CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients.

Front Pharmacol. 2019;10:481

Authors: Ahmed JH, Makonnen E, Yimer G, Seifu D, Bekele A, Assefa M, Aseffa A, Howe R, Fotoohi A, Hassan M, Aklillu E

Abstract
Chemotherapy-induced hematologic toxicity is the primary reasons of dose reductions and/or delays, low relative dose intensity (RDI), and predicts anticancer response. We investigated the incidence and predictors of chemotherapy-induced hematologic toxicities and reduced RDI in Ethiopian breast cancer patients, and implication of pharmacogenetics variations. Breast cancer patients (n = 249) were enrolled prospectively to receive cyclophosphamide based chemotherapy. Hematological toxicity (neutropenia, anemia, and thrombocytopenia) were monitored throughout chemotherapy cycle. The primary and secondary outcomes were incidence of grade 3 or 4 toxicity and reduced RDI, respectively. CYP2B6∗6, CYP3A5∗3, CYP2C9 (∗2,∗3), CYP2C19 (∗2,∗3), CYP2J2∗7, POR∗28, and ABCB1 (rs3842) genotyping were done. Cox proportional hazard and logistic regression were used to estimate risk predictors of toxicity and reduced RDI, respectively. Majority (73.5%) of the patients were < 45 years of age. The incidence of grade 3 or 4 hematological toxicity was 51.0% (95% CI = 44.54-57.46%). Multivariate Cox proportional hazard regression indicated CYP2J2∗7 genotype [Hazard ratio (HR) = 1.82; 95% CI = 1.14-2.90], pretreatment grade 1 leukopenia (HR = 2.75; 95% CI = 1.47-5.15) or grade 1 or 2 neutropenia (HR = 2.75; 95% CI = 1.73-4.35) as significant predictors of hematologic toxicities. The odds of having hematologic toxicities was lower in CYP2C9∗2 or ∗3 carriers (p = 0.024). The prevalence of reduced RDI was 56.6% (95% CI = 50.3-62.9%). Higher risk of reduced RDI was associated with CYP2J2∗7 allele [Adjusted odds ratio (AOR) = 2.79; 95% CI = 1.21-6.46], BMI ≤ 18.4 kg/m2 (AOR = 5.98; 95% CI = 1.36-26.23), baseline grade 1 leukopenia (AOR = 6.09; 95% CI = 1.24-29.98), and baseline neutropenia (AOR = 3.37; 95% CI = 1.41-8.05). The odds of receiving reduced RDI was lower in patients with CYP2B6 ∗6/∗6 genotype (AOR = 0.19; 95% CI = 0.06-0.77). We report high incidence of chemotherapy-induced hematological toxicities causing larger proportion of patients to receive reduced RDI in Ethiopian breast cancer patients. Patients carrying CYP2J2∗7 allele and low baseline blood counts are at a higher risk for chemotherapy-induced hematologic toxicities and receiving reduced RDI, and may require prior support and close follow up during chemotherapy.

PMID: 31139078 [PubMed]

Implementation and Obstacles of Pharmacogenetics in Clinical Practice: An International Survey.

Br J Clin Pharmacol. 2019 May 29;:

Authors: Abou Diwan E, Zeitoun R, Abou Haidar L, Cascorbi I, Zgheib NK

Abstract
AIMS: Eight years ago, a paper-based survey was administered during the World Pharma 2010 meeting, asking about the challenges of implementing pharmacogenetics (PGx) in clinical practice. The data collected at the time gave an idea about the progress of this implementation and what still needs to be done. Since then, although there have been major initiatives to push PGx forward, PGx clinical implementation may still be facing different challenges in different parts of the world. Our aim was therefore to distribute a follow up international survey in electronic format to elucidate an overview on the current stage of implementation, acceptance, and challenges of PGx in academic institutions around the world.
METHODS: This is an online anonymous LimeSurvey based study launched on November 11, 2018. Survey questions were adapted from the initially published manuscript in 2010. An extensive web search for worldwide scientists potentially involved in PGx research resulted in a total of 1973 names. Countries were grouped based on the Human Development Index.
RESULTS: There were 204 respondents from 43 countries. Despite the wide availability of PGx tests, the consistently positive attitude towards their applications and advances in the field, progress of the clinical implementation of PGx still faces many challenges all around the globe.
CONCLUSIONS: Clinical implementation of PGx has started over a decade ago but there is a gap in progress around the globe and discrepancies between the challenges reported by different countries, despite some challenges being universal. Further studies on ways to overcome these challenges are warranted.

