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Both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group provide therapeutic recommendations for well‐known gene‐drug pairs. Published recommendations show a high rate of concordance. However, as a result of different guideline development methods used by these two consortia, differences between the published guidelines exist. The aim of this paper is to compare both initiatives and explore these differences, with the objective to achieve harmonization. [ABSTRACT FROM AUTHOR]

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with development of acute hemolytic anemia (AHA) induced by a number of drugs. We provide guidance as to which G6PD genotypes are associated with G6PD deficiency in males and females. Rasburicase is contraindicated in G6PD-deficient patients due to the risk of AHA and possibly methemoglobinemia. Unless preemptive genotyping has established a positive diagnosis of G6PD deficiency, quantitative enzyme assay remains the mainstay of screening prior to rasburicase use. The purpose of this article is to help interpret the results of clinical G6PD genotype tests so that they can guide the use of rasburicase. Detailed guidelines on other aspects of the use of rasburicase, including analyses of cost-effectiveness, are beyond the scope of this document. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are published and updated periodically on https://www.pharmgkb.org/page/cpic to reflect new developments in the field. [ABSTRACT FROM AUTHOR]

The pace of discovery of potentially actionable pharmacogenetic variants has increased dramatically in recent years. However, the implementation of this new knowledge for individualized patient care has been slow. The Pharmacogenomics Research Network (PGRN) Translational Pharmacogenetics Program seeks to identify barriers and develop real‐world solutions to implementation of evidence‐based pharmacogenetic tests in diverse health‐care settings. Dissemination of the resulting toolbox of “implementation best practices” will prove useful to a broad audience. Clinical Pharmacology & Therapeutics (2013); 94 2, 207–210. doi:10.1038/clpt.2013.59 [ABSTRACT FROM AUTHOR]

Ototoxicity is a debilitating side effect of platinating agents with substantial interpatient variability. We sought to evaluate the association of thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) genetic variations with cisplatin-related hearing damage in the context of frontline pediatric cancer treatment protocols. In 213 children from the St. Jude Medulloblastoma-96 and -03 protocols, hearing loss was related to younger age (P = 0.013) and craniospinal irradiation (P = 0.001), but did not differ by TPMT or COMT variants. Results were similar in an independent cohort of 41 children from solid-tumor frontline protocols. Functional hearing loss or hair cell damage was not different in TPMT knockout vs. wild-type mice following cisplatin treatment, and neither TPMT nor COMT variant was associated with cisplatin cytotoxicity in lymphoblastoid cell lines. In conclusion, our results indicated that TPMT or COMT genetic variation was not related to cisplatin ototoxicity in children with cancer and did not influence cisplatin-induced hearing damage in laboratory models. [ABSTRACT FROM AUTHOR]

The article discusses the role of pharmacogenetic testing in clinical research and informs that it will be helpful in the expansion of pharmacogenetic variants. It informs that using computational tools integrated with electronic medical record are used for prescribing drugs on the basis of genetic data and this process can increase efficiency for disease interpretation.

Research on genes and medications has advanced our understanding of the genetic basis of individual drug responses. The aim of pharmacogenomics is to develop strategies for individualizing therapy for patients, in order to optimize outcome through knowledge of the variability of the human genome and its influence on drug response. Pharmacogenomics research is translational in nature and ranges from discovery of genotype-phenotype relationships to clinical trials that can provide proof of clinical impact. Advances in pharmacogenomics offer significant potential for subsequent clinical application in individual patients; however, the translation of pharmacogenomics research findings into clinical practice has been slow. Key components to successful clinical implementation of pharmacogenomics will include consistent interpretation of pharmacogenomics test results, availability of clinical guidelines for prescribing on the basis of test results, and knowledge-based decision support systems. [ABSTRACT FROM AUTHOR]

There are several hurdles to the clinical implementation of pharmacogenetics. One approach is to employ pre-prescription genotyping, involving interrogation of multiple pharmacogenetic variants using a high-throughput platform. We compared the performance of the Drug Metabolizing Enzymes and Transporters (DMET) Plus array (1,931 variants in 225 genes) with that of orthogonal genotyping methods in 220 pediatric patients. A total of 1,692 variants had call rates >98% and were in Hardy-Weinberg equilibrium. Of these, 259 were genotyped by at least one independent method, and a total of 19,942 single-nucleotide polymorphism (SNP)-patient sample pairs were evaluated. The concordance rate was 99.9%, with only 28 genotype discordances observed. For the genes deemed most likely to be clinically relevant (TPMT, CYP2D6, CYP2C19, CYP2C9, VKORC1, DPYD, UGT1A1, and SLCO1B1), a total of 3,799 SNP-patient sample pairs were evaluable and had a concordance rate of 99.96%. We conclude that the DMET Plus array performs well with primary patient samples, with the results in good concordance with those of several lower-throughput genotyping methods. [ABSTRACT FROM AUTHOR]

