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Personalized medicine has been a booming area in clinical research for the past decade, in which the detailed information about the patient genotype and clinical conditions were collected and considered to optimize the therapy to prevent adverse reactions. However, the utility of commercially available personalized medicine has not yet been maximized due to the lack of a structured protocol for implementation. In this narrative review, we explain the role of pharmacogenetics in personalized medicine, next-generation personalized medicine, i.e., patient-centric personalized medicine, in which the patient's comfort is considered along with pharmacogenomics to be a primary factor. We extensively discuss the classifications, strategies, tools, and drug delivery systems that can support the implementation of patient-centric personalized medicine from an industrial perspective.

Introduction: Coumarin vitamin K antagonists are the mainstay of anticoagulant therapy in atrial fibrillation, prosthetic heart valves and thromboembolic conditions. Concerns with these drugs include large inter-individual variability in dose requirements, narrow therapeutic index and need to monitor prothrombin time repeatedly., Areas Covered: Pharmacogenetic studies and dosing algorithms for warfarin and phenprocoumon., Expert Opinion: Gene candidate studies in Brazilian patients verified consistently the association of warfarin and pheprocoumon stable dose requirements with CYP2C9 and VKORC1 polymorphisms, and minor or no influence of other pharmacogenes (e.g., CYP4F2 and F7). The predictive power of warfarin and phenprocoumon dosing algorithms developed for Brazilians compares favorably with those reported for other populations. A warfarin dosing algorithm derived for an admixed cohort performed equally well in self-reported White and Black patients, in marked contrast with the considerably poorer performance of other warfarin algorithms in patients of African descent compared to those of European ancestry. This discrepancy is ascribed to the extensive European/African admixture among Brazilians. Prospective studies of clinical utility of coumarin dosing algorithms, in the context of the Brazilian Public Health System, would represent an important counterpart to recently published trials in European and North American cohorts with predominant or exclusive European ancestry.

Warfarin is the most commonly prescribed oral anticoagulant worldwide despite its narrow therapeutic index and the notorious inter- and intra-individual variability in dose required for the target clinical effect. Pharmacogenetic polymorphisms are major determinants of warfarin pharmacokinetic and dynamics and included in several warfarin dosing algorithms. This review focuses on warfarin pharmacogenomics in sub-Saharan peoples, African Americans and admixed Brazilians. These 'Black' populations differ in several aspects, notably their extent of recent admixture with Europeans, a factor which impacts on the frequency distribution of pharmacogenomic polymorphisms relevant to warfarin dose requirement for the target clinical effect. Whereas a small number of polymorphisms in VKORC1 (3673G > A, rs9923231), CYP2C9 (alleles *2 and *3, rs1799853 and rs1057910, respectively) and arguably CYP4F2 (rs2108622), may capture most of the pharmacogenomic influence on warfarin dose variance in White populations, additional polymorphisms in these, and in other, genes (e.g. CALU rs339097) increase the predictive power of pharmacogenetic warfarin dosing algorithms in the Black populations examined. A personalized strategy for initiation of warfarin therapy, allowing for improved safety and cost-effectiveness for populations of African descent must take into account their pharmacogenomic diversity, as well as socio-economical, cultural and medical factors. Accounting for this heterogeneity in algorithms that are 'friendly' enough to be adopted by warfarin prescribers worldwide requires gathering information from trials at different population levels, but demands also a critical appraisal of racial/ethnic labels that are commonly used in the clinical pharmacology literature but do not accurately reflect genetic ancestry and population diversity., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Genetic polymorphisms significantly influence responses to warfarin and clopidogrel. Polymorphisms in the cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase genes change warfarin pharmacokinetics and pharmacodynamics, respectively. Because these polymorphisms influence warfarin dose requirements, they may primarily help determine therapeutic warfarin doses in patients who newly start on the drug. To assist in estimating therapeutic warfarin doses, the warfarin label provides a pharmacogenomic dosing table and various warfarin pharmacogenomic dosing algorithms are available. On the other hand, polymorphisms in the CYP2C19 gene affect clopidogrel pharmacokinetics. These polymorphisms may be useful to identify clopidogrel nonresponders who may benefit from taking an alternative antiplatelet agent such as prasugrel and ticagrelor. Although both drugs have pharmacogenomic tests available for clinical use, their clinical utilities have not been established and are currently being actively studied. In this review, clinical application of warfarin and clopidogrel pharmacogenomics will be focused. With the current level of evidence, potential patients who may get benefit from warfarin and clopidogrel pharmacogenomic testing will be discussed. In addition, the interpretation of the warfarin and clopidogrel test results and the current barriers to widespread use of warfarin and clopidogrel pharmacogenomic testing will be discussed.