PMID: 31141189 [PubMed - as supplied by publisher]

ADORA2A Polymorphisms Influence Methotrexate Adverse Events in Rheumatoid Arthritis.

Isr Med Assoc J. 2019 May;5(21):333-338

Authors: Kobold N, Jenko B, Tomšič M, Dolžan V, Praprotnik S

Abstract
BACKGROUND: Methotrexate is the most frequently administered first-line treatment for rheumatoid arthritis (RA). The disease-modifying effects of methotrexate are mainly associated with enhanced release of free adenosine. The downstream anti-inflammatory effects of adenosine are mediated via its binding to adenosine receptor 2A (ADORA2A) and 3 (ADORA3). Many clinically important single nucleotide polymorphisms (SNPs) were reported in ADORA2A and ADORA3 genes.
OBJECTIVES: To investigate whether tagging ADORA2A and ADORA3 polymorphisms influences methotrexate treatment in RA.
METHODS: In total, 212 RA patients treated with methotrexate were genotyped for tagging ADORA2A (rs2298383, rs8141793, rs2236624, rs5751876, rs35320474, and rs17004921) and ADORA3 SNPs (rs2298191, rs1544223, rs78594984, rs35511654, rs2229155, rs3393, and rs3394).
RESULTS: RA patients who carried ADORA3 rs35511654 G allele showed a tendency toward better response to methotrexate treatment (P = 0.054). Carriers of ADORA2A polymorphic allele rs2298383 (P = 0.011), rs2236624 (P = 0.027), rs5751876 (P = 0.018), and rs35320474 (P = 0.026) were less likely to experience methotrexate induced adverse events. All associations remained significant after adjustment for clinical factors. The effects of these polymorphisms were also significant in haplotype analyses.
CONCLUSIONS: Polymorphisms in the ADORA2A gene may influence methotrexate treatment response and may be considered as a potential biomarker for methotrexate treatment in rheumatoid arthritis.

PMID: 31140226 [PubMed - in process]

Estimating In Vivo Fractional Contribution of OATP1B1 to Human Hepatic Active Uptake by Mechanistically Modeling Pharmacogenetic Data.

AAPS J. 2019 May 28;21(4):69

Authors: Li R

Abstract
A reasonable estimate on the fractional contribution of transporters to total hepatic active uptake (FT) is a critical factor in understanding and predicting human clearance, drug-drug interaction, and pharmacokinetic variability for hepatic transporter substrates. FT values for organic-anion-transporting polypeptide (OATP) 1B1 have been previously determined using in vitro assays. However, to date, none of the published in vitro FT values has been validated against or compared with in vivo FT values due to the lack of clinical data from selective substrates or inhibitors. The possible transporter-dependent in vitro to in vivo scaling further weakens the predictive power of these in vitro-determined FT values. In facing this challenge, a method is developed in this study to estimate in vivo OATP1B1 FT values by mechanistically modeling genotyped clinical pharmacokinetic data. The method is based on the hypothesis that observed change in hepatic active uptake clearance due to OATP1B1 polymorphism depends on two factors: (1) the contribution of OATP1B1 to the hepatic active uptake clearance and (2) the change of OATP1B1-mediated intrinsic uptake activity by the polymorphism. Conversely, if the changes caused by genetic variations in hepatic active uptake clearance and in OATP1B1-mediated clearance are known, then the OATP1B1 contribution to the hepatic active uptake clearance can be calculated. This is the first time that in vivo hepatic transporter FT values and a method to estimate these values are reported. Both FT values and the estimation method will facilitate future understanding and prediction on the transporter-mediated drug disposition.

