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when conducting an in vitro DDI study using midazolam as the substrate, both the 1 - and 4-hydroxy metabolites should be measured. And when conducting an in vivo DDI study, not only should the parent drug be measured but also these two metabolites. An alteration in their ratio can suggest the potential for heterotropic effects. Additional examples of heterotropic effectors of drug-metabolizing enzymes should be explored to determine whether the observations made in the case of fluconazole and midazolam are seen for other drugs and enzymes.
CONFLICT OF INTEREST The author declared no conflict of interest.
2012 ASCPT

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Pharmacogenomic Testing: Knowing More, Doing Better

JE Lunshof1,2 and D Gurwitz3
The clinical uptake of pharmacogenomic (PGx) testing and genotype-based prescribing has been disappointingly slow even though research on PGx is thriving. A recent survey on the adoption of PGx testing by US physicians suggests that this trend may start changing for the better.1 Acquiring more knowledge of PGx tests and their clinical significance during graduate and postgraduate education will enable physicians to make better use of the available and upcoming PGx diagnostics in clinical practice.
Early expectations, current developments

1. Yang, J., Atkins, W.M., Isoherranen, N., Paine, M.F. & Thummel, K.E. Evidence of CYP3A allosterism in vivo: analysis of interaction between fluconazole and midazolam. Clin. Pharmacol. Ther. 91, 442449 (2012). 2. Niwa, T., Murayama, N. & Yamazaki, H. Heterotropic cooperativity in oxidation mediated by cytochrome P450. Curr. Drug Metab. 9, 453462 (2008). 3. Kenworthy, K.E., Bloomer, J.C., Clarke, S.E. & Houston, J.B. CYP3A4 drug interactions: correlation of 10 in vitro probe substrates. Br. J. Clin. Pharmacol. 48, 716727 (1999). 4. Obach, R.S. et al. The utility of in vitro cytochrome P450 inhibition data in the prediction of drugdrug interactions. J. Pharmacol. Exp. Ther. 316, 336348 (2006). 5. Bjornsson, T.D. et al. The conduct of in vitro and in vivo drugdrug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab. Dispos. 31, 815832 (2003). 6. US Food and Drug Administration. Guidance for Industry: Drug Interaction StudiesStudy Design, Data Analysis, and Implications for Dosing and Labeling. Draft guidance <http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/ucm072101.pdf> (September 2006). 7. Yano, J.K. et al. The structure of human microsomal cytochrome P450 3A4 determined by x-ray crystallography to 2.05 resolution. J. Biol. Chem. 279, 3809138094 (2004). 8. Williams, P.A. et al. Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science 305, 683686 (2004). 9. Tang, W. et al. Interaction of diclofenac and quinidine in monkeys: stimulation of diclofenac metabolism. J. Pharmacol. Exp.Ther. 291, 10681074 (1999). 10. Egnell, A.C., Houston, B. & Boyer, S. In vivo CYP3A4 heteroactivation is a possible mechanism for the drug interaction between felbamate and carbamazepine. J. Pharmacol. Exp. Ther. 305, 12511262 (2003).

Great expectations and waves of optimism concerning the development and clinical uptake of PGx have been alternating with disappointment and pessimism for over a decade. In 1999, before the completion of the Human Genome Project, Evans and Relling published a seminal review2 on the importance of PGx for drug discovery and clinical therapeutics. Their vision includes a model of a comprehensive diagnostic DNA array to guide therapy decision making in acute lymphatic leukemia, a pioneering example of a systems approach. One year earlier, in 1998, the anticancer monoclonal antibody trastuzumab (Herceptin) and a companion diagnostic test kit for determining levels of HER2 in breast tumor biopsy specimens reached the market following very promising clinical trials with this targeted therapy for an aggressive breast cancer subtype. This has been the first PGx test to be widely embraced by the clinical communityin part because of the very high cost of trastuzumab, which made payers enthusiastic about the potential it offered for saving drug