The purpose of this review is to discuss the clinical application of pharmacogenomics for select drug therapies (eg, proton pump inhibitors [PPIs], codeine, and carbamazepine) and to highlight limitations and challenges that preclude implementation of pharmacogenomics into clinical practice. Genetic polymorphisms of cytochrome P450 (CYP) enzymes and the presence of the human leukocyte antigen (HLA)-B*1502 allele influence drug disposition and/or response. A portion of PPI pharmacokinetic and pharmacodynamic variability can be explained by CYP2C19 genotype. However, conflicting evidence exists related to Helicobacter pylori cure rates based on CYP2C19 genotype. For codeine, adverse drug reactions in neonates through breast-feeding from CYP2D6 ultra-rapid metabolizers have been reported. However, there is lack of conclusive evidence regarding the overall influence of CYP2D6 polymorphisms on codeine efficacy and toxicity. Although CYP2C19 and CYP2D6 genotyping tests are available, clinical utility remains low. The presence of the HLA-B*1502 allele is associated with carbamazepine-induced Stevens-Johnson syndrome (SJS) and/or toxic epidermal necrolysis (TEN). Pharmacogenomic testing is required prior to initiating carbamazepine in high-risk patients. Lack of sufficient resources, provider knowledge, and ethical, legal, and social issues are several limitations and challenges to implementing pharmacogenomic testing in clinical practice.

Polymorphisms in genes encoding drug metabolizing enzymes, drug transporters, and drug targets can influence drug effects and contribute to inter-individual differences in drug response. Genotype for drug metabolizing enzymes and drug transporters can influence drug disposition in the body (pharmacokinetics), whereas genotype for drug targets may influence sensitivity to a drug (pharmacodynamics). In some cases, response to a particular drug is contingent on genotype for both drug disposition and drug target proteins. For example, warfarin dose requirements are influenced by both cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) genotypes. The goal of pharmacogenetics is to maximize drug effectiveness while limiting drug toxicity, based on an individual's DNA. Over 80 drugs now contain genetic information in their FDA-approved labeling. In addition to influencing warfarin dose requirements, genotype contributes to the efficacy of clopidogrel in coronary artery disease, risk for hypersensitivity reactions to abacavir in the treatment of human immunodeficiency virus, risk for statin-induced myopathy, and responses to numerous other drugs. Genetic information is routinely integrated into decisions regarding cancer chemotherapy and treatment for human immunodeficiency virus. Clinical implementation of pharmacogenetics is becoming a reality in other therapeutic areas, such as for patients requiring dual antiplatelet therapy following coronary artery stent implantation. In the future, it is possible that individuals will be broadly genotyped so that genetic information can guide drug therapy decisions throughout their lifetime.

Oncology chemotherapeutics frequently exhibit a narrow therapeutic index, further complicated by the serious nature of dosing either too high (dangerous toxicities) or too low (loss of antitumor benefits). This underscores the need for optimal individualized drug selection and dosing, especially with agents that have wide interpatient variability. Pharmacogenomic assessment of drug metabolizing enzymes can improve the ability to optimally dose patients being treated with certain agents such as 6-mercaptopurine, irinotecan, tamoxifen, and flurouracil. Two of these agents (6-mercaptopurine and irinotecan) already have mention of pharmacogenomic testing in their FDA approved package inserts. Ongoing retrospective and prospective trials will help to further optimize the place in clinical practice for not only performing these pharmacogenomic assessments but, more importantly, how the results should be incorporated into therapy dosing decisions for patients.