PMID: 31140055 [PubMed - in process]

Efficient estimation of grouped survival models.

BMC Bioinformatics. 2019 May 28;20(1):269

Authors: Li Z, Lin J, Sibley AB, Truong T, Chua KC, Jiang Y, McCarthy J, Kroetz DL, Allen A, Owzar K

Abstract
BACKGROUND: Time- and dose-to-event phenotypes used in basic science and translational studies are commonly measured imprecisely or incompletely due to limitations of the experimental design or data collection schema. For example, drug-induced toxicities are not reported by the actual time or dose triggering the event, but rather are inferred from the cycle or dose to which the event is attributed. This exemplifies a prevalent type of imprecise measurement called grouped failure time, where times or doses are restricted to discrete increments. Failure to appropriately account for the grouped nature of the data, when present, may lead to biased analyses.
RESULTS: We present groupedSurv, an R package which implements a statistically rigorous and computationally efficient approach for conducting genome-wide analyses based on grouped failure time phenotypes. Our approach accommodates adjustments for baseline covariates, and analysis at the variant or gene level. We illustrate the statistical properties of the approach and computational performance of the package by simulation. We present the results of a reanalysis of a published genome-wide study to identify common germline variants associated with the risk of taxane-induced peripheral neuropathy in breast cancer patients.
CONCLUSIONS: groupedSurv enables fast and rigorous genome-wide analysis on the basis of grouped failure time phenotypes at the variant, gene or pathway level. The package is freely available under a public license through the Comprehensive R Archive Network.

PMID: 31138120 [PubMed - in process]

Unearthing new genomic markers of drug response by improved measurement of discriminative power.

BMC Med Genomics. 2018 02 06;11(1):10

Authors: Dang CC, Peón A, Ballester PJ

Abstract
BACKGROUND: Oncology drugs are only effective in a small proportion of cancer patients. Our current ability to identify these responsive patients before treatment is still poor in most cases. Thus, there is a pressing need to discover response markers for marketed and research oncology drugs. Screening these drugs against a large panel of cancer cell lines has led to the discovery of new genomic markers of in vitro drug response. However, while the identification of such markers among thousands of candidate drug-gene associations in the data is error-prone, an appraisal of the effectiveness of such detection task is currently lacking.
METHODS: Here we present a new non-parametric method to measuring the discriminative power of a drug-gene association. Unlike parametric statistical tests, the adopted non-parametric test has the advantage of not making strong assumptions about the data distorting the identification of genomic markers. Furthermore, we introduce a new benchmark to further validate these markers in vitro using more recent data not used to identify the markers.
RESULTS: The application of this new methodology has led to the identification of 128 new genomic markers distributed across 61% of the analysed drugs, including 5 drugs without previously known markers, which were missed by the MANOVA test initially applied to analyse data from the Genomics of Drug Sensitivity in Cancer consortium.
CONCLUSIONS: Discovering markers using more than one statistical test and testing them on independent data is unusual. We found this helpful to discard statistically significant drug-gene associations that were actually spurious correlations. This approach also revealed new, independently validated, in vitro markers of drug response such as Temsirolimus-CDKN2A (resistance) and Gemcitabine-EWS_FLI1 (sensitivity).

PMID: 29409485 [PubMed - indexed for MEDLINE]

Ask the Authors.

PM R. 2018 03;10(3):243-244

Authors: Weinstein SM, McLaughlin M

PMID: 29127054 [PubMed - indexed for MEDLINE]

The importance and challenges of developing a pharmacogenetics test for hypertension.

Pharmacogenomics. 2019 May 28;:

Authors: Snyder EM, Kelley EF, Sprissler R, Olson TP

PMID: 31136254 [PubMed - as supplied by publisher]

Recent developments in lipodystrophy.

