Optimising the use of medicines to reduce acute kidney injury in children and babies.

Pharmacol Ther. 2017 Feb 12;:

Authors: Oni L, Hawcutt DB, Turner MA, Beresford MW, McWilliam S, Barton C, Park BK, Murray P, Wilm B, Copple I, Floyd R, Peak M, Sharma A, Antoine DJ

Abstract
The majority of medications in children are administered in an unlicensed or off-label manner. Paediatricians are obliged to prescribe using the limited evidence available. The 2007 EU regulation on the use of paediatric drugs means pharmaceutical companies are now obliged to (and receive incentives for) contributing to paediatric drug data and carrying out paediatric clinical trials. This is important, as the efficacy and adverse effect profiles of medicines vary across childhood. Additionally, there are significant age-related changes in the pharmacodynamic and pharmacokinetic activity of many drugs. This may be related to physiological (differential expressions of cytochrome P450 enzymes or variable glomerular filtration rates at different ages for example) and psychological (increasing autonomy and risk perception in teenage years) changes. Increasing numbers of children are surviving life-threatening childhood conditions due to medical advances. This means there is an increasing population who are at risk of the consequences of the long-term, early exposure to nephrotoxic agents. The kidney is an organ that is particularly vulnerable to damage as a consequence of drugs. Drug-induced acute kidney injury (AKI) episodes in children and babies are principally due to non-steroidal anti-inflammatory drugs, antibiotics or chemotherapeutic agents. The renal tubules are vulnerable to injury because of their concentrating ability and high-energy hypoxic environment. This review focuses on drug-induced AKI and the methods to minimise its effect, including general management plus the role of child-specific pharmacokinetic data, the use of pharmacogenomics and early detection of AKI using urinary biomarkers and electronic triggers.

PMID: 28202365 [PubMed - as supplied by publisher]

Clinical pharmacogenetics implementation consortium (cpic) guideline for pharmacogenetics-guided warfarin dosing: 2017 update.

Clin Pharmacol Ther. 2017 Feb 15;:

Authors: Johnson JA, Caudle KE, Gong L, Whirl-Carrillo M, Stein CM, Scott SA, Lee MT, Gage BF, Kimmel SE, Perera MA, Anderson JL, Pirmohamed M, Klein TE, Limdi NA, Cavallari LH, Wadelius M

Abstract
This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry. This article is protected by copyright. All rights reserved.

PMID: 28198005 [PubMed - as supplied by publisher]

Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism.

Drug Metab Dispos. 2017 Feb 10;:

Authors: Annalora AJ, Marcus CB, Iversen PL

Abstract
The human genome encodes 57 cytochrome P450 (CYP) genes whose enzyme products metabolize hundreds of drugs, thousands of xenobiotics and unknown numbers of endogenous compounds including steroids, retinoids and icosinoids. Indeed, CYP genes are the first line of defense against daily environmental chemical challenges in a manner that parallels the immune system. Several databases, including PubMed, AceView, and Ensembl, were queried to establish a comprehensive analysis of the full human CYP transcriptome. This review describes a remarkable diversification of the 57 human CYP genes, which may be alternatively processed into nearly 1000 distinct mRNA transcripts to shape an individual's CYP proteome. Important CYP splice variants from families: 1A, 1B, 2C, 2D, 3A, 4F, 19A and 24A have now been documented, with some displaying alternative subcellular distribution or catalytic function directly linked to a disease pathology. The expansion of CYP transcript diversity involves tissue-specific splicing factors, transformation-sensitive alternate splicing, trans-splicing between gene transcripts, single-nucleotide polymorphisms (SNPs), and epigenetic regulation of alternate splicing. Homeostatic regulation of variant CYP expression also is influenced by nuclear receptor (NR) signaling, suppression of nonsense mediated decay (NMD) or premature termination codons (PTC), mitochondrial dysfunction or host infection. This review focuses on emergent aspects of the adaptive gene splicing process, which when viewed through the lens of CYP-NR gene interactions, resembles a primitive immune-like system that can rapidly monitor, respond and diversify to acclimate to fluctuations in endo-xenobiotic exposure. Insights gained from this review should aid future drug discovery and improve therapeutic management of personalized drug regimens.