5-Fluorouracil (5FU), a widely used chemotherapeutic drug, inhibits the DNA replicative enzyme, thymidylate synthase (Tyms). Prior studies implicated a VNTR (variable numbers of tandem repeats) polymorphism in the 5'-untranslated region (5'-UTR) of the TYMS gene as a determinant of Tyms expression in tumors and normal tissues and proposed that these VNTR genotypes could help decide fluoropyrimidine dosing. Clinical associations between 5FU-related toxicity and the TYMS VNTR were reported, however, results were inconsistent, suggesting that additional genetic variation in the TYMS gene might influence Tyms expression. We thus conducted a detailed genetic analysis of this region, defining new polymorphisms in this gene including mononucleotide (poly A:T) repeats and novel single nucleotide polymorphisms (SNPs) flanking the VNTR in the TYMS genetic region. Our haplotype analysis of this region used data from both established and novel genetic variants and found nine SNP haplotypes accounting for more than 90% of the studied population. We observed non-exclusive relationships between the VNTR and adjacent SNP haplotypes, such that each type of VNTR commonly occurred on several haplotype backgrounds. Our results confirmed the expectation that the VNTR alleles exhibit homoplasy and lack the common ancestry required for a reliable marker of a linked adjacent locus that might govern toxicity. We propose that it may be necessary in a clinical trial to assay multiple types of genetic polymorphisms in the TYMS region to meaningfully model linkage of genetic markers to 5FU-related toxicity. The presence of multiple long (up to 26 nt), polymorphic monothymidine repeats in the promoter region of the sole human thymidylate synthetic enzyme is intriguing.

The response to thienopyridine antiplatelet therapy is heterogeneous and is in part explained by clinical and genetic factors. A recent meta-analysis has demonstrated the clinical significance of a genetic polymorphism in the cytochrome P450 2C19 gene. Carriers of this polymorphism have a higher incidence of stent thrombosis and cardiovascular death, whilst on the thienopyridine clopidogrel. The polymorphism and rarer variants display higher carrier frequencies in ethnic groups with disproportionate cardiovascular mortality, such as Māori. Knowledge of an individual's genetic status may assist in optimising antiplatelet therapy, thereby reducing the cost of adverse events, expenditure on new medicines, and the ethnic disparities seen in healthcare outcomes. A demonstration of the cost-effectiveness of genetic testing, on a population basis, and a proven alternative, personalised strategy is required before the adoption of this technology can be advocated.

The completion of the human genome sequencing project and the establishment of new methods for the detection of point mutations have lead to a remarkable increase of sequence variants identification in a growing number of genes. As a result of this, a new field of research has emerged, pharmacogenomics, which deals with the influence of genetic variation on drug response by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. Genetic databases are continuously updated online repositories of mutation data, described for a single or more genes or specifically for a population or ethnic group. Genetic databases can also fulfil the mission of pharmacogenomics by helping elucidate gene function, estimate the prevalence of genes in populations, differentiate among subtypes of diseases, trace how genes may predispose to or protect against illnesses, and improve medical intervention. Therefore, it is expected that genetic databases will gradually assume an increasing importance in all aspects of genome medicine. This article aims to provide an update of the current and emerging types of genetic databases relevant to the field of pharmacogenomics. Moreover, the key elements that are holding back the field as well as the challenges that should be addressed in the near future are also commented.

Even though treatment of several types of solid tumors has improved in the past few years with the introduction of molecular targeted agents in the therapeutic armamentarium of the medical oncologist, response rates to these agents are generally modest. Increasing evidence is now revealing that genetic factors are affecting patients' response to these therapeutic agents as well as the frequency and intensity of toxic reactions. Importantly, pharmacogenetic analysis is now required for the administration of several molecular targeted agents in clinical practice. For the vast majority of these agents, however, data remain purely experimental. Herein, we provide an overview of the genetic changes (mutations and polymorphisms) that have been associated with response to treatment with anticancer molecular targeted agents. Special emphasis is given on molecules (monoclonal antibodies and tyrosine kinase inhibitors) that target critical mediators in the epidermal growth factor receptor (EGFR), the human epidermal growth factor receptor 2 (HER2/ERBB2/NEU) and the vascular endothelial growth factor receptor (VEGFR) pathways. The true clinical utility of these applications remains to be proven in future prospective, randomized clinical trials in large patient cohorts of all different ethnic backgrounds.

Heart disease represents the primary cause of death worldwide, with mortality rates being predicted to remain constant within the next couple of decades. Cardiac disease treatment currently includes the administration of drugs, predominantly aiming at improving heart performance, through controlling heart rhythm, blood pressure, as well as reducing cholesterol and blood clotting. Despite, however, the medical advances that have lead towards a better understanding of heart disease pathophysiology and the development of new therapeutic approaches, the degree of success of the available drug therapies varies among patients. The existence of polymorphisms in a number of genes has been shown to result in differences in pharmacokinetics, pharmacodynamics and drug metabolism and have therefore been associated with response to drug treatment. The occurrence of adverse drug reactions that may lead to drug-induced toxicity represents another factor influencing outcome of therapeutic treatment. While the influence of genetic polymorphisms in patient's response to heart disease drugs is being unveiled, the rapidly evolving field of pharmacogenetics is promising to aid clinicians in choosing the best suited drug/dose for each patient and the pharmaceutical companies in the design of better targeted, more effective new chemical compounds. In the near future individualized, targeted therapy will become part of clinical care routine maximizing patient therapeutic benefits and minimizing risks of adverse effects.

