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1 For personal use only. Not to be reproduced without permission of the publisher Pharmacogenetics in clinical practice AUTHORS: Luc JJ Derijks, PharmD, PhD 1, H Jeroen Derijks, MSc, PharmD 2,3, Daan J Touw, PharmD, PhD 1,4, Jean MH Conemans, PharmD 5, Antoine CG Egberts, PharmD, PhD 3,6 ABSTRACT The availability of data from pharmacogenetic studies is reflected in therapeutic practice, and pharmacogenetics is slowly entering the medical arena. Preconditions for the utilisation of pharmacogenetic knowledge are that: 1) genetic variation and prevalence are known 2) pharmacological consequences (concerning efficacy or toxicity) are known 3) clinical relevance is demonstrated 4) data from pharmacogenetic studies are translated in to practical guidelines 5) knowledge and techniques are available. Tasks and responsibilities should be clearly set out regarding the request for pharmacogenetic analysis, the pharmacogenetic analysis itself, interpretation of the results and advice to the medical practitioner. The advice to give or not to give a drug to a patient, or to adjust drug dose or frequency, cannot be based exclusively on someone s genotype, but is the result of several factors. These include age, sex, weight, liver and renal function, concomitant medication, drug blood levels, serum albumin and protein binding, whether the patient smokes, nutrition and genetic factors (a combination of several genotypes). Pharmacogenetics will be an important and useful tool for individualising pharmacotherapy in the near future, as is therapeutic drug monitoring at present. The first examples of pharmacogenetic knowledge in medical practice are already in use. KEYWORDS Pharmacogenetics, daily practice, preconditions, tasks INTRODUCTION In the first article, in a series about pharmacogenetics, (Eur J Hosp Pharm Prac. 2007;13(6):32-6), we provided an introduction into basic concepts and principles of pharmacogenetics. A logical question to ask oneself is: What are the consequences of the availability of pharmacogenetic data for the pharmacist in medical practice?. This article focuses especially on the utilisation of pharmacogenetic CONTACT FOR CORRESPONDENCE: Luc JJ Derijks, PharmD, PhD Department of Clinical Pharmacy Màxima Medical Center PO Box MB Veldhoven, The Netherlands Tel: Fax: L.derijks@mmc.nl 1 Department of Clinical Pharmacy, Máxima Medical Center, PO Box 7777, 5500 MB Veldhoven, The Netherlands 2 Department of Clinical Pharmacy, Orbis Medical Center, PO Box 5500, 6130 MB Sittard, The Netherlands 3 Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands 4 Department of Clinical Pharmacy, Apotheek Haagse Ziekenhuizen, Postbus 43100, 2504 AC Den Haag, The Netherlands 5 Hospital Pharmacy North-East Brabant, PO Box 3406, 5203 DK s-hertogenbosch, The Netherlands 6 Department of Clinical Pharmacy, University Medical Center, PO Box 85500, 3508 GA Utrecht, The Netherlands 25

2 knowledge in medical practice and the preconditions that are needed for implementation. Attention is paid to the setting of tasks and responsibilities, examples from medical practice and future perspectives. PRECONDITIONS Pharmacogenetics is the science studying the interindividual variability in drug response resulting from genetic factors. The first and most obvious precondition is knowing the gene mutation that underlies the difference in drug response, and its exact location on the chromosome. Also, it is important to know the prevalence of the polymorphism of interest. The second precondition is that the pharmacological consequences of the possession of certain variant alleles are clinically relevant. Although pharmacogenetics is scientifically interesting, it is not a goal in itself but an instrument to better predict the clinical manifestations of a drug regarding efficacy or toxicity. There will only be a place for pharmacogenetics in medical practice when these predictions result in significant therapeutic benefits. Subsequently, this information has to be translated in to practical advice or a particular action. Therefore, the third precondition is the availability of evidence-based practical guidelines with information on how to act therapeutically (what drug in what dose) for certain gene mutations. In the past two decades, knowledge about pharmacogenetics has been extended dramatically, but translation in to practical guidelines is scarce and it will take much effort to close this gap and to give tailor-made advice. In the Netherlands, the Pharmacogenetics Working Party has developed national guidelines to moderate pharmacogenetic advice. These guidelines are available online for every Dutch pharmacist after registering with the website [1]. Finally, the fourth precondition is that pharmacogenetic techniques are available for genotyping. To make decisions based on pharmacogenetic knowledge in medical practice, it has to be considered for which drug or therapeutic class of drugs