prescribing costs for patients unlikely to benefit from its use. Expectations were high at the turn of the millennium. With increasing knowledge regarding genetic polymorphisms relevant to drug metabolism and the development of microarray-based genotyping methods, the translation of PGx into clinical practice seemed around the corner. Rapid progress toward genomicsbased personalized medicine was promised, starting with individualized drug therapy, but this promise turned out to be unrealistic. Today, although PGx research is carried out by countless investigators, as reflected in nearly 12,000 PubMed-listed articles, only a handful of PGx-based tests have made it to the clinic.3 Most of these applications are in oncology, with trastuzumab and imatinib (Gleevec) being the best-known success stories, followed by an increasing number of other drugs with companion diagnostics. In cancer, the therapeutic targets are clear somatic mutations and highly specific markers that allow a direct step from diagnostics to therapy. In antiretroviral therapy, the clinical utility of HLA-B*5701 screen-

2Department of Molecular Cell Physiology, Faculty of Earth and Life Sciences, VU University Amsterdam, Amsterdam, The Netherlands; 3Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Correspondence: D Gurwitz (gurwitz@post.tau.ac.il)

1Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands;

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ing to avoid abacavir hypersensitivity has been convincingly shown.4 The road from testing for polymorphisms for drugmetabolizing enzymes and drug targets to rational drug therapy is much less clear, and this is one of several factors underlying the lagging translation of PGx insights into broader clinical practice in spite of intensive research.
Barriers to PGx clinical uptake

There are a number of reasons for the slow uptake of PGx into the clinical setting.5 A key barrier is definitely the lack of solid evidence for their advantage over current medical practice and the inconclusive recommendations by, for example, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) working group (http://www.egappreviews.org/recommendations/index.htm). In particular, lack of controlled clinical trials is often cited as a barrier, as most published clinical PGx research projects are based on retrospective patient data. Novel methods and study design are needed to prove clinical utility6 and to enhance the potential for much-needed PGx tests. In a recent call for action, Amstutz and Carleton7 highlighted the urgent need for developing evidencebased clinical practice guidelines on PGx testing as a prerequisite for overcoming the barriers hindering its clinical implementation. However, for the private sector, incentives are lacking to invest in prospective controlled trials for PGx tests as part of drug choice decision making. This is a key drawback considering that the bulk of marketed drugs are out of patent; hence, drug companies have little interest in investing in such clinical trials, while the public sector is already overburdened by escalating health-care costs and the ongoing economic crisis. Additional reasons include concerns by pharmaceutical companies about market segmentation and by payers about costs and cost-effectiveness; all are hefty reasons that call for more support from the public sector. Notably, one reason that barriers to implementing PGx into clinical practice seem to be higher in Europe compared with the United States is that, unlike in the latter, in Europe there are no harmonized regulations and a central
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regulator for medical diagnostics.5 In the United States this role is overseen by the US Food and Drug Administration, which also oversees the drug approval process, whereas in the European Union diagnostics are still regulated at the member-state level (and drug approval is regulated by the European Medicines Agency). However, the clinical utility of approved tests may turn out to be unsustainable once in practice, whereas tests that lack approval may find use in the clinic, as shown by the recent example of KRAS testing.8
Training increases PGx test adoption

There is one key barrier that may be easier to overcome: lack of PGx education for health professionals.9 Stanek et al.1 conducted a nationwide survey on the adoption of PGx testing by US physicians and their exposure to PGx during their graduate and postgraduate studies, and their findings are published in this issue. Their report, based on more than 10,000 returned questionnaires, notes that an overwhelming 97% majority of survey responders were aware that genetic variations affect drug response, but only ~13% had ordered a PGx test in the past 6 months and only ~10% felt adequately informed about PGx tests.1 The study examines the reasons for this large gap between beliefs and medical practice. The authors found that oncologists were at least fivefold more likely to adopt PGx tests compared with other clinical disciplines;1 this is not surprising, given that most PGx tests that have made it to the clinical setting concern the safety or efficacy of very expensive anticancer drugs. A drawback of the study is that only 3% of questionnaires were returned;1 thus, a bias could have been introduced if clinicians more interested or informed about PGx tests were more likely to respond to the survey. However, the authors show that the demographics of the >10,000 responding clinicians are well matched with those of US clinicians with respect to age, sex, geographic location, years since medical school graduation, and practice specialty.1 Therefore, such a bias is unlikely to have significantly affected the study results. That said, it is noteworthy that only 29% of