Systems biology has emerged as a major trend in biological research during the past decade. As living organisms are described in more and more detail, it aims at filling the gap between understanding basic molecular processes and complex biological systems in which new properties often emerge from the combination of these elementary processes. This approach culminates in the development of computer-based mathematical models of physiological and pathophysiological processes. We review the state of the art in dynamic modelling, with emphasis on two complementary approaches: the modelling of small systems that is mostly developed by academic teams and aims at understanding generic biological properties, and the modelling of large systems that is mostly implemented by industrial companies and aims at the generation of new therapeutic strategies. We also provide an example of such large-scale modelling applied to the identification of drug targets for neurodegeneration.

Inter-individual variations in drug response are all-too common and, throughout medical history have often posed problems, many of them serious ones. The variations could stem from multiple factors, which include those of both the host (age, genetic and environmental factors) and disease (pathophysiological phenotypes, somatic mutations in case of cancers). The complex interplay of these factors can influence pharmacodynamic responses, such as adverse effects and efficacy, as well as pharmacokinetic manifestations through variability in drug absorption, distribution, metabolism and excretion. Recently, several potentially powerful tools to decipher such intricacies are emerging in various fields of science, and the translation of such knowledge to personalized medicine, called, in general, pharmacogenomics, has been promoted and has occasioned strong expectations from almost every sector of health care. However, at present, few biomarkers can predict which group of patients will respond positively, which will be non-responders and who might experience adverse reactions from the same medication and dosage. This review highlights several important aspects related to the design and statistical analysis for pharmacogenomics studies or clinical trials, which incorporate biomarkers. First, we review biomarker development: how biomarkers may be used as targets and the difference between prognostic and predictive markers. Second, in confirmatory clinical trials, we focus on issues related to study design for evaluating biomarkers and how they can be used to determine which patients might optimally benefit from a specific therapy. Finally, we review exploratory statistical screening techniques for detecting biomarkers in Phase I or pharmacokinetics studies.

It is known that the frequency of men and women suffering from stress-related neuropsychiatric disorders is all but proportionally distributed. Notably, women are far more susceptible than men to the precipitation of depressive symptomatology. Some studies attribute this sex-specific vulnerability to the pronounced genetic predisposition that women may present towards the development of depressive disorders. Furthermore, clinical evidence support the notion that antidepressant response is also characterized by sex-specific manifestations; women may have a better outcome when treated with selective serotonin re-uptake inhibitors, in comparison to tricyclic antidepressants. Despite the fact that the contribution of the "genome" remains elusive when it comes to major depression, intriguing evidence has recently emerged pointing to sexually dimorphic influences of certain polymorphisms in genes related to the pathophysiology of major depression and antidepressant response, such as the serotonin transporter (5-HTT), serotonin 1A (5HT1A) receptor, monoamine oxidase A (MAO-A) and others. Given that the ultimate goal of pharmacogenetics is to provide "tailor-made" pharmacotherapies based on the genetic makeup of an individual, the factor of "sex" needs to be carefully addressed in disorders that are characterized by sex specific manifestations. The aim of the present article is to highlight the impact of sex in depression and in antidepressant pharmacoresponse by providing intriguing insights from the field of pharmacogenetics.

Large interindividual variation is observed in both the response and toxicity associated with anticancer therapy. The etiology of this variation is multifactorial, but is due in part to host genetic variations. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this variation in susceptibility to chemotherapy. This review provides an overview of the progress made in the field of pharmacogenetics and pharmacogenomics using a five-stage architecture, which includes 1) determining the role of genetics in drug response; 2) screening and identifying genetic markers; 3) validating genetic markers; 4) clinical utility assessment; and 5) pharmacoeconomic impact. Examples are provided to illustrate the identification, validation, utility, and challenges of these pharmacogenetic and pharmacogenomic markers, with the focus on the current application of this knowledge in cancer therapy. With the advance of technology, it becomes feasible to evaluate the human genome in a relatively inexpensive and efficient manner; however, extensive pharmacogenetic research and education are urgently needed to improve the translation of pharmacogenetic concepts from bench to bedside., ((c) 2009 American Cancer Society.)