Curr Opin Lipidol. 2019 May 22;:

Authors: Melvin A, Stears A, Savage DB

Abstract
PURPOSE OF REVIEW: Lipodystrophy syndromes have an estimated prevalence of 1.3-4.7 cases per million and as with other rare diseases conducting research can be challenging. The present review highlights recently published work that has provided insights into the field of non-HIV--associated lipodystrophy syndromes.
RECENT FINDINGS: Lipodystrophies are a heterogenous group of disorders, as such research is often focused on specific subtypes of the condition. The identification of children carrying LMNA mutations has provided insights into the natural history of FPLD2, specifically that the adipose tissue phenotype predates the onset of puberty. Recent reports of PLIN1 heterozygous null variant carriers and the apparent absence of a lipodystrophy phenotype challenges our understanding of the molecular biology of perilipin 1 and its role in the pathogenesis of FPLD4. With a focus on therapeutics, studies delineating the differential responsiveness of PPARγ mutants to endogenous and synthetic ligands has illustrated the potential for pharmacogenetics to inform therapeutic decisions in lipodystrophy related to PPARG mutations, whereas robust human studies have provided insight into the food independent metabolic effects of leptin in lipodystrophy. Finally, rare syndromes of lipodystrophy continue to serve as an exemplar for the contribution of genetically determined adipose tissue expandability to metabolic disease in the general population.
SUMMARY: Lipodystrophy research continues to illuminate our understanding of this rare disease and the possibility that lipodystrophy syndromes and the metabolic syndrome may have shared pathophysiology.

PMID: 31135595 [PubMed - as supplied by publisher]

PharmGKB summary: oxycodone pathway, pharmacokinetics.

Pharmacogenet Genomics. 2018 10;28(10):230-237

Authors: Huddart R, Clarke M, Altman RB, Klein TE

PMID: 30222708 [PubMed - indexed for MEDLINE]

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Metformin reverses the schizophrenia-like behaviors induced by MK-801 in rats.

Brain Res. 2019 May 20;:

Authors: Wang X, Luo C, Mao XY, Li X, Yin JY, Zhang W, Zhou HH, Liu ZQ

Abstract
Schizophrenia is known to be a complex and disabling psychiatric disorder. Dopamine receptor antagonists have a significant therapeutic effect in improving the positive symptoms that are associated with the illness. Therefore, dopamine receptor antagonists are commonly used in the treatment of schizophrenia; however, they do not achieve satisfactory results in improving negative symptoms and cognitive impairment. Metformin, widely known as an antidiabetic drug, has been found to enhance spatial memory formation and improve anxiety-like behaviors in rodents. Metformin's neuroprotective effect has been well documented in several neurological disorders including Alzheimer's disease, Parkinson's disease, strokes, Huntington's disease, and seizures. In the present study, we used a rat model to explore the effect of metformin on schizophrenia-like behaviors induced by MK-801 (dizocilpine), an N-methyl-D-aspartate (NMDA) receptor antagonist. We found that the pre-pulse inhibition (PPI) deficit caused by MK-801 could be alleviated by metformin. The hyperlocomotion in the open field test induced by chronic treatment of MK-801 was reversed by administration of metformin. Metformin has no effect on the baseline level of anxiety in normal naive rats, while metformin could relieve the anxiety-like behaviors in MK-801-treatment rats, though this effect is not reaching a significant level. Additionally, metformin could significantly ameliorate working memory impairments induced by MK-801. Moreover, the increased level of phosphorylation of Akt and GSK3β in the frontal cortex induced by MK-801 was normalized by metformin. In conclusion, our results demonstrate that metformin improved schizophrenia-like symptoms in rats, and is therefore a potential agent for the treatment of schizophrenia.

PMID: 31121159 [PubMed - as supplied by publisher]

Pharmacogenetics of anticoagulants used for stroke prevention in patients with atrial fibrillation.