Little is known about how genetic variations in enhancers influence drug response. In this study, we investigated whether nucleotide variations in enhancers that regulate drug transporters can alter their expression levels. Using comparative genomics and liver-specific transcription factor binding site (TFBS) analyses, we identified evolutionary conserved regions (ECRs) surrounding nine liver membrane transporters that interact with commonly used pharmaceuticals. The top 50 ECRs were screened for enhancer activity in vivo, of which five-located around ABCB11, SLC10A1, SLCO1B1, SLCO1A2, and SLC47A1-exhibited significant enhancer activity. Common variants identified in a large ethnically diverse cohort (n = 272) were assayed for differential enhancer activity, and three variants were found to have significant effects on reporter activity as compared with the reference allele. In addition, one variant was associated with reduced SLCO1A2 mRNA expression levels in human liver tissues, and another was associated with increased methotrexate (MTX) clearance in patients. This work provides a general model for the rapid characterization of liver enhancers and identifies associations between enhancer variants and drug response. [ABSTRACT FROM AUTHOR]

Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30-60% of individuals who are heterozygotes (~3-14% of the population) show moderate toxicity, and homozygous wild-type individuals (~86-97% of the population) show lower active thioguanine nucleolides and less myelosuppression. We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype. [ABSTRACT FROM AUTHOR]

The article offers information on the guidelines for pharmacogenetic tests developed by the Clinical Pharmacogenetics Implementation Consortium (CPIC) under the Pharmacogenomics Research Network. It says that the guidelines were established to guide physicians in their translation of the results of laboratory tests in prescribing specific drugs. Furthermore, the guidelines will contain information on the drugs' dosages as the result of genetic tests, gene-based and drug based information.

We investigated whether genetic polymorphisms in the promoter region of the proapoptotic β-2 adrenergic receptor gene (ADRB2) influence treatment-induced changes in ADRB2 expression in leukemia cells and response to chemotherapy. The ADRB2 promoter region was genotyped in germline DNA from 369 children with acute lymphoblastic leukemia (ALL). For 95 of the patients, sufficient RNA was available before and after in vivo treatment to assess treatment-induced gene expression changes in ALL cells. After treatment, the median ADRB2 mRNA expression was ninefold lower in leukemia cells of patients who ultimately relapsed as compared with patients who remained in continuous complete remission (CCR). Polymorphisms in the ADRB2 promoter were significantly linked to methotrexate (MTX)-induced upregulation in ADRB2 gene expression in ALL cells. Moreover, the ADRB2 promoter haplotype was significantly related to early treatment response in 245 children with ALL who received uniform treatment. We conclude that germline polymorphisms in ADRB2 are linked to the antileukemic effects of ALL chemotherapy. [ABSTRACT FROM AUTHOR]

The genetic variations that result in allergy to asparaginase are as yet undetermined. We interrogated more than 500,000 single-nucleotide polymorphisms (SNPs) in 485 children with acute lymphoblastic leukemia (ALL), 322 in a discovery cohort, and 163 in a validation cohort. In the top 100 SNPs associated with allergy in the discovery cohort, chromosome 5 was overrepresented as compared with other chromosomes (P = 0.00032), hosting 10 SNPs annotated to genes. Among these 10 SNPs, one SNP (rs4958381), in GRIA1 on chromosome 5q33, was replicated in the validation cohort (P = 1.8 × 10−5, 2.9 × 10−3, and 3.5 × 10−7 in the discovery, validation, and combined cohorts, respectively). Four additional SNPs annotated to GRIA1 were also significantly associated with allergy (P < 0.05) in both cohorts. Chromosome 5q33 has previously been associated with asthma and atopy. These data contribute to the growing body of evidence that there is an inherited component to predisposition to drug allergy. [ABSTRACT FROM AUTHOR]

Asparaginase (ASP) is used routinely in frontline clinical trials for the treatment of childhood acute lymphoblastic leukemia (ALL). The goals of this study were to assess the pharmacokinetics and pharmacodynamics of ASP and to mathematically model the dynamics between ASP and asparagine (ASN) in relapsed ALL. Forty children were randomized to receive either native or polyethylene glycolated (PEG) Escherichia coli ASP during reinduction therapy. Serial plasma ASP and ASN, cerebrospinal fluid (CSF) ASN, and serum anti-ASP antibody samples were collected. The ASP clearance was higher (P = 0.001) for native vs. PEG ASP. Patients with antibodies to PEG ASP had faster PEG ASP clearance (P = 0.004) than did antibody-negative patients. Patients who were positive for antibodies had higher CSF ASN concentrations than did those who were negative (P = 0.04). The modeling suggests that by modifying dosages, comparable ASN depletion is achievable with both preparations. At relapse, there were significant pharmacokinetic and pharmacodynamic differences attributable to ASP preparation and antibody status. [ABSTRACT FROM AUTHOR]