PMID: 28188297 [PubMed - as supplied by publisher]

Are evidence standards different for genomic- vs. clinical-based precision medicine? - A quantitative analysis of individualized warfarin therapy.

Clin Pharmacol Ther. 2017 Feb 10;:

Authors: Dhanda DS, Guzauskas GF, Carlson JJ, Basu A, Veenstra DL

Abstract
Evidence requirements for implementation of precision medicine (PM), whether informed by genomic or clinical data, are not well defined. Evidence requirements are driven by uncertainty and its attendant consequences; these aspects can be quantified by a novel technique in health economics, value of information analysis (VOI). We utilized VOI analysis to compare the evidence levels over time for warfarin dosing based on pharmacogenomic- vs. amiodarone-warfarin drug-drug interaction information. The primary outcome was the expected value of perfect information (EVPI), which is an estimate of the upper limit of the societal value of conducting future research. Over the past decade, the EVPI for the pharmacogenomic strategy decreased from $1550 to $140 vs. $1220 to $280 per patient for the drug-interaction strategy. Evidence levels thus appear to be higher for pharmacogenomic-guided vs. drug interaction-guided warfarin dosing. Clinical guidelines and reimbursement policies for warfarin PM could be informed by these findings. This article is protected by copyright. All rights reserved.

PMID: 28187492 [PubMed - as supplied by publisher]

Pharmacological profile and Pharmacogenomics of anti-cancer drugs used for targeted therapy.

Curr Cancer Drug Targets. 2017 Feb 08;:

Authors: Di Francia R, De Monaco A, Saggese M, Iaccarino G, Crisci S, Frigeri F, De Filippi R, Berretta M, Pinto A

Abstract
BACKGROUND: Drugs for targeted therapies are primarily Small Molecules Inhibitors (SMIs), monoclonal antibodies (mAbs), interfering RNA molecules and microRNA. The use of these new agents generates a multifaceted step in the pharmacokinetics (PK) of these drugs. Individual PK variability is often large, and unpredictability observed in the response to the pharmacogenetic profile of the patient (e.g. cytochome P450 enzyme), patient characteristics such as adherence to treatment and environmental factors. Objective This review aims to overview the latest anticancer drugs eligible for targeted therapies and the most recent finding in pharmacogenomics related to toxicity/resistance because either individual gene polymorphisms or acquired mutation in a cancer cell. In addition, an early outline evaluation of the genotyping costs and methods have been taken into consideration. Future outlook To date, therapeutic drug monitoring (TDM) of mAbs and SMIs is not yet supported by heavy scientific evidence. Extensive effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomized trials of classic dosing versus PK-guided adaptive dosing. The detection of individual pharmacogenomics profile could be the key for the oncologists that will have new resources to make treatment decisions for their patients in order to maximize the benefit and minimize the toxicity. Based on this purpose, the clinician should evaluate advantages and limitations, in terms of costs and applicability, of the most appropriate pharmacological approach to performing a tailored therapy.

PMID: 28183252 [PubMed - as supplied by publisher]

Personalised Healthcare: the DiMA clinical model.

Curr Pharm Biotechnol. 2017 Feb 08;:

Authors: Borro M, Gentile G, Fineschi V, Földes-Papp Z, Frati P, Santurro A, Lionetto L, Simmaco M

Abstract
Large-scale application of Personalized Medicine requires a multi-disciplinal environment allowing synergic cooperation among different competences. Strict collaboration between medical and medical sciences, as informatics, ethics, politics, are needed to face the challenges of one-sized healthcare. In spite of the increasing interest, how this system can be globally realized remains tentative. Yet, a relatively small, Personalised Healthcare Service is providing a proof-of principle organizational model to guide implementation into clinical practice.

PMID: 28183244 [PubMed - as supplied by publisher]

Cytochrome P450 Genetic Variations Can Predict mRNA Expression, Cyclophosphamide 4-Hydroxylation, and Treatment Outcomes in Chinese Patients With Non-Hodgkin's Lymphoma.