Oral anticoagulants (OA) are a leading cause of fatal haemorrhagic adverse events in relation with an important interindividual variability of response to these drugs. Besides several clinical factors, this interindividual variability of response to OA has a pharmacogenetic basis. Carriers of cytochrome P450 2C9 (CYP2C9)-deficient alleles have a reduced clearance of warfarin and are exposed to dramatic overdoses in the first weeks of treatment. Genetic polymorphisms of vitamin K epoxide reductase (VKORC1), the target of OA, identify patients with a high sensitivity to OA who are at risk of early overdose. Most pharmacogenetic evidence is presently restricted to warfarin. Several warfarin dosing algorithms have been constructed, adapted on CYP2C9 and VKORC1 genotypes and clinical factors, to predict the best dose for each patient. Carriers of one of allelic variant need a 20-30% reduction of warfarin dose. However, definite evidence concerning the usefulness of these algorithms in terms of reducing the frequency of major bleeding episodes is still lacking. Ongoing prospective randomised trials will ascertain definitive answer over the coming years.

Amodiaquine is a central drug in the new global strategy of combination therapies for the control of malaria. Amodiaquine is mainly metabolized hepatically towards its major active metabolite desethylamodiaquine, by the polymorphic P450 isoform CYP2C8. Amodiaquine is associated with rare but serious side effects, as well as with relatively frequent mild ones. These are expected to be at least partially related to CYP2C8 alleles. Pharmacogenetic knowledge of amodiaquine exposed populations is important for pharmacovigilance issues and in being a first step for future realistic applications from a personal medicine perspective.

Manifestation of tardive dyskinesia (TD) among schizophrenia subjects on long-term antipsychotic treatment with typical drugs has been a clinical concern. Despite its association with extrapyramidal symptoms, typical drugs are still routinely prescribed globally though marginally superior atypical drugs have long been available. The genetic component in the etiology of TD is well documented. Search for these determinants has led to a few consensus associations of CYP2D6 *10, CYP1A2*1F, DRD2 Taq1A (rs1800497), DRD3 Ser9Gly (rs6280) and MnSOD Ala9Val (rs4880) variants with TD. However, translation of these observations into the clinic has not been achieved so far. This review discusses the salient features of TD etiopathology, current status of TD genetics, interactions between genetic and nongenetic factors, some major drawbacks, challenges and expected focus in TD research over the next decade, with emphasis on pharmacogenetics.

The 5,10-methylenetetrahydrofolate reductase (MTHFR) is a key enzyme for intracellular folate homeostasis and metabolism. Two common MTHFR polymorphisms, C677T and A1298C, which lead to an altered amino acid sequence, have been associated with a decreased enzyme activity and susceptibility to cancer suggesting that these genetic variants may modulate the risk of several malignancies. C667T, and to a lesser extent A1298C polymorphisms, are also reported to influence the cytotoxic effect of fluoropyrimidines and antifolates providing support for their pharmacogenetic role in predicting the efficacy and the toxicity in cancer and rheumatoid arthritis patients. A combined polymorphisms and haplotype analysis may result in a more effective approach than a single polymorphism one. Moreover gene-nutrient/environmental and gene-racial/ethnic interactions have been shown to affect the impact of these MTHFR genetic variants. Further well-designed studies are needed to clarify the role of MTHFR polymorphisms to derive dose adjustment recommendations on the basis of the patient's genotype.

Evaluation of: Legro RS, Barnhart HX, Schlaff WD et al.: Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. J. Clin. Endocrinol. Metab. 93(3), 792-800 (2008). The current study by Legro et al. is a substudy of the recent multicenter, double-blinded, prospective study Pregnancy in Polycystic Ovary Syndrome. Legro et al. randomly assigned 626 infertile women with polycystic ovary syndrome to receive 50 mg clomiphene citrate plus placebo (n = 209), 2 g extended-release metformin plus placebo (n = 208), or a combination of metformin and clomiphene (n = 209) for up to six cycles. Of 626 patients in the original study, 312 women participated in the pharmacogenetic substudy; 98 received metformin XR (2 g/day), 102 clomiphene and 112 combined clomiphene-metformin XR treatment. This study was designed "to identify predictive genetic polymorphism and other determinants of ovulatory response" in prospective fashion. Candidate genes tested included estrogen receptor 1 (ESR1), CYP genes (CYP2C9 and CYP2D6) and STK11. STK11, formerly known as LKB1, is a serine-threonine kinase gene expressed in the liver, which phosphorylates and activates AMP-activated protein kinase. It was shown to be a site of metformin action. The C allele of a SNP in the STK11 gene was associated with a significantly decreased chance of ovulation in polycystic ovary syndrome women treated with metformin. In analysis of ovulation per cycle, the adjusted odds ratio for CC versus GG (wild-type normal) was 0.30 (95% CI: 0.14-0.66) and the odds ratio for CG versus GG was 0.30 (95% CI: 0.14-0.66). This elegant study is of great importance because despite treatment, many women with polycystic ovary syndrome fail to ovulate, 24.9% in the clomiphene group, 44.7% in the metformin group and 16.7% in the clomiphene-metformin group.

