Pharmacogenetics Moving From Research To The Clinic

As this chapter has described, the field of pharmacogenetics is a rapidly evolving science, which heralds great promise for improving patient healthcare. However, to date, little of this new research is finding its way to the physician's office. So what is stopping these new scientific advances moving routinely into the clinic?

With a few exceptions, the current level of knowledge of efficacy pharmacogenetics in psychiatry is still in the exploratory stage, with as yet no robust results for genes predicting efficacy. However, some findings are replicating in independent sample sets and promising leads are developing, for example the serotonin gene promoter gene and SSRI response, dopamine D3 receptor gene and risk of anti-psychotic induced tardive dyskinesia. Many of these are presented within the following chapters of this book. Understanding of the impact of allelic variance on pharmacokinetic parameters can perhaps be considered to represent our current, most advanced state of pharmacogenetic knowledge. An example of this was recently seen in the approval of atomoxetine (Strattera; Eli Lilly), approved by the FDA in November 2002 for attention-defeceit/hyperreactive disorder. This drug is metabolised by CYP2D6 with the ratio (PM/EM) for an area under the curve (AUC) of ~10. Lilly conducted a post-facto stratification to determine the impact of genotype on adverse events risk. This analysis found the AUC to be increased in PM by 3% (EM, 6%; PM 9% for the main adverse events of insomnia and irritability). The FDA, however, stopped short of mandating a test for prescribing, since the benefit/risk for the drug was considered to be acceptable in the unselected patient group (Lesko & Woodstock 2002). However, genotype data was required to be available, along with other data, in the label to help guide physicians in their dose adjustments. In fact, information on CYP2D6 genotype is mentioned 7 times in label for atomoxetine. Tests for CYP2D6 alleles are widely available in CLIA laboratories. Furthermore, in the Unitied States, the FDA (Federal Drug Agency ) as recently approved a genomic test to assess both CYP2D6 and CYP2C19, the AmplicChip CYP450 genomic test, developed by Roche Diagnostics). These two cytochrome P450 iso-enzymes play a role in the metabolism of ~25% of all prescription drugs and are of particular relevance for psychiatry where many of the drugs have a major contribution to their metabolism by CYP2D6, including risperdal, Haldo, Paxil, effexor and tricyclic antidepressants.

Also currently lacking is evidence from prospective clinical studies to more fully determine the impact of using genotype as part of prescribing algorithms on the benefit/risk outcome of drug response. Studies to date largely report on retrospective analyses. Such prospective studies are now underway, for example investigating the impact of CYP2C9 on warfarin treatment outcome. The outcome and reporting of these studies will provide critical data to help guide both regulatory authorities in their decisions on label requirements and physicians on how pharmacogenetic knowledge can best be used to more fully inform drug treatment and dosing decisions.

It is anticipated that regulatory authorities will increasingly expect to see this type of application of scientific advances, such as pharmacogenetics, being employed in the assessment of new medicines. The FDA Critical Path White paper, issued 14 March 2004 entitled "Innovation or stagnation? Challenge & opportunity on the critical path to new medical products" (http://fda.gov/oc/-iniatives/criticalpath/whitepaper.html), sets out this vision and expectation for clinical drug development. Regulatory authorities are under increasing public opinion scrutiny to understand safety risk, particularly in the wake of the recent voluntary withdrawal of the widely used pain-killer and anti-inflammatory inhibitor drug, Vioxx (rofecoxib) by Merck in September 2004 due to cardiovascular risk concerns. Pharmacogenetics is about assessing individuals and must be a core component of the strategy to explore safety signals of clinical concern observed in patients following drug administration. Regulatory authorities are likely to be a key driving force in bringing pharmacogenetic data to the clinic and its inclusion as part of treatment decisions. Pharmaceutical companies and clinical researchers alike need, therefore, to be applying genetic technologies to obtain robust data-sets, to build and share knowledge in this area and to apply this knowledge to enhance our understanding of the clinical safety and efficacy of psychiatry medicines.

In addition, patients themselves, their relatives and carers are predicted to play key roles in seeing pharmacogenetics, along with other advances in scientific knowledge, come to bear in guiding their drug treatment choices. Availability of information through the internet has resulted in patients and carers becoming increasingly more informed about the drug choices available to them and the latest research for their specific disorder. They seek to understand and gain more knowledge on the drugs they are given, particularly regarding potential safety risks and expect to be see these scientific advances being applied to their benefit and to improve their health care.

So in a time of increasing patient demand for information, increasing regulatory pressure for more detailed drug evaluation, coupled to economic constraints on health care budgets, pharmacogenetics holds great promise for playing a central role in guiding provision of health care and as standard information available to physicians. It is anticipated that the ever enquiring minds of physicians and clinical researchers, and their search to understand the complexities of psychiatric illness and patients' drug response will, over the next 3-5 years, begin to move the field of psychopharmacogenetics from the exploratory stage to one in which robust data-sets are available that can provide new knowledge to incorporate into prescribing algorithms. It will be this triad of physician, patient and regulator that are predicted to be key players in driving this new science into the clinic. Ultimately, it will be patients who will benefit, not only from the identification of new and novel psychiatry drugs, but also physicians will be equipped with greater ability to make more informed, evidence-based decisions to prescribe patients the most effective drug choices, providing therapeutic benefit, whilst minimising potential safety risks.

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