J Clin Pharmacol. 2017 Feb 09;:

Authors: Shu W, Chen L, Hu X, Zhang M, Chen W, Ma L, Liu X, Huang J, Pang T, Li J, Zhang Y

Abstract
To investigate the impact of cytochrome P450 (CYP) genetic polymorphisms CYP2B6, CYP2C19, and CYP3A5 on mRNA expression, cyclophosphamide/4-hydroxycyclophosphamide pharmacokinetics, and treatment outcomes of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in Chinese patients with non-Hodgkin's lymphoma, 567 cases were investigated. Plasma concentrations of cyclophosphamide/4-hydroxycyclophosphamide were determined using liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters calculated. The frequencies of CYP2B6*1/*29 and CYP2B6*1/*30 were 18 (3.2%) and 30 (5.3%), respectively. Liver samples with CYP2B6*29/*30, CYP2C19*2, CYP2B6*6, or CYP3A5*3 had significantly lower target mRNA expression. Samples with CYP2B6*6 and/or CYP2C19*2 had lower exposure to 4-hydroxycyclophosphamide, whereas those with CYP2B6*1G/*1H had higher exposure. Multivariate model showed that samples with CYP2C19*2 or CYP2B6 785A>raG had worse treatment response than samples with CYP3A5*3. CYP2C19*2, CYP2B6*6, CYP2B6*29, and CYP2B6*30 were protective factors for toxicity in the multivariate model. The best model for gene-gene interactions for treatment response contained CYP2C19*2, CYP2B6 785A>G, and CYP3A5*3 (cross-validation consistency [CVC], 8/10; P = .0035). The best prediction model for grade 2-4 toxicities had CYP2C19*2, CYP2B6 785A>G, and 516 G>T (CVC, 10/10; P < .0001). In previous reports, we were the first to report that the frequency of copy-number variations in CYP2B6 is higher among Chinese than among other ethnic populations. Genetic variations in CYP2B6, CYP2C19, and CYP3A5 dramatically affected the mRNA expression of proteins, the pharmacokinetics of 4-hydroxycyclophosphamide, and the R-CHOP treatment response in Chinese subjects. Patients carrying CYP3A5*3 were more likely to have a better treatment response, whereas patients with CYP2C19*2 or CYP2B6 516G>T, or CYP2B6 785A>G had higher tolerance to treatment.

PMID: 28181240 [PubMed - as supplied by publisher]

Antidepressant prescribing in the precision medicine era: a prescriber's primer on pharmacogenetic tools.

BMC Psychiatry. 2017 Feb 08;17(1):60

Authors: Bousman CA, Forbes M, Jayaram M, Eyre H, Reynolds CF, Berk M, Hopwood M, Ng C

Abstract
About half of people who take antidepressants do not respond and many experience adverse effects. These detrimental outcomes are in part a result of the impact of an individual's genetic profile on pharmacokinetics and pharmcodynamics. If known and made available to clinicians, this could improve decision-making and antidepressant therapy outcomes. This has spurred the development of numerous pharmacogenetic-based decision support tools. In this article, we provide an overview of pharmacogenetic decision support tools, with particular focus on tools relevant to antidepressants. We briefly describe the evolution and current state of antidepressant pharmacogenetic decision support tools in clinical practice, followed by the evidence-base for their use. Finally, we present a series of considerations for clinicians contemplating use of these tools and discuss the future of antidepressant pharmacogenetic decision support tools.

PMID: 28178974 [PubMed - in process]

1237PASSOCIATION OF PHARMACOKINETICS OR PHARMACOGENOMICS WITH TOXICITY OF ERLOTINIB IN PATIENTS WITH RECURRENT ADVANCED NON-SMALL CELL LUNG CANCER.