The ATP-binding cassette transporter ABCG2 (BCRP, MXR and ABCP) is highly expressed in the gastrointestinal tract and liver, and governs absorption, distribution and excretion of a wide variety of clinically important drugs. Common germline polymorphisms in the ABCG2 gene have been described that can affect expression, cellular localization and/or substrate recognition of the encoded protein. Alteration of transporter function by either of these mechanisms contributes significantly to interindividual variability in drug disposition and treatment outcome with certain, but not all, substrates for ABCG2.

The immunosuppressive drugs used in solid-organ transplantation are potent and toxic agents with narrow therapeutic ranges. Underdosing is associated with immunological rejection of the transplanted organ, whereas overdosing results in infections, malignancy and direct toxicity to a number of organs. Pharmacokinetic heterogeneity makes initial dose determination difficult, as there is a poor correlation between dose and blood concentration. Therapeutic drug monitoring is available but the pharmacokinetic-pharmacodynamic association is imperfect and it does not help in achieving target blood concentrations during the critical early 2-3 days after transplantation. Genetic polymorphisms in drug targets, drug-metabolizing enzymes and drug efflux pumps have been identified as potential targets for developing a pharmacogenetic strategy to individualize initial drug choice and dose. To date, use of the CYP3A5 genotype to predict the appropriate initial dose of tacrolimus is the most promising option for individualization of drug therapy in organ transplantation.

Adverse drug reactions (ADRs) associated with antifungal therapy are major problems in patients with invasive fungal infections. Whether by clinical history or patterns of genetic variation, the identification of patients at risk for ADRs should result in improved outcomes while minimizing deleterious side effects. A major contributing factor to ADRs with antifungal agents relates to drug distribution, metabolism and excretion. Genetic variation in key genes can alter the structure and expression of genes and gene products (e.g., proteins). Thus far, the effort has focused on identifying polymorphisms with either empirical or predicted in silico functional consequences; the best candidate genes encode phase I and II drug-metabolizing enzymes (e.g., CYP2C19 and N-acetyltransferase), plasma proteins (albumin and lipoproteins) and drug transporters (P-glycoprotein and multidrug resistance proteins), which can affect the disposition of antifungal agents, eventually leading to dose-dependent (type A) toxicity. Less is known regarding the key genes that interact with antifungal agents, resulting in idiosyncratic (type B) ADRs. The possible role of certain gene products and genetic polymorphisms in the toxicities of antifungal agents are discussed in this review. The preliminary data address the following: low-density lipoproteins and cholesteryl ester transfer protein in amphotericin B renal toxicity; toll-like receptor 1 and 2 in amphotericin B infusion-related ADRs; phosphodiesterase 6 in voriconazole visual adverse events; flavin-containing monooxygenase, glutathione transferases and multidrug resistance proteins 1 and 2 in ketoconazole and terbinafine hepatotoxicity; CYP enzymes and P-glycoprotein in drug interactions between azoles and coadministered medications; multidrug resistance proteins 8 and 9 on 5-flucytosine bone marrow toxicity; and mast cell activation in caspofungin histamine release. This will focus on high-priority candidate genes, which could provide a starting point for molecular studies to elucidate the potential mechanisms for understanding toxicity associated with antifungal drugs as well as identifying candidate genes for large population prospective genetic association studies.

Objective: To examine the effect of the I405V and TaqIB polymorphisms of cholesteryl ester transfer protein (CETP) on the lipid response after simvastatin treatment in 180 hypercholesterolaemic patients., Methods: Hypercholesterolaemic patients (n = 180) attending the lipid clinic at the Onassis Cardiac Surgery Center were genotyped and their response to simvastatin was evaluated., Results: Sequence variations in the CETP gene influenced the effect of lipid-lowering treatment. Specifically, the I allele of the I405V polymorphism was associated with a greater reduction in triglyceride (TG; p = 0.04) and a significant increase in high-density lipoprotein cholesterol (HDL-C) levels (p = 0.05) after treatment compared with the V allele., Conclusions: The authors' findings suggest that CETP I405V polymorphism modifies the effect of simvastatin on TG reduction and HDL-C elevation; the carriers of the I allele responded better to treatment. These findings need to be confirmed in larger studies.