pharmacogenetics is of most importance. Initially, priority goes to drugs that are used in chronic medical conditions or to those used at least frequently, with a narrow therapeutic range, without equivalent alternatives and without an unambiguous relationship between dose and clinical effect. Therefore, it is most unlikely that pharmacogenetics would be applied in antihypertensive treatment with beta-blockers because the intended clinical effect, the lowering of blood pressure, can be easily measured. Also, genotyping is of less value when a suitable alternative, such as therapeutic drug monitoring (TDM), is available. Current practice, with population models and the so-called optimal sampling principal, results in very fast and adequate adjustments. However, when serious, sometimes life-threatening complications can be prevented by adapting the initial dose based on genotype, genotyping is a most important tool. Moreover, genotyping is useful when therapeutic failure can be predicted by determining someone s genotype, especially when the drugs to be given are extremely expensive. Finally, the patient s genotype is a single measurement that can be used over a lifetime, in contrast to TDM results which change over time. TASKS Application of pharmacogenetics demands efforts from several disciplines. It should be clear which discipline is responsible for a specific task. First, there must be a request for pharmacogenetic analysis. Is this task the preserve of the physician or the pharmacist? Probably, this will differ locally depending on local or regional agreements as is already the case for TDM. Subsequently, the patient s genotype has to be determined. Genotyping usually consists of determination of single nucleotide polymorphisms (SNPs) that alter the amino acid sequence of encoded proteins and is performable in every laboratory with the essential equipment and knowledge. The clinical chemistry laboratory seems a reasonable choice, because most endogenous substances in blood are determined in this laboratory, and DNA is the most endogenous substance we know. In Dutch hospitals that already perform genotyping, the clinical chemistry laboratory is often the place where the genotype is determined. The microbiology laboratory is also a good candidate to perform genotyping. An obvious advantage of this laboratory is the familiarity with the techniques used, such as real-time polymerase chain reaction (PCR) in combination with fluorescence detection or normal PCR in combination with gel electrophoresis. After that, the result, accompanied by practical advice, has to be reported to the physician. For this task, hospital pharmacists have a role to play. As the drug specialists par excellence, hospital pharmacists can interpret and translate the pharmacogenetic testing result in to practical advice for the physician. In exactly the same way as tailor-made advice is given by hospital pharmacists in TDM in the Dutch hospital setting, so will they do for pharmacogenetic testing. The advice to give or not to give a drug to a patient, or to adjust drug dose or frequency, cannot be based exclusively on someone s genotype. Such advice should also consider other factors such as age, sex, weight, liver and renal function, concomitant medication, drug blood levels, serum albumin and protein binding, whether the patient smokes, nutrition and genetic factors (a combination of several genotypes). 26 Volume /1

3 Finally, the physician, strengthened by advice from the capable hospital pharmacist, has to make a decision regarding pharmacotherapy, and monitor and evaluate the advice. Pharmacogenetics may be a relatively new specialty for many pharmacists; for physicians this probably is an understatement. Figure 1: The most frequently occurring thiopurine S-methyl transferase genotypes EXAMPLES At present, much effort is being put into actually implementing pharmacogenetic knowledge in medical practice, and the first examples are already in use. Several examples from both first and second-line health care are shown below; some of these examples have led to implementation of pharmacogenetic testing in medical practice and some have not. A case report is also presented. Clinical pharmacy Pharmacodynamics Trastuzumab is a recombinant humanised IgG1 monoclonal antibody used in the treatment of breast cancer. It is one of the first drugs in which pharmacogenetic knowledge has been used in clinical practice. This drug is indicated exclusively in patients with intermediate to strong overexpression (3+ determined by immunohistochemistry) of the human epidermal growth factor receptor (HER-2) gene [2]. In 20-30% of all breast cancer patients, the HER-2 gene is over-expressed, resulting in abnormal production of HER- 2, mainly in malignant cells [3]. In healthy women, HER-2 is involved in the control of growth and differentiation of breast cells, but it stimulates the proliferation of cancer cells in breast cancer patients. It was demonstrated