Expert Opin Drug Metab Toxicol. 2019 May 23;:

Authors: Kampouraki E, Kamali F

Abstract
Introduction: The inclusion of pharmacogenetics alongside clinical information in anticoagulant therapy offers the opportunity for a tailored approach to treatment according to individual patient characteristics. Areas covered: Literature was searched using PubMed database, focusing on pharmacogenetics of oral anticoagulants. Original research articles and review articles in English language were included in the literature reviewed. This article includes all information available for the genetic cause of inter-individual variability in anticoagulation response to oral anticoagulant drugs. The pharmacogenetics of VKAs and NOACs are described in detail. Expert opinion: There have been numerous studies focusing on the pharmacogenetics of VKAs, particularly warfarin. Current evidence suggests that known genetic and clinical factors explain a large proportion of the inter-individual variability in response to warfarin. Pharmacogenetic-based algorithms have been validated to determine their clinical utility with equivocal results. To date only a limited number of mostly small studies on the pharmacogenetics of NOACs exists. The latter have highlighted genetic polymorphisms in specific genes that may affect clinical outcomes. Further evaluations of these polymorphisms are needed before firm conclusions can be drawn about the significance of pharmacogenetics on NOAC therapy.

PMID: 31120800 [PubMed - as supplied by publisher]

RasGRP1 is a target for VEGF to induce angiogenesis and involved in the endothelial-protective effects of metformin under high glucose in HUVECs.

IUBMB Life. 2019 May 23;:

Authors: Xu J, Liu M, Yu M, Shen J, Zhou J, Hu J, Zhou Y, Zhang W

Abstract
Impaired angiogenesis in endothelial cells is a hallmark of diabetes vascular complications. Ras guanine-releasing protein 1 (RasGRP1) is a guanine nucleotide exchange factor for Ras, and its role in endothelial angiogenesis has not been investigated. Given the importance of Ras in vascular endothelial growth factor (VEGF)-induced angiogenesis, we hypothesized that RasGRP1 may be a critical pathway downstream of VEGF and involved in endothelial angiogenesis. Furthermore, we investigate whether RasGRP1-dependent VEGF signaling was downregulated under high glucose conditions mimicking diabetes and required for the endothelial protective action of metformin in human umbilical vein endothelial cells (HUVECs). HUVECs were transfected with either RasGRP1 small interfering RNA (siRNA) or pEnter-RasGRP1 plasmid to down- and upregulate RasGRP1 expression before different treatments, such as added VEGF or not, exposed to high glucose (35 mM) or normal glucose (5 mM) in the presence or absence of metformin. Expression of VEGF, RasGRP1, and their signaling targets were analyzed by Western blot; migration and tube formation were detected by transwell chamber assay and Matrigel angiogenesis assay, respectively. Knockdown of RasGRP1 significantly attenuated VEGF-induced migration and tube formation activities of HUVECs and activation of AKT pathway. The expression of VEGF, RasGRP1, and AKT phosphorylation was downregulated in HUVECs exposed to high glucose compared with normal glucose, whereas metformin upregulated the RasGRP1-dependent VEGF signaling and ameliorates the impaired angiogenesis caused by high glucose. RasGRP1 is involved in the VEGF-induced angiogenesis and the pro-angiogenesis effects of metformin under hyperglycemia. © 2019 IUBMB Life, 2019.

PMID: 31120617 [PubMed - as supplied by publisher]

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Nature. 2019 May 22;:

Authors: Flannick J, Mercader JM, Fuchsberger C, Udler MS, Mahajan A, Wessel J, Teslovich TM, Caulkins L, Koesterer R, Barajas-Olmos F, Blackwell TW, Boerwinkle E, Brody JA, Centeno-Cruz F, Chen L, Chen S, Contreras-Cubas C, Córdova E, Correa A, Cortes M, DeFronzo RA, Dolan L, Drews KL, Elliott A, Floyd JS, Gabriel S, Garay-Sevilla ME, García-Ortiz H, Gross M, Han S, Heard-Costa NL, Jackson AU, Jørgensen ME, Kang HM, Kelsey M, Kim BJ, Koistinen HA, Kuusisto J, Leader JB, Linneberg A, Liu CT, Liu J, Lyssenko V, Manning AK, Marcketta A, Malacara-Hernandez JM, Martínez-Hernández A, Matsuo K, Mayer-Davis E, Mendoza-Caamal E, Mohlke KL, Morrison AC, Ndungu A, Ng MCY, O'Dushlaine C, Payne AJ, Pihoker C, Broad Genomics Platform, Post WS, Preuss M, Psaty BM, Vasan RS, Rayner NW, Reiner AP, Revilla-Monsalve C, Robertson NR, Santoro N, Schurmann C, So WY, Soberón X, Stringham HM, Strom TM, Tam CHT, Thameem F, Tomlinson B, Torres JM, Tracy RP, van Dam RM, Vujkovic M, Wang S, Welch RP, Witte DR, Wong TY, Atzmon G, Barzilai N, Blangero J, Bonnycastle LL, Bowden DW, Chambers JC, Chan E, Cheng CY, Cho YS, Collins FS, de Vries PS, Duggirala R, Glaser B, Gonzalez C, Gonzalez ME, Groop L, Kooner JS, Kwak SH, Laakso M, Lehman DM, Nilsson P, Spector TD, Tai ES, Tuomi T, Tuomilehto J, Wilson JG, Aguilar-Salinas CA, Bottinger E, Burke B, Carey DJ, Chan JCN, Dupuis J, Frossard P, Heckbert SR, Hwang MY, Kim YJ, Kirchner HL, Lee JY, Lee J, Loos RJF, Ma RCW, Morris AD, O'Donnell CJ, Palmer CNA, Pankow J, Park KS, Rasheed A, Saleheen D, Sim X, Small KS, Teo YY, Haiman C, Hanis CL, Henderson BE, Orozco L, Tusié-Luna T, Dewey FE, Baras A, Gieger C, Meitinger T, Strauch K, Lange L, Grarup N, Hansen T, Pedersen O, Zeitler P, Dabelea D, Abecasis G, Bell GI, Cox NJ, Seielstad M, Sladek R, Meigs JB, Rich SS, Rotter JI, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D, ESP, SIGMA-T2D, T2D-GENES, AMP-T2D-GENES, Altshuler D, Burtt NP, Scott LJ, Morris AP, Florez JC, McCarthy MI, Boehnke M

Abstract
Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

PMID: 31118516 [PubMed - as supplied by publisher]

Genetics and adverse events with irinotecan treatment: what do we know?

Pharmacogenomics. 2019 Apr;20(6):393-395

Authors: Páez D

PMID: 31117929 [PubMed - in process]

VKORC1 variants as significant predictors of warfarin dose in Emiratis.

Pharmgenomics Pers Med. 2019;12:47-57

Authors: Al-Mahayri ZN, Al Jaibeji HS, Saab Y, Soliman K, Al-Gazali L, Patrinos GP, Ali BR

Abstract
Purpose: Variability in response to warfarin is one of the main obstacles challenging its use in clinical practice. Vitamin K epoxide reductase complex (VKORC) is the target enzyme of warfarin, and variations in the form of single nucleotide polymorphisms (SNPs) in VKORC1, coding for this enzyme, are known to cause resistance to warfarin treatment. This study aimed to explore VKORC1 variants in Emirati patients receiving warfarin treatment and to correlate their genotypes at the studied SNPs to their maintenance warfarin dose. Patients and methods: Sanger sequencing of the majority of the VKORC1 gene was applied to samples from 90 patients and 117 normal individuals recruited from Tawam Hospital, Al-Ain, UAE. Genotypes at the following variants were determined (rs9923231, rs188009042, rs61742245, rs17708472, rs9934438, rs8050894, rs2359612, rs7294). Statistical analysis was applied, including ANOVA, cross-tabulation, and multiple linear regression analysis, to determine the ability of nongenetic factors (age and gender) and genetic factors (VKORC1 genotypes) to explain variability in warfarin dose in patients. Results: Different frequencies of minor alleles were detected in the selected SNPs. Significant variation among genotypes at six VKORC1 variants were identified (rs9923231, rs9934438, rs8050894, rs2359612, rs7294). The main predictors for warfarin dose were rs9923231, age, and rs61742245 with 50.7% of the average warfarin dose in our sample could be explained by a regression model built on these three factors. Conclusion: This is the first report of the explanatory power of VKORC1 genotypes and nongenetic factors (age and gender) on warfarin dose among Emiratis. Also, this study highlighted the positive effect of considering rare pharmacogenomic variants on explaining warfarin dose variability.