The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which mercaptopurine doses are individualized on the basis of TPMT genotype.Clinical Pharmacology & Therapeutics (2009); 85, 2, 164–172 doi:10.1038/clpt.2008.154 [ABSTRACT FROM AUTHOR]

Therapy-related acute myeloid leukemia (t-AML) caused by MLL rearrangements (rMLL) can arise from topoisomerase II agents. However, whether rMLL-related leukemogenesis is inextricably linked to drug cytotoxicity remains controversial. We therefore compared (i) rMLL in children with acute lymphoblastic leukemia (ALL) who developed t-AML and those who did not, (ii) epipodophyllotoxin toxicity in patients with t-AML and in controls, and (iii) rMLL in cells sensitive to etoposide and in those resistant to etoposide. In children with ALL, rMLL appeared to be more frequent in children who developed t-AML than in those who did not (seven pairs, P = 0.04), although independent of the cumulative etoposide dose (P = 0.5). Similarly, the frequency of epipodophyllotoxin-related toxicities did not differ between patients with t-AML and controls (26 pairs, P > 0.17). Moreover, in 25 cell lines, etoposide-induced MLL fusions did not differ in sensitive vs. resistant lines at equitoxic concentrations (P = 0.65). Together, these results indicate that epipodophyllotoxin-mediated leukemogenesis is not directly linked to drug cytotoxicity.Clinical Pharmacology & Therapeutics (2008); 84, 6, 691–697 doi:10.1038/clpt.2008.86 [ABSTRACT FROM AUTHOR]

One purpose of the International HapMap Project is to provide a genome-wide resource to discover pharmacogenetic determinants of drug response. The thiopurine methyltransferase (TPMT) 719A>G single-nucleotide polymorphism (SNP) causes decreased TPMT activity, increased intracellular thiopurines, and drug toxicities. Using HapMap cell lines and 3.3 million SNPs, we tested whether the TPMT 719A>G SNP could be identified as predicting TPMT phenotype. Assuming TPMT was a candidate gene, five SNPs and four haplotypes predicted TPMT phenotype, two of which were in complete linkage disequilibrium with the functional 719A>G SNP. We also used a genome-wide approach to rank all 17,542 genes as predictors of TPMT activity. A TPMT haplotype, HAP1, significantly predicted TPMT phenotype; however, haplotypes of 96 genes ranked higher than TPMT. Our findings show that HapMap resources are useful for pharmacogenetic discovery when the candidate gene is known, but challenges remain for definitive gene identification when a genome-wide agnostic approach is employed.Clinical Pharmacology & Therapeutics (2007) 81, 729–734. doi:10.1038/sj.clpt.6100135; published online 28 February 2007 [ABSTRACT FROM AUTHOR]

The field of pharmacogenetics has existed since the 1950s, when it was demonstrated that some drug effects could differ substantially among race and ethnic groups, and that some drug metabolizing enzyme activities were inherited. During the 1990s, application of molecular biology to the study of inherited drug-related phenotypes proved the genetic basis of several genetic polymorphisms. Genomic technology has now demonstrated that germline genetic variability among humans is extremely common. The combined weight of proven examples whereby pharmacogenetics affects drugs, and the possibility of even more examples being elucidated in the coming decades, dictates that pharmacogenetics be incorporated into the drug approval process. It is our contention that minimal pharmacogenetic testing should be required for all new drug applications to the Food and Drug Administration (FDA). This would include a requirement for germline DNA to be prospectively collected from all subjects participating in preapproval clinical trials. For drugs that are metabolized by enzymes whose genes have clearly inactivating polymorphisms, clinical trial participants should be genotyped for those polymorphisms.Clinical Pharmacology & Therapeutics (2007) 81, 425–428. doi:10.1038/sj.clpt.6100097 [ABSTRACT FROM AUTHOR]

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.Clinical Pharmacology & Therapeutics (2007) 81, 328–345. doi:10.1038/sj.clpt.6100087 [ABSTRACT FROM AUTHOR]

Tricyclic antidepressant (TCA) clinical pharmacogenetic implementation guidelines for CYP2D6 and CYP2C19 genotypes highlight the importance of both genes. However, studies of the combined impact of the two genes are sparse, limiting the ability to make strong recommendations based on both genes. The warfarin pharmacogenetics literature highlights the strength of a multigenic approach for discovery and clinical implementation. For optimal impact and interpretation, investigators are encouraged to conduct studies in the context of previously well-defined pharmacogenetics markers. [ABSTRACT FROM AUTHOR]

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up‐to‐date information on thiopurine methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org). Clinical Pharmacology & Therapeutics (2013); 93 4, 324–325. doi:10.1038/clpt.2013.4 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Pharmacogenetic Testing: Time for Clinical Practice Guidelines."