by Slamon and colleagues that antagonising HER-2 with trastuzumab in breast cancer patients with HER-2 gene over-expression improves the efficacy of chemotherapy [4]. Nowadays, HER-2 gene over-expression is locally or regionally tested in breast cancer patients world wide. Pharmacokinetics Azathioprine (AZA) and 6-mercaptopurine are widely used for the treatment of inflammatory bowel disease and have proven efficacy in treating active disease and maintaining remission [5]. However, the use of thiopurines is limited by the occurrence of adverse events leading to treatment discontinuation in up to 20% of treated patients [6, 7]. Myelosuppression, manifesting itself most often as leukopaenia, is potentially the most serious side effect leading to severe complications [8]. Myelosuppression is a dose-dependent event caused by significantly elevated 6- thioguaninenucleotides (6-TGN) concentrations, the active metabolites of AZA [9]. Thiopurine S-methyl transferase (TPMT) is an important enzyme in thiopurine metabolism, because it determines the balance between two active The black and white boxes represent translated and untranslated exons (coding regions) respectively. The grey boxes represent translated exons on mutant alleles containing a single nucleotide polymorphism (SNP); the SNP is captioned below the relevant exon. metabolite groups: the potentially hepatotoxic 6- methylmercaptopurine ribonucleotides (6-MMPR) and the myelosuppressive 6-TGN. The gene encoding TPMT is subject to a genetic polymorphism (Figure 1) that has been studied intensively. It has been demonstrated that patients with one or two mutant alleles have reduced enzyme activity, leading to elevated 6-TGN concentrations, resulting in an increased risk of developing bone marrow suppression [10-12]. In general, a starting dose of 10% or 50% of the standard dose is advocated in patients with homozygous and heterozygous TPMT alleles respectively [13]. In some Dutch hospitals, TPMT genotyping before thiopurine pharmacotherapy is already carried out. Community pharmacy Gastro-oesophageal reflux disease (GERD) is a common disorder and is successfully treated with proton pump inhibitors (PPIs). These medicines inhibit acid production in the stomach which leads to an elevation of intragastric ph. This pharmacological effect can only be established when the amount of drug available in the blood is sufficient for binding to the H+/K+-ATPase receptor in the parietal cells of the stomach. After oral administration, PPIs are metabolised in the liver by CYP2C19 that shows genetic polymorphism. It has been demonstrated that the acid inhibitory effect is related to the AUC (area under the curve) in the blood, which depends highly on a subject s genotype. CYP2C19 profile differs greatly among different populations. In the Caucasian population, 3% of people are poor metabolisers whereas in the Japanese population, 30% of people are poor metabolisers. The influence of CYP2C19 genotype on pharmacokinetics and pharma- 27

4 codynamics of PPIs is not straightforward. At high doses of a PPI (e.g. 40 mg esomeprazole once daily [14]), in extensive metabolisers the AUC is large enough for the maximum acid inhibitory effect to be exerted, and no difference in healing rate between genotypes is found. However, GERD is generally treated with low doses of a PPI or even on demand. Two studies investigating lansoprazole 30 mg showed significantly different cure rates among genotypes with a significantly lower healing rate in homozygous extensive metabolisers than in heterozygous extensive metabolisers and poor metabolisers for CYP2C19 [15, 16]. This has been confirmed in pharmacokinetic-pharmacodynamic studies [17]. The main point is that the efficacy of low doses of PPIs is highly influenced by CYP2C19 status in contrast to high doses of PPIs. Given the high prevalence of extensive metabolisers in Caucasians compared with Asians, a higher dose of a PPI is needed in Caucasians to obtain the same effect as in Asians. Thus, results of clinical trials conducted in Asians cannot be used to establish the optimal dose in Caucasians if genotypes are not taken into account. The question, whether genotyping would be beneficial in Caucasians could be answered as follows: PPIs have to be dosed adequately based on the metabolic capacity of extensive metabolisers and given the excellent safety profile of PPIs, poor metabolism of CYP2C19 will not harm the patient. Case report A community pharmacist referred a lady, born in 1963, to our pharmacogenetic expertise centre. She had an extensive history of side effects to prescribed medication, including objective serious side effects, which had even led to hospital admission. The lady ed her "pharmaceutical" history over a 24-year period. She described a hospital admission in 1982 (to an intensive care unit) for deterioration after administration of promethazine 50 mg and diazepam 10 mg, both intramuscularly, by her general practitioner for