• We provide the first critical quantitative review of this rapidly developing area of research to serve as a basis for subsequent research and overviews.• We summarize data on population prevalence and functional effects of CYP2C19*17.• We argue on the basis of current evidence that potentially significant clinical effects are unlikely except for drugs with very narrow therapeutic windows. Of studied substrates, only clopidogrel may fall into this category. Even then, only homozygotes of the variant allele are likely to be at significantly increased risk.• The assignment of CYP2C19*17 homozygotes as EM, rather than UM, is adequate as the metabolic ratios of all probe drugs studied so far overlap completely the range of values seen in wild-type homozygotes.• The implications of CYP2C19*17 on the clinical effects of tamoxifen require further study. AIMSCytochrome P450 2C19 metabolizes many important drugs. In 2006, a variant allele (CYP2C19*17) associated with increased activity was discovered, but its likely clinical significance is controversial. Investigators disagree about the phenotype to be assigned to the two CYP2C19*17 genotypes. The aim of this study was to provide a critical summary, helpful to prescribers. METHODSWe searched MEDLINE for papers on the allele from 2006 and then undertook historical searches through the reference lists of papers retrieved. The relevant information was critically assessed and summarized. RESULTSCYP2C19*17 was associated with increased enzymic activity. Substrates studied were omeprazole, pantoprazole, escitalopram, sertraline, voriconazole, tamoxifen and clopidogrel. Most studies used pharmacokinetic variables as outcome measure. For clopidogrel, activated by CYP2C19, pharmacodynamic consequences focused on platelet aggregation. While for most pharmacokinetic parameters of the substrates studied the average value was altered, the range of values showed mostly complete overlap for CYP2C19*1/*17 heterozygotes and wild-type homozygotes. Even for CYP2C19*17 homozygotes, the absolute effect was modest compared with the effect of previously identified loss-of-function alleles. In Helicobacter pylori eradication CYP2C19*2 carriage was associated with an altered eradication rate (odds ratio 4.20, 95% confidence interval 1.23, 16.44) relative to the wild-type, but CYP2C19*17 homozygosity was not. Prevalence of the variant allele was typically <5% in Asians and about four times higher in White and African populations. CONCLUSIONSAssignment of CYP2C19*17 homozygotes as extensive metabolizers rather than ultrarapid metabolizers is adequate. CYP2C19*17 genotyping is unlikely to have clinical utility except for drugs with very narrow therapeutic indices.

Advances in genomics promise to deliver personalized medicine both for prevention and treatment of disease. Considerable effort is being directed towards translating observed associations between various genetic variants, such as single nucleotide polymorphisms (SNPs), and disease or drug response into clinically useful genetic tests. Unfortunately, because reported associations are usually weak or moderate, tests based on them are generally not accurate enough for use in routine clinical practice, and therefore, ensuring the appropriate use of genetic tests is important. In a recent report, a combination of 5 SNPs was claimed to improve the predictive value of the test for prostate cancer, compared with the individual SNPs. This led the authors to suggest that a 5-SNP-test could be used to predict the risk of prostate cancer. We evaluate the characteristics of the proposed test, comment on it, and summarize the views of others on its potential clinical utility. We hope that this may serve as a case-example for the evaluation of the many new genetic tests being suggested for adoption.

The translational path from pharmacological insight to effective therapy can be a long one. We aim to describe the management of Marfan syndrome as a case-example of how pharmacological and genomic insights can contribute to improved therapy. We undertook a literature search for studies of Marfan syndrome, to identify milestones in description, understanding and therapy of the syndrome. From the studies retrieved we then weaved an evidence-based description of progress. Marfan syndrome shows considerable heterogeneity in clinical presentation. It relies on defined clinical criteria with confirmation based on FBN1 mutation testing. Surgical advances have prolonged life in Marfan syndrome. First-line prophylaxis of complications with b-adrenoceptor blockers became established on the basis that reduction of aortic pressure and heart rate would help. Over-activity of proteinases, first suggested in 1980, has since been confirmed by evidence of over-expression of matrix metalloproteinases (MMP), notably MMP-2 and MMP-9. The search for MMP inhibitors led to the evaluation of doxycycline, and both animal studies and small trials, provided early evidence that this widely used antimicrobial agent was useful. Identification of the importance of TGF-b led to evaluation of angiotensin II type I receptor (AT1R) blockers with highly promising results. Combination prophylactic therapy would appear rational. Pharmacological and genomic research has provided good evidence that therapy with losartan and doxycycline would prevent the aortic complications of Marfan syndrome. If on-going well designed trials confirm their efficacy, the outlook for Marfan syndrome patients would be improved considerably.

Purpose To illustrate the interface of pharmacogenetics and therapeutic drug monitoring and to estimate target blood level for imatinib in the treatment of chronic myelogenous leukemia Methods A literature review to provide the evidence and necessary data to support the case for the interface, and quantitative analysis of the data to estimate the target blood level for imatinib using receiver operating curve (ROC; signal detection theory) analysis. Results and discussion One study estimated the optimum target level of imatinib in chronic myelogenous leukaemia as 1002 ng/mL (1.70 µM) through ROC analysis. Using individual-patient level data reported in another study and the same methodology, we estimated the target level as 0.95 µM. This is consistent with the results of other observational studies where dose-response was not the primary research objective. The available evidence suggests considerable inter-individual variability in dose-blood level response. In addition to the pharmacogenetics of metabolic enzymes and transporters, genetic mutations in genes participating in the signalling pathways may also account for the wide inter-individual variability in dose-blood level and dose-clinical response relationships. Conclusion A single-dose regimen for all pharmacogenetically eligible patients is not the optimum strategy for prescribing imatinib to patients with chronic myelogenous leukaemia. We suggest that therapeutic drug monitoring aimed at ensuring a trough target level of 1 µM would reduce the incidence of pseudo-resistance and hence personalize treatment and optimise response to imatinib. Persistent resistance can then be probed further for other causes.

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Summary What is known and Objective:  Pharmacogenetic studies, to help us understand variability in human drug response, have hitherto focussed largely on our own germline mutations, and in the context of anticancer and antimicrobial drugs, also on mutations of the tumour cell or invader microorganism. Here, we wish to draw attention to how our microbiome may contribute to variability in drug effects. Comment:  Irinotecan, a prodrug which is activated to the topoisomerase I inhibitory metabolite (SN‐38), is commonly used for the treatment of a range of cancers. SN‐38 is subsequently detoxified by uridine diphosphate‐glycosyltransferase 1, encoded by the UGT1A1 gene. It is well known that the variant allele UGT1A*18 is associated with the more common adverse effects of irinotecan. A recent study shows that the potentially dose‐limiting irinotecan‐induced diarrhoea is due to enterohepatic circulation of SN‐38, and its reactivation in the gut by bacterial β‐glucuronidases. Importantly, the authors used specific inhibitors of the microbial enzymes to reduce the gastro‐intestinal toxicity in mice. What is new and Conclusion:  We draw attention to the increasing range of diseases, including diabetes and obesity, associated with our microbiome. This pharmacogenetic example reminds us that in personalised medicine, there is more than our own genome to take account of.

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No need for rescue medication is a reliable outcome measure for use in acute pain trials. As it is more readily understandable than 50% TOTPAR, it should be the preferred primary outcome measure in acute pain trials.