Ann Oncol. 2014 Sep 01;25(suppl_4):iv433

Authors: Hirose T, Fujita K, Kusumoto S, Oki Y, Murata Y, Sugiyama T, Ishida H, Shirai T, Nakashima M, Yamaoka T, Okuda K, Ohnishi T, Ohmori T, Sasaki Y, Tamura A, Ohta K

PMID: 28172192 [PubMed]

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Pharmacogenomics[Title/Abstract]

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Aripiprazole-induced priapism.

Ind Psychiatry J. 2016 Jan-Jun;25(1):119-121

Authors: Trivedi SK, Mangot AG, Sinha S

Abstract
Priapism is a urologic emergency representing a true disorder of penile erection that persists beyond or is unrelated to sexual interest or stimulation. A variety of psychotropic drugs are known to produce priapism, albeit rarely, through their antagonistic action on alpha-1 adrenergic receptors. We report such a case of priapism induced by a single oral dose of 10 mg aripiprazole, a drug with the least affinity to adrenergic receptors among all atypical antipsychotics. Polymorphism of alpha-2A adrenergic receptor gene in schizophrenia patients is known to be associated with sialorrhea while on clozapine treatment. Probably, similar polymorphism of alpha-1 adrenergic receptor gene could contribute to its altered sensitivity and resultant priapism. In future, pharmacogenomics-based approach may help in personalizing the treatment and effectively prevent the emergence of such side effects.

PMID: 28163420 [PubMed - in process]

Pharmacogenetics of hypersensitivity drug reactions.

Therapie. 2017 Jan 03;:

Authors: Negrini S, Becquemont L

Abstract
Adverse drug reactions are a significant cause of morbidity and mortality and represent a major burden on the healthcare system. Some of those reactions are immunologically mediated (hypersensitivity reactions) and can be clinically subdivided into two categories: immediate reactions (IgE-related) and delayed reactions (T-cell-mediated). Delayed hypersensitivity reactions include both systemic syndromes and organ-specific toxicities and can be triggered by a wide range of chemically diverse drugs. Recent studies have demonstrated a strong genetic association between human leukocyte antigen alleles and susceptibility to delayed drug hypersensitivity. Most notable examples include human leukocyte antigen (HLA)-B*57:01 allele and abacavir hypersensitivity syndrome or HLA-B*15:02 and HLA-B*58:01 alleles related to severe cutaneous reactions induced by carbamazepine and allopurinol, respectively. This review aims to explore our current understanding in the field of pharmacogenomics of HLA-associated drug hypersensitivities and its translation into clinical practice for predicting adverse drug reactions.

PMID: 28162244 [PubMed - as supplied by publisher]

More Efficient Compliance with European Medicines Agency and Food and Drug Administration Regulations for Pediatric Oncology Drug Development: Problems and Solutions.

Clin Ther. 2017 Feb 01;:

Authors: Milne CP

Abstract
5w?>The morbidity and mortality toll of pediatric cancer affects the public health of children worldwide, but despite the gains in the fight against cancer, more progress needs to take place against this disease, which is a leading cause of death and chronic disability in children. In response, leading regulatory authorities in the developed world have been ratcheting up their efforts to induce the private sector to expand their research and development focus during drug development for adult cancers to include children. In mid-May 2016, the Center for the Study of Drug Development at Tufts University held a roundtable workshop on pediatric oncology to explore how companies could maximize the efficiency of pediatric assessment of adult cancer indications while minimizing resource expenditures to comply with regulatory requirements under the European Medicines Agency and the U.S. Food and Drug Administration. Although worldwide a child is diagnosed with cancer every 3 minutes, pediatric cancer is a rare disease, and trial participants are hard to come by. Thus, the market hardly sustains research and development expenses, advances in pharmacogenomics are not reaching down the age scale, and even in the public sector, basic research funding for pediatric cancer pales in comparison to the amount spent on cancer overall. The goal of the roundtable was to acknowledge these problems, and more importantly, to raise the level of awareness of potential solutions, including: more efficient use of the data hierarchy of informative events in clinical trials; new innovative clinical trial platforms for rapid assessment of new drugs in children; new developments in formulation technology; and optimization of speed in pediatric drug development through a multi-stakeholder network collaboration separate from the adult development plan.