Study Objective: To determine the activity of CYP2D6, N-acetylation, and xanthine oxidase, three drug-metabolizing enzyme systems, in patients with cystic fibrosis and compare the findings with those in individuals without the disease., Design: Prospective cohort study., Setting: General pediatrics service., Patients: Fifty-nine patients with cystic fibrosis and 480 healthy Caucasian volunteers., Interventions: Enzyme activity was determined based on urinary molar metabolite ratios of caffeine and dextromethorphan probes., Measurements and Main Results: The percentage of poor metabolizers of CYP2D6 in patients with cystic fibrosis was not different from that in the control group (p = 0.45). N-Acetylation activity was significantly lower in the patients (p = 0.007), but no statistically significant difference was found in xanthine oxidase activity (p = 0.12)., Conclusion: The activity of these drug-metabolic pathways does not appear to be increased in cystic fibrosis. Whether the activity of other pathways is increased, thus providing a partial explanation for the generally increased drug clearance in this disease, remains to be determined.

Teniposide is a widely used anticancer drug that is extensively bound to plasma proteins (greater than 95%). We evaluated the drug's plasma protein binding in nine patients with acute lymphocytic leukemia who were in their first complete remission, and in a second group of nine patients at the time of relapse and subsequently after achieving another complete remission. Plasma protein binding was assessed by equilibrium dialysis, with direct high-performance liquid chromatographic measurement of total and free teniposide. The mean unbound fraction was 0.44% (0.21-0.88%) in the plasma of patients in first remission. It was significantly higher in patients at the time of relapse (mean = 0.86%; range 0.68-1.08%) and after achieving another complete remission (mean = 1.25%; range 0.51-2.11%). Serum albumin values were significantly lower at the time of relapse (mean = 4.6 vs 4.0 mg/dl; p less than 0.014), and decreased further during intensive postremission therapy containing L-asparaginase (mean = 3.2; p less than 0.05). For all 18 patients, a significant negative correlation (r2 = 0.667; p less than 0.001) was found between serum albumin and unbound teniposide, with low albumin being associated with higher unbound fraction. Such patients have higher systemic exposure to unbound (presumably active) teniposide at any given total plasma concentration of the agent.

1. The major pathway for 4-hydroxylation of debrisoquine in man is polymorphic and under genetic control. More than 90% of subjects (extensive metabolizers, EMs) have active debrisoquine 4-hydroxylase (cytochrome P450IID6) while in the remainder (poor metabolizers, PMs), cytochrome P450IID6 activity is greatly impaired. 2. Within the EM group, cytochrome P450IID6-mediated metabolism of a range of substrates varies widely. Some of this intra-phenotype non-uniformity may be explained by the presence of two subsets of subjects with different genotypes (heterozygotes and homozygotes). 3. Cytochrome P450IID6 substrates have not differentiated between these two genotypes. However, a restriction fragment length polymorphism (RFLP) which identifies mutant alleles of cytochrome P450IID6 locus has been described and can definitively assign genotype in some heterozygous EM subjects. 4. In this study, we used RFLP analysis and encainide as a model substrate to determine if non-uniformity in cytochrome P450IID6 activity among EMs is related to genotype. We tested the hypothesis that heterozygotes exhibit intermediate metabolic activity and that homozygous dominants exhibit the highest activity. We proposed encainide as a useful substrate for this purpose since cytochrome P450IID6 catalyzes not only its biotransformation to O-desmethyl encainide (ODE) but also the subsequent metabolism of ODE to 3-methoxy-O-desmethyl encainide (MODE). 5. A single 50 mg oral dose of encainide was administered to 139 normal volunteers and 14 PMs were identified. Urinary ratios among encainide, ODE and MODE in the remaining 125 EM subjects revealed a wide range of cytochrome P450IID6 activity. However, Southern blotting of genomic DNA digested with XbaI identified obligate heterozygotes in both extremes of all ratio distributions.(ABSTRACT TRUNCATED AT 250 WORDS)