Genomic variations influencing response to pharmacotherapy of pain are under investigation. Candidate genes such as (opioid)-receptors, transporters and other molecules important for pharmacotherapy are discussed. Drug metabolising enzymes represent a further major target of ongoing research in order to identify associations between an individual's genetic profile and drug response (pharmacogenetics). Polymorphisms of the cytochrome P450 enzymes influence analgesic efficacy of codeine, tramadol and tricyclic antidepressants (CYP2D6). Blood levels of some NSAIDs are dependent on CYP2C9 activity, whereas opioid-receptor polymorphisms are discussed for differences in opioid mediated analgesia and side effects. Pharmacogenetics as a diagnostic tool has the potential to improve patient therapy and care, and it is hoped that pharmacogenetics will individualise drug treatment to a greater extent in the near future.

The response to beta2-agonist treatment shows large repeatability within individuals and may thus be determined by genetic influences. Here we present a systematic overview of the available genetic association and linkage data for beta2-agonist treatment response. Systematic searches identified 66 eligible articles, as of March 2007, pertaining either to B2AR gene polymorphisms and short-acting or long-acting beta2-agonists or to another 29 different genes. We systematize these study results according to gene, agent and type of outcomes addressed. The systematic review highlights major challenges in the field, including extreme multiplicity of analyses; lack of consensus for main phenotypes of interest; typically small sample sizes; and poor replicability of the proposed genetic variants. Future studies will benefit from standardization of analyses and outcomes, hypothesis-free genome-wide association testing platforms, potentially additional fine mapping around new discovered variants, and large-scale collaborative studies with prospective plans for replication among several teams, with transparent public recording of all data.

Interindividual differences in tumor response and normal tissue toxicities are consistently observed with most chemotherapeutic agents or regimens. While many clinical variables have been associated with drug responses (e.g., age, gender, diet, drug-drug interactions), inherited variations in drug disposition (metabolism and transport) genes and drug target genes also likely contribute to the observed variability in cancer treatment outcome. Pharmacogenomic studies aim to elucidate the genetic bases for interindividual differences and to use such genetic information to predict the safety, toxicity, and/or efficacy of drugs. There exist several clinically relevant examples of the utility of pharmacogenomics that associate specific genetic polymorphisms in drug metabolizing enzymes (e.g., TPMT, UGT1A1, DPD), drug transporters (MDR1), and drug target enzymes (TS) with clinical outcomes in patients treated with commonly prescribed chemotherapy drugs, such as 5-fluorouracil and irinotecan (Camptosar; Pfizer Pharmaceuticals; New York, NY http://www.pfizer.com). Techniques to discover and evaluate the functional significance of these polymorphisms have evolved in recent years and may soon be applied to clinical practice and clinical trials of currently prescribed anticancer drugs as well as new therapeutic agents. This review discusses the current and future applications of pharmacogenomics in clinical cancer therapy and cancer drug development.

Pharmacogenetics, the inherited basis for interindividual differences in drug response, has rapidly expanded with the advent of new molecular tools and the sequencing of the human genome, yielding pharmacogenomics. We review here recent ideas and findings regarding pharmacogenomics of components of the autonomic nervous system, in particular, neuronal nicotinic acetylcholine receptors, postsynaptic receptors with which the parasympathetic and sympathetic neurotransmitters, acetylcholine (ACh) and norepinephrine, respectively, interact. The receptor subtypes that mediate these responses, M(1-3) muscarinic cholinergic receptors (mAChRs), and alpha(1A,B,D)-, alpha(2A,B,C)-, and beta(1,2,3)-adrenergic receptors (AR), show highly variable expression of genetic variants; variants of mAChRs and alpha(1)-ARs are relatively rare, whereas alpha(2)-AR and beta-AR subtype variants are quite common. The largest amount of data is available regarding variants of the latter ARs and represents efforts to associate certain receptor genotypes, most commonly, single nucleotide polymorphisms, with particular phenotypes (e.g., cardiovascular and metabolic responses). In vitro and in vivo studies have yielded inconsistent results; definitive conclusions are limited. We identify several conceptual and methodological problems with available data: sample size, ethnicity, tissue differences, coding versus noncoding variants, limited studies of haplotypes, and interaction among variants. Thus, although progress has been made in identifying genetic variation that influences drug response fo autonomic nervous system components, we are still at the early stages of defining the most critical genetic determinants and their role in human physiology and pharmacology.

