Pharmacogenetics
Using pharmacogenetics to improve existing medicines
3.20 We have concluded that the application of pharmacogenetics to the development of new medicines offers potential benefits (paragraph 3.12). In the case of existing medicines, the application of pharmacogenetic analysis may be of value, but this will not necessarily be the case. We noted in Chapter 2 (Box 2.2: Case study 1) that genetic variations of CYP2D6 may result in differential metabolism of various medicines. This effect has been widely accepted for over 20 years, and it is known that 7% of Caucasians have genetic variations of CYP2D6 that cause poor metabolism of certain medicines and may therefore result in adverse reactions or reduced efficacy. But tests for these variants are not routinely carried out before prescribing the relevant medicines, which include common treatments for mental illness and heart disease. This is because the adverse reactions, while unpleasant, are rarely life-threatening and because alternative therapies exist. In addition, testing for the numerous variants has in the past been complicated and unreliable. This may change as knowledge develops and the technology of genetic testing improves. Nevertheless, it may be quicker and easier in many clinical settings simply to prescribe the medicines, observe any problems, and try a different medicine if necessary, rather than undertaking a pharmacogenetic test. It may be that for other existing medicines, pharmacogenetics could not generate predictive information of sufficient value to justify its use in clinical practice. The ability of a test to predict a particular outcome, may be proven. But such clinical validity does not necessarily correspond with clinical utility, that is, the ability of the use of the test to improve the treatment of patients.
3.21 In other cases, the application of pharmacogenetics to existing medicines could generate substantial benefits for patients. For example, clozapine is an antipsychotic medicine used in the treatment of schizophrenia which is effective in at least one third of patients who have failed to respond to other treatments.14 However, it also causes a serious reduction in the white blood count of 1 in 200 patients. As a consequence, patients’ blood counts have to be monitored, at monthly intervals, for long periods of time. If pharmacogenetic information could predict which patients are likely to respond well to clozapine, and which patients are likely to develop white blood cell problems, this would clearly be of value. Recently, research was published in which response to clozapine was successfully predicted in the majority of patients on the basis of six polymorphisms in genes related to neurotransmitter receptors. The researchers have suggested the first test to predict response to clozapine and other antipsychotic medicines could be available in 3–5 years.
3.22 A second example concerns warfarin, a medicine used to prevent the formation of blood clots, which is often prescribed for patients who have had a heart attack or surgery to replace heart valves. It has been estimated that over 500,000 people in the UK are receiving warfarin. However, its use can result in serious complications such as haemorrhage, which affects between eight and 26 patients of every 100 patients treated with warfarin for a year.15 In order to minimise the risk of bleeding, it is important to obtain an accurate prediction of the dosage required. However, this is often difficult because there is wide variation between individuals in the dose necessary to maintain the appropriate degree of anticoagulation. Decisions about dosage are based on clinical judgement, and haemorrhages associated with warfarin remain a common problem. Warfarin is metabolised by the protein CYP2C9. Recent studies have shown that certain genetic variants of CYP2C9 result in a reduced ability to break down warfarin. Patients with these variants can only tolerate lower doses of the medicine.16 Some researchers have suggested that the CYP2C9*2 and CYP2C9*3 variants are associated with an increased risk of over-anticoagulation and bleeding, but there is a lack of consensus on the validity of these findings.17
Footnotes14 Kane J et al. (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine, Arch Gen Psychiatry 45: 789-96.
15 Petty GW et al. (1999) Frequency of major complications of aspirin, warfarin, and intravenous heparin for secondary stroke prevention. A population-based study, Ann Intern Med 130: 14-22.
16 Taube J, Halsall D and Baglin T (2000) Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment, Blood 96: 1816-9; Higashi MK et al. (2002) Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy, JAMA 287: 1690-8.
17 Taube J, Halsall D and Baglin T (2000) Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment, Blood 96: 1816-9; Higashi MK et al. (2002) Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy, JAMA 287: 1690-8; Steward DJ et al. (1997) Genetic association between sensitivity to warfarin and expression of CYP2C9*3, Pharmacogenetics 7: 361-7; Daly AK and King BP (2003) Pharmacogenetics of oral anticoagulants, Pharmacogenetics 13: 247-52.