treatment of side effects of a second dose of perphenazine (prescribed for a driving test). On another occasion she called in her general practitioner because of metoclopramide side effects, which resolved after an injection with biperidene. After a laparotomic hysterectomy in 1994 (peri-operative medication unknown), she suffered from post-operative nausea and vomiting for days, and experienced hallucinations on anti-emetic medication. Several years later, oral oestrogens caused vomiting that resolved with nasal oestrogen delivery. In 2003 she experienced side effects on diclofenac, naproxen and rofecoxib, and more recently, she was hospitalised after a lidocaine injection in her arm. Based on this , we advised her to send us a plasma sample for PCR genotyping of cytochromes. The laboratory checked for the most relevant variant genotypes in the Netherlands: CYP2D6*1, *2, *3, *4, *5, *6, *7, duplication; CYP 2C9 *1, *2 and *3; CYP2C19*1 and *2. We found CYP2D6 *4/*6 (lack of 2D6 enzyme); CYP2C19 was wt/wt (normal) and CYP2C9 was wt/*2 (half of metabolic 2C9 capacity). Most of the lady s side effects were caused by drugs metabolised by cytochromes. This patient lacks one important metabolic route, and a second important route is partly blocked. She is more vulnerable to side effects and she is at greater risk of drug interactions. Because her pharmacogenetic profile for the most relevant cytochrome enzymes is known, her physician and pharmacist can take this information into account when prescribing and dispensing medication; at present, implementation of this knowledge results in significantly fewer adverse events because of her medication. THE NEAR FUTURE In the past decade, the amount of pharmacogenetic data has increased enormously and this has had a direct effect on medical practice. Pharmacogenetics will be one of the important tools for providing tailor-made medicine. If all the preconditions for applying pharmacogenetics as described in this article are met, it is a missed chance, or maybe even an unethical one, not to perform pharmacogenetic testing. Furthermore, the position of the patient is becoming legally stronger and it is not unimaginable that a physician or a pharmacist will be prosecuted where there has been iatrogenic damage that could have been predicted by genotyping. Possibly, in one or two decades, every patient will have a gene passport, which can be consulted by both physician and pharmacist whenever needed. Such a passport could be part of the electronic patient dossier. Pharmacogenetics is a relatively new area of expertise for many physicians and pharmacists. Nevertheless, we have been confronted with it a lot sooner than most professionals would have thought. After all, as demonstrated in this paper, the first examples in medical practice are already here. REFERENCES 1. The Royal Dutch Pharmaceutical Society. Pharmacogenetics Working Party guidelines can be accessed after registration via (accessed 14 September 2007). 2. Electronic medicines compendium. Summary of product characteristics for trastuzumab. page=displaydoc.asp&documentid=3567 (accessed 7 September 2007). 28 Volume /1

5 REFERENCES 3. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu protooncogene in human breast and ovarian cancer. Science. 1989;244: Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Eng J Med. 2001;344(11): Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol. 1996;91(3): de Jong DJ, Derijks LJ, Naber AH, et al. Safety of thiopurines in the treatment of inflammatory bowel disease. Scand J Gastroenterol Suppl. 2003;(239): Present DH, Meltzer SJ, Krumholz MP, et al. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med. 1989;111(8): Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut. 1993;34(8): Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000;118(4): Ansari A, Hassan C, Duley J, et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther. 2002;16(10): Black AJ, McLeod HL, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med. 1998;129(90: Lennard L. TPMT in the treatment of Crohn's disease with azathioprine. Gut. 2002;5192): Sandborn WJ. Rational dosing of azathioprine and 6-mercaptopurine. Gut. 2001;48(5): Schwab M, Klotz U, Hofmann U, et al. Esomeprazole-induced healing of gastroesophageal reflux disease is unrelated to the genotype of CYP2C19: evidence from clinical and pharmacokinetic data. Clin Pharmacol Ther. 2005:78(6); Furuta T, Shirai N, Watanabe F, et al. Effect of cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole. Clin Pharmacol Ther. 2002:72(4); Kawamura M, Ohara S, Koike T, et al. The effects of lansoprazole on erosive reflux oesophagitis are influenced by CYP2C19 polymorphism. Aliment Pharmacol Ther. 2003:17(7); Shimatani T, Inoue M, Kuroiwa T, et al. Effect of omeprazole 10 mg on intragastric ph in three different CYP2C19 genotypes, compared with omeprazole 20 mg and lafutidine 20 mg, a new H2-receptor antagonist. Aliment Pharmacol Ther. 2003:18(11-12);