacogenomic test for the prediction of abacavir hypersensitivity reaction: HLA-B*57:01 detection by real-time PCR. Pharmacogenomics. 2011 Apr;12(4):567-76.
- Badulli C, Sbarsi I, Di Giorgio D et al. A new approach to safely type for HLA the HIV infected people eligible to abacavir therapy: saliva or buccal swab as reliable DNA sources. Clin Chim Acta. 2011 Oct 9;412(21-22):1995-8.
- Harr T, French LE. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis. 2010 Dec 16;5:39.
- Phillips EJ, Chung WH, Mockenhaupt M et al. Drug hypersensitivity: pharmacogenetics and clinical syndromes. J Allergy Clin Immunol. 2011 Mar;127(3 Suppl):S60-6.
- Locharernkul C, Shotelersuk V, Hirankarn N. Pharmacogenetic screening of carbamazepine-induced severe cutaneous allergic reactions. J Clin Neurosci. 2011 Oct;18(10):1289-94.
- Kulkantrakorn K, Tassaneeyakul W, Tiamkao S et al. HLA-B*1502 Strongly Predicts Carbamazepine-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Thai Patients with Neu-ropathic Pain. Pain Pract. 2011 Jun 16.
- Zhang Y, Wang J, Zhao LM et al. Strong association between HLA-B*1502 and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in mainland Han Chinese patients. Eur J Clin Pharmacol. 2011 Sep;67(9):885-7.
- Wang Q, Zhou JQ, Zhou LM et al. Association between HLA-B*1502 allele and carbamazepine-induced severe cutaneous ad-verse reactions in Han people of southern China mainland. Seizure. 2011 Jul;20(6):446-8.
- Kaniwa N, Saito Y, Aihara M et al. HLA-B*1511 is a risk factor for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Epilepsia. 2010 Dec;51(12):2461-5.
- Aihara M. Pharmacogenetics of cutaneous adverse drug reactions. J Dermatol. 2011 Mar;38(3):246-54.
- Hirsch LJ, Arif H, Nahm EA et al. Cross-sensitivity of skin rashes with antiepileptic drug use. Neurology. 2008 Nov 4;71(19):1527-34.
- Alvestad S, Lydersen S, Brodtkorb E.Cross-reactivity pattern of rash from current aromatic antiepileptic drugs. Epilepsy Res. 2008 Aug;80(2-3):194-200.
- Jones GL, Amato RJ, Wimbish GH et al. Comparison of anti-convulsant potencies of cyheptamide, carbamazepine, and phenytoin. J Pharm Sci. 1981 Jun;70(6):618-20.
- Abdelmegeed MA, Moon KH, Chen C et al. Role of cyto-chrome P450 2E1 in protein nitration and ubiquitin-mediated deg-radation during acetaminophen toxicity. Biochem Pharmacol. 2010 Jan 1;79(1):57-66.
- Ueshima Y, Tsutsumi M, Takase S et al. Acetaminophen metabolism in patients with different cytochrome P-4502E1 geno-types. Alcohol Clin Exp Res. 1996 Feb;20(1 Suppl):25A-28A.
- Wiwanitkit V. Pharmacogenomic effect of cytochrome P450 2C9 polymorphisms in different populations. Clin Appl Thromb He-most. 2006 Apr;12(2):219-22.
- Yuen E, Gueorguieva I, Wise S et al. Ethnic differences in the population pharmacokinetics and pharmacodynamics of warfarin. J Pharmacokinet Pharmacodyn. 2010 Feb;37(1):3-24.
- Oh IY, Park KW, Kang SH et al. Association of cytochrome P450 2C19*2 polymorphism with clopidogrel response variability and cardiovascular events in Koreans treated with drug-eluting stents. Heart. 2011 Jun 23.
- Yamamoto K, Hokimoto S, Chitose T et al. Impact of CYP2C19 polymorphism on residual platelet reactivity in patients with coronary heart disease during antiplatelet therapy. J Cardiol. 2011 Mar;57(2):194-201.
- Sawada T, Shinke T, Shite J et al. Impact of cytochrome P450 2C19*2 polymorphism on intra-stent thrombus after drug-eluting stent implantation in Japanese patients receiving clopidogrel. Circ J. 2010 Dec 24;75(1):99-105.
- Campo G, Miccoli M, Tebaldi M et al. Genetic determinants of on-clopidogrel high platelet reactivity. Platelets. 2011;22(6):399-407.
- U.S. Food and Drug Administration. FDA Drug Safety Com-munication: Reduced effectiveness of Plavix (clopidogrel) in pa-tients who are poor metabolizers of the drug. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm accessed October 22, 2011.
- Gleevec® [package insert]. Novartis Pharmaceuticals Corporation. East Hanover, New Jersey.
- Tasigna® [package insert]. Novartis Pharmaceuticals Corporation. East Hanover, NJ.
- Sprycel® [package insert]. Bristol-Myers Squibb. Princeton, New Jersey.