PMID: 28161118 [PubMed - as supplied by publisher]

Pharmacogenetics of dipeptidyl peptidase 4 inhibitors in a Taiwanese population with type 2 diabetes.

Oncotarget. 2017 Feb 01;:

Authors: Liao WL, Lee WJ, Chen CC, Lu CH, Chen CH, Chou YC, Lee IT, Sheu WH, Wu JY, Yang CF, Wang CH, Tsai FJ

Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral anti-hyperglycemic drugs enabling effective glycemic control in type 2 diabetes (T2D). Despite DPP-4 inhibitors' advantages, the patients' therapeutic response varies. In this retrospective cohort study, 171 Taiwanese patients with T2D were classified as sensitive or resistant to treatment based on the mean change in HbA1c levels. Using an assumption-free genome-wide association study, 45 single nucleotide polymorphisms (SNPs) involved in the therapeutic response to DPP-4 inhibitors (P < 1 × 10-4) were identified at or near PRKD1, CNTN3, ASK, and LOC10537792. A SNP located within the fourth intron of PRKD1 (rs57803087) was strongly associated with DPP-4 inhibitor response (P = 3.2 × 10-6). This is the first pharmacogenomics study on DPP-4 inhibitor treatment for diabetes in a Taiwanese population. Our data suggest that genes associated with β-cell function and apoptosis are involved in the therapeutic effect of DPP-4 inhibitors, even in the presence of additional oral anti-diabetic drugs. Our findings provide information on how genetic variants influence drug response and may benefit the development of personalized medicine.

PMID: 28160554 [PubMed - as supplied by publisher]

En route to precision medicine through the integration of biological sex into pharmacogenomics.

Clin Sci (Lond). 2017 Feb 01;131(4):329-342

Authors: Gaignebet L, Kararigas G

Abstract
Frequently, pharmacomechanisms are not fully elucidated. Therefore, drug use is linked to an elevated interindividual diversity of effects, whether therapeutic or adverse, and the role of biological sex has as yet unrecognized and underestimated consequences. A pharmacogenomic approach could contribute towards the development of an adapted therapy for each male and female patient, considering also other fundamental features, such as age and ethnicity. This would represent a crucial step towards precision medicine and could be translated into clinical routine. In the present review, we consider recent results from pharmacogenomics and the role of sex in studies that are relevant to cardiovascular therapy. We focus on genome-wide analyses, because they have obvious advantages compared with targeted single-candidate gene studies. For instance, genome-wide approaches do not necessarily depend on prior knowledge of precise molecular mechanisms of drug action. Such studies can lead to findings that can be classified into three categories: first, effects occurring in the pharmacokinetic properties of the drug, e.g. through metabolic and transporter differences; second, a pharmacodynamic or drug target-related effect; and last diverse adverse effects. We conclude that the interaction of sex with genetic determinants of drug response has barely been tested in large, unbiased, pharmacogenomic studies. We put forward the theory that, to contribute towards the realization of precision medicine, it will be necessary to incorporate sex into pharmacogenomics.

PMID: 28159880 [PubMed - in process]

Pharmacogenetics of antidepressant response: A polygenic approach.

Prog Neuropsychopharmacol Biol Psychiatry. 2017 Jan 31;:

Authors: García-González J, Tansey KE, Hauser J, Henigsberg N, Maier W, Mors O, Placentino A, Rietschel M, Souery D, Žagar T, Czerski PM, Jerman B, Buttenschøn HN, Schulze TG, Zobel A, Farmer A, Aitchison KJ, Craig I, McGuffin P, Giupponi M, Perroud N, Bondolfi G, Evans D, O'Donovan M, Peters TJ, Wendland JR, Lewis G, Kapur S, Perlis R, Arolt V, Domschke K, Major Depressive Disorder Working Group of the Psychiatric Genomic Consortium, Breen G, Curtis C, Sang-Hyuk L, Kan C, Newhouse S, Patel H, Baune BT, Uher R, Lewis CM, Fabbri C