PMID: 31114289 [PubMed]

Pharmacogenomics in Palliative Medicine.

Indian J Palliat Care. 2019 Apr-Jun;25(2):169-171

Authors: Rao M

PMID: 31114099 [PubMed]

Sequencing XMET genes to promote genotype-guided risk assessment and precision medicine.

Sci China Life Sci. 2019 May 20;:

Authors: Jin Y, Chen G, Xiao W, Hong H, Xu J, Guo Y, Xiao W, Shi T, Shi L, Tong W, Ning B

Abstract
High-throughput next generation sequencing (NGS) is a shotgun approach applied in a parallel fashion by which the genome is fragmented and sequenced through small pieces and then analyzed either by aligning to a known reference genome or by de novo assembly without reference genome. This technology has led researchers to conduct an explosion of sequencing related projects in multidisciplinary fields of science. However, due to the limitations of sequencing-based chemistry, length of sequencing reads and the complexity of genes, it is difficult to determine the sequences of some portions of the human genome, leaving gaps in genomic data that frustrate further analysis. Particularly, some complex genes are difficult to be accurately sequenced or mapped because they contain high GC-content and/or low complexity regions, and complicated pseudogenes, such as the genes encoding xenobiotic metabolizing enzymes and transporters (XMETs). The genetic variants in XMET genes are critical to predicate inter-individual variability in drug efficacy, drug safety and susceptibility to environmental toxicity. We summarized and discussed challenges, wet-lab methods, and bioinformatics algorithms in sequencing "complex" XMET genes, which may provide insightful information in the application of NGS technology for implementation in toxicogenomics and pharmacogenomics.

PMID: 31114935 [PubMed - as supplied by publisher]

Pharmacokinetic comparison of a fixed-dose combination versus concomitant administration of amlodipine, olmesartan, and rosuvastatin in healthy adult subjects.

Drug Des Devel Ther. 2019;13:991-997

Authors: Oh M, Shin JG, Ahn S, Kim BH, Kim JY, Shin HJ, Shin HJ, Ghim JL

Abstract
Objective: The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of a fixed dose combination (FDC) formulation and co-administration of amlodipine, olmesartan, and rosuvastatin. Materials and methods: This study was an open-label, randomized, cross-over design conducted in healthy male volunteers. All subjects received either a single FDC tablet containing amlodipine 10 mg/olmesartan 40 mg/rosuvastatin 20 mg, or were co-administered an FDC tablet containing amlodipine 10 mg/olmesartan 40 mg and a tablet containing rosuvastatin 20 mg, for each period, with 14-day washout periods. Plasma concentrations of amlodipine, olmesartan, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was evaluated by measuring vital signs, clinical laboratory parameters, physical examinations, and medical interviews. Results: Sixty-four subjects were enrolled, and 54 completed the study. The geometric mean ratios and 90% CI for the maximum plasma concentration (Cmax) and area under the curve from time zero to the last sampling time (AUCt) were 1.0716 (1.0369,1.1074) and 1.0497 (1.0243,1.0757) for amlodipine, 1.0396 (0.9818,1.1009) and 1.0138 (0.9716,1.0578) for olmesartan, and 1.0257 (0.9433,1.1152) and 1.0043 (0.9453,1.0669) for rosuvastatin. Fourteen cases of adverse events occurred in 12 subjects. There was no statistically significant clinical difference between the formulation groups. Conclusion: The 90% CI of the primary PK parameters were within the acceptance bioequivalence criteria, which is ln (0.8) and ln (1.25). These results indicate that the FDC formulation and co-administration of amlodipine, olmesartan and rosuvastatin are pharmacokinetically bioequivalent and have similar safety profiles.

PMID: 31114155 [PubMed - in process]