Unpredictable efficacy and toxicity are major hurdles in the administration of many medications. By identifying inherited DNA polymorphisms that influence drug disposition and effects, pharmacogenomics is an exciting tool for the individualization of drug therapies. Single nucleotide polymorphisms (SNP) in genes encoding drug metabolizing enzymes, drug transporters, and DNA repair genes have recently been shown to influence drug toxicity and efficacy. This review will discuss clinically relevant examples of genetic polymorphisms that influence the outcome of drug therapy, and possibilities for future applications of pharmacogenomics.

Genetic variability has recently been implicated in the development of familial epilepsy syndromes and in heterogeneous responses of epilepsy patients to drug treatment. Mutations in distinct proteins have been shown to underlie the development of epilepsy, increase propensity for drug resistance, and alter drug metabolism. Improved understanding of how individual genetic variability may alter the efficacy of pharmacological therapeutic interventions is an important and timely goal. The investigation of relationships between genotype and patient responses to drug treatment is termed pharmacogenomics.

This review summarizes the current status of our knowledge about the role of pharmacogenetic variation in response to diuretics and suggests future research topics for the field. Genes with a role in the pharmacokinetics of most diuretics are renal drug transporters, especially OAT1, OAT3 and OCT2 (genes SLC22A6, SLC22A8 and SLC22A2) whereas variants in carbonic anhydrase (CA), cytochrome P450 enzymes and sulfotransferases are relevant only for specific substances. Genes on the pharmacodynamic side include the primary targets of thiazide, loop, K(+)-sparing and aldosterone antagonistic diuretics: NCC, NKCC2, ENaC and the mineralocorticoid receptor (genes SLC12A3, SLC12A1, SCNN1A, B, G and NR3C2). Rare variants of these proteins cause Gitelman's syndrome, Bartter's syndrome, Liddle's syndrome or pregnancy-induced hypertension. Polymorphisms in these and in associated proteins such as GNB3, alpha-adducin and angiotensin-converting enzyme (ACE) seem to be clinically relevant. In conclusion, first knowledge has evolved that efficacy of diuretic drugs may be determined by genetic polymorphisms in genes determining pharmacokinetics and pharmacodynamics of this drug class. In the future, the selection of a diuretic drug or the dosing schedules may be individually chosen based on pharmacogenetic parameters, however, many questions remain to be answered before this fantasy becomes reality.

Cytochrome P450 (CYP) 2C19 mediates the major metabolic transformations of the proton pump inhibitors (PPIs) omeprazole, pantoprazole, lansoprazole, esomeprazole, and rabeprazole. Genetic polymorphism of CYP2C19 can lead to significant phenotypic variation in the activity of this isoenzyme and thus in the metabolism of PPIs. We systematically reviewed the pharmacogenetic studies of PPIs with respect to the effects of CYP2C19 polymorphism on the clinical outcomes of PPI therapy. We searched MEDLINE (January 1966-August 2002) and EMBASE (January 1988-August 2002) for English-language articles on the pharmacogenetics of PPIs; the search was supplemented by a bibliographic review of all relevant articles. Seventeen pertinent citations were identified, and the quality (level) of evidence for each was categorized according to the rating scale of the United States Preventive Services Task Force. We found that the relationship between CYP2C19 genetic polymorphism and clinical outcomes after PPI therapy has not yet been clearly delineated. Virtually all pharmacogenetic studies of PPIs have been performed in Japanese men; thus, the clinical relevance of CYP2C19 genetic polymorphism in non-Asian patients and women is unknown. Differences among dual- and triple-therapy drug regimens make it difficult to compare H. pylori eradication studies and assess their applicability to current practice patterns. Drug adherence, a pivotal factor in the success of eradication therapy, was addressed in only four trials. Future directions for research include performing more studies with larger sample sizes, particularly in non-Asian populations and women; measuring plasma PPI concentrations to directly correlate H. pylori infection and ulcer cure rates with plasma drug availability; expanding the study population to patients with gastroesophageal reflux disease; and exploring the influence of CYP3A4 in the success or failure of PPI therapy. Although CYP2C19 genotyping is currently only a research instrument, it may be a valuable clinical tool in select patients to ensure optimal PPI therapy.