Abstract
BACKGROUND: Major depressive disorder (MDD) has a high personal and socio-economic burden and >60% of patients fail to achieve remission with the first antidepressant. The biological mechanisms behind antidepressant response are only partially known but genetic factors play a relevant role. A combined predictor across genetic variants may be useful to investigate this complex trait.
METHODS: Polygenic risk scores (PRS) were used to estimate multi-allelic contribution to: 1) antidepressant efficacy; 2) its overlap with MDD and schizophrenia. We constructed PRS and tested whether these predicted symptom improvement or remission from the GENDEP study (n=736) to the STAR*D study (n=1409) and vice-versa, including the whole sample or only patients treated with escitalopram or citalopram. Using summary statistics from Psychiatric Genomics Consortium for MDD and schizophrenia, we tested whether PRS from these disorders predicted symptom improvement in GENDEP, STAR*D, and five further studies (n=3756).
RESULTS: No significant prediction of antidepressant efficacy was obtained from PRS in GENDEP/STAR*D but this analysis might have been underpowered. There was no evidence of overlap in the genetics of antidepressant response with either MDD or schizophrenia, either in individual studies or a meta-analysis. Stratifying by antidepressant did not alter the results.
DISCUSSION: We identified no significant predictive effect using PRS between pharmacogenetic studies. The genetic liability to MDD or schizophrenia did not predict response to antidepressants, suggesting differences between the genetic component of depression and treatment response. Larger or more homogeneous studies will be necessary to obtain a polygenic predictor of antidepressant response.

PMID: 28159590 [PubMed - as supplied by publisher]

Sex-specific effects of serum sulfate level and SLC13A1 nonsense variants on DHEA homeostasis.

Mol Genet Metab Rep. 2017 Mar;10:84-91

Authors: Tise CG, Anforth LE, Zhou AE, Perry JA, McArdle PF, Streeten EA, Shuldiner AR, Yerges-Armstrong LM

Abstract
CONTEXT: Sulfate is critical in the biotransformation of multiple compounds via sulfation. These compounds include neurotransmitters, proteoglycans, xenobiotics, and hormones such as dehydroepiandrosterone (DHEA). Sulfation reactions are thought to be rate-limited by endogenous sulfate concentrations. The gene, SLC13A1, encodes the sodium-sulfate cotransporter NaS1, responsible for sulfate (re)absorption in the intestines and kidneys. We previously reported two rare, non-linked, nonsense variants in SLC13A1 (R12X and W48X) associated with hyposulfatemia (P = 9 × 10(- 20)).
OBJECTIVE: To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis.
DESIGN: Retrospective cohort study.
SETTING: Academic research.
PATIENTS: Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study.
MAIN OUTCOME MEASURES: DHEA, DHEA-S, and DHEA-S/DHEA ratio.
RESULTS: Increased serum sulfate was associated with decreased DHEA-S (P = 0.03) and DHEA-S/DHEA ratio (P = 0.06) in males but not females. Female SLC13A1 nonsense variant carriers, who had lower serum sulfate (P = 9 × 10(- 13) ), exhibited 14% lower DHEA levels (P = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers (P = 0.002). Consistent with this finding, female SLC13A1 nonsense variant carriers also had lower total testosterone levels compared to non-carrier females (P = 0.03).
CONCLUSIONS: Our results demonstrate an inverse relationship between serum sulfate, and DHEA-S and DHEA-S/DHEA ratio in men, while also suggesting that the sulfate-lowering variants, SLC13A1 R12X and W48X, decrease DHEA and testosterone levels, and increase DHEA-S/DHEA ratio in women. While paradoxical, these results illustrate the complexity of the mechanisms involved in DHEA homeostasis and warrant additional studies to better understand sulfate's role in hormone physiology.

PMID: 28154797 [PubMed - in process]

Cancer patients' and physicians' preferences for decision making regarding pharmacogenomic testing (PGT).