the study responders indicated that they received PGx training as part of their medical school or postgraduate training,1 and it is safe to assume that this percentage represents the overall numbers of PGx-trained US clinicians. It may well be that most of those who received PGx training are the clinicians who have graduated more recently and, presumably, those who were educated in US medical schools, although the authors do not present the data on education by age groups or location of medical schools. A surprising finding is that clinicians who graduated from US medical schools were almost twice as likely to have adopted PGx tests for their patients compared with those who graduated in European schools. 1 Unfortunately, the survey does not include information regarding which PGx tests have been prescribed by responders, which would have made it more useful for analyzing trends in the clinical uptake of PGx. Nonetheless, a key finding of the study is that clinicians who received PGx training, either in medical school or during postgraduate studies, were far more likely to use PGx tests in their practice.1 The conclusion is obvious: including PGx training during medical studies is a key facilitator of using PGx tests in clinical practice. The 2005 call by the International Society of Pharmacogenomics on deans of education to include PGx education in the medical curriculum9 therefore remains as pertinent as ever.
PGx education: no perfect prescriptions

Pharmacogenomics is a rapidly developing field. Medical curriculum cannot be exhaustive and fully current. It must, however, reflect on modern medicines focus on probabilities, and PGx is no exception. Learning the principles of genetic variation and response to drugs will enable physicians to improve accuracy, to use available diagnostics, and to better predict the best drug at the most appropriate dosage for the individual patient. There can be no certainty, and there are no perfect prescriptions for personalized pharmacotherapy, at least not in the foreseeable future, because drug response is not determined by an individuals genetic makeup alone.10 But

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incremental implementation in clinical practice is one way to gain new knowledge and to gather evidence on the utility of PGx testbased prescribing.
Conflict of interest The authors declared no conflict of interest.
2012 ASCPT

3.

4.

5. 6.

1. Stanek, E.J. et al. Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey. Clin. Pharmacol. Ther. 91, 450458 (2012). 2. Evans, W.E. & Relling, M.V. Pharmacogenomics:

translating functional genomics into rational therapeutics. Science 286, 487491 (1999). Flockhart, D.A., Skaar, T, Berlin, D.S. Klein, T.E. & Nguyen, A.T. Clinically available pharmacogenomic tests. Clin. Pharmacol. Ther. 86, 109113 (2009). Hughes, A.R. et al. Pharmacogenetics of hypersensitivity to abacavir: from PGx hypothesis to confirmation to clinical utility. Pharmacogenomics J. 8, 365374 (2008). Gurwitz, D. et al. Pharmacogenetics in Europe: barriers and opportunities. Public Health Genomics 12, 134141 (2009). Lesko, L.J., Zineh, I. & Huang, S.-M. What is clinical utility and why should we care? Clin.

Pharmacol. Ther. 88, 729733 (2010). 7. Amstutz, U. & Carleton, B.C. Pharmacogenetic testing: time for clinical practice guidelines. Clin. Pharmacol. Ther. 89, 924927 (2011). 8. Faruki, H. & Lai-Goldman, M. Application of a pharmacogenetic test adoption model to six oncology biomarkers. Pers. Med. 7, 441450 (2010). 9. Gurwitz, D. et al. Pharmacogenomics education: International Society of Pharmacogenomics recommendations for medical, pharmaceutical, and health schools deans of education. Pharmacogenomics J. 5, 221225 (2005). 10. Offit, K. Personalized medicine: new genomics, old lessons. Hum. Genet. 130, 314 (2011).

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