J Clin Oncol. 2012 Dec;30(34_suppl):13

Authors: Hon H, Qiu X, Masroor S, De Souza B, McFarlane G, Wong CA, Tobros K, Azad AK, Hasani E, Rozanec N, Leighl NB, Atehortua NA, Alibhai SM, Xu W, Issa AM, Liu G

Abstract
13 Background: Pharmacogenomics is increasingly utilized in oncology; however, there is little knowledge concerning cancer patients' or oncologists' attitudes toward PGT decision-making in clinical practice.
METHODS: A broad cross-section of cancer patients were interviewed regarding their attitudes toward PGT using hypothetical time, efficacy and toxicity trade-off and willingness-to-pay scenarios (N=278) and/or quantitative choice-based conjoint analysis surveys (N=264); 64 cancer specialists/physicians in training were surveyed similarly.
RESULTS: Of patients participating in the trade-off scenario phase of study, >94% accepted chemotherapy, and of these, >98% wanted PGT that identifies a subset of patients either benefiting from chemotheraphy or who were at risk of severe toxicity. Patients were willing to pay between CAD $1,000-$1,900 for PGT and accept wait times for results of 2-3 weeks. Similar findings were observed in the conjoint phase of the study, with preferences for PGT starting to decline when the out-of-pocket costs reached CAD $500-$1,500, wait time for results exceeded 14 days, and when the prevalence of the genetic variant fell below 25%. Adjuvant patients' acceptance of PGT was most influenced by cost (decision weight [DW]=41%) and prevalence of the genetic variant associated with lack of benefit from chemo (DW=26%). Metastatic patients were most influenced by cost (DW=49%) and wait times (DW=31%). More patients reported difficulty understanding conjoint surveys (14%) than trade-off scenarios (7%; p=0.01). 81% of patients wanted to be involved in decision-making regarding PGT; while 30% of physicians felt it should be a physician-only decision (p=0.006). However, 21% of patients and 5% of physicians admitted to not understanding PGT, while just 14% of physicians rated themselves as very knowledgeable regarding PGT.
CONCLUSIONS: Cancer patients overwhelmingly accept and want to be involved in decision-making regarding PGT, to a greater extent than what physicians prefer. However, communication of PGT information was a potential barrier, as a considerable minority lacked the necessary knowledge to facilitate informed decision-making. Improved patient and physician education is necessary.

PMID: 28146908 [PubMed - in process]

New tissue aquisition tools for molecular biology.

J Clin Oncol. 2012 Oct 20;30(30_suppl):102

Authors:

Abstract
102 Background: Histological and biomolecular examinations are a prerequisite to understand diseases, determine optimal individualized care, and identify targets for potential novel therapies. Despite this key role of tissue-based research the act of biopsy still remains troublesome. New direct and frontal biopsy technologies are emerging with the aim to alleviate the bottleneck of inappropriate minimal invasive interventions. Recent clinical trials evaluated the use of macrobiopsies in providing the necessary tissues for molecular biology.
METHODS: The new instruments for minimal-invasive procedures were evaluated in different single and multicenter clinical trials to generate data on providing enough high-quality tissue for biomolecular research in comparison to diagnostic surgery for various soft tissues and bone lesions throughout the body. In addition, patient comfort and costs data were taken up in the survey.
RESULTS: Direct and frontal type macrobiopsy systems give tissue samples between 150 mg and 300 mg of highly specified parts of the diseased area in a way very similar to open surgery. In addition, biopsy procedures are increasingly more patient friendly with appropriate comfort and safety. The new macrobiopsies are less expensive, making molecular biology at reach for every oncological patient, company, and health care provider.
CONCLUSIONS: Direct and frontal macrobiopsies open new avenues for future bio-banking, pharmacogenomics, biomolecular research, and personalized medicine. It is anticipated that drug discovery and clinical implementation of targeted therapies will be highly facilitated, and that clinical research time for multicenter trials will be significantly shortened.

PMID: 28142432 [PubMed - in process]

The importance of drug transporter characterization to precision medicine.

Expert Opin Drug Metab Toxicol. 2017 Jan 31;:

Authors: Fisel P, Nies AT, Schaeffeler E, Schwab M

PMID: 28140687 [PubMed - as supplied by publisher]