Pharmacogenetics of Atremorine-Induced Neuroprotection and Dopamine Response in Parkinson's Disease.

Planta Med. 2019 Sep 26;:

Authors: Cacabelos R, Carrera I, Alejo R, Fernández-Novoa L, Cacabelos P, Corzo L, Rodríguez S, Alcaraz M, Tellado I, Cacabelos N, Pego R, Carril JC

Abstract
Atremorine is a novel bioproduct with neuroprotective effects on dopaminergic neurons and a natural L-DOPA donor in Parkinson's disease (PD). In the present study, we show the effects of a single dose of Atremorine (5 g, p. o.) on plasma dopamine (DA) response and brain function in PD (n = 183) and the influence that pathogenic (LRRK2), metabolic (CYP2D5, CYP2C9, CYP2C19, CYP3A5, NAT2), transporter (ABCB1), pleiotropic (APOE), and detoxifying genes (CYP1B1, GSTT1, GSTP1, GSTM1, SOD2) involved in the pharmacogenetic network exerts on Atremorine-induced DA response. Over 90% of PD patients at diagnosis show plasma DA levels below 20 pg/mL. Atremorine induces DA synthesis causing a significant increase in plasma DA levels 1 h after administration in practically 100% of patients. Females tend to show lower basal DA levels than males and the response of DA to Atremorine is stronger in males than in females. Atremorine-induced DA response is pharmacogenotype-specific and lasts from 6 - 12 h depending upon the pharmacogenetic profile of each patient. Genetic variants in pathogenic genes, metabolic genes, and genes involved in the detoxification processes affect the response of DA to Atremorine in a genotype-specific manner. Atremorine or any of its bioactive components can cross the blood-brain barrier and improve brain function and motor function, as revealed by the reduction in slow wave activity in brain mapping and psychometric assessment, respectively. Atremorine is a selective neuroprotective agent for dopaminergic neurons with prophylactic and therapeutic potential in PD.

PMID: 31559607 [PubMed - as supplied by publisher]

Polymorphisms in miRNAs Gene (146a, 149, 196a) and Susceptibility to ARV-associated Hepatotoxicity.

Curr Genomics. 2019 Feb;20(2):134-150

Authors: Singh HO, Jadhav S, Samani D, Dhole TN

Abstract
Background: Micro RNAs act as a regulatory layer for pharmacogenomics-related gene ex-pression. It could play a role in the efficacy and toxicity of the drug. The SNPs in miRNA genes are linked with different functional consequences.
Methods: Hence, we examined the miR (146a G/C, 149C/T, and 196aC/T) polymorphisms in 34 pa-tients with hepatotoxicity, 123 patients without hepatotoxicity, and 155 healthy controls using a PCR-RFLP method.
Results: In patients with hepatotoxicity, miR196aCT genotype and combined genotype GCT showed a risk for hepatotoxicity severity with borderline significance (OR=2.08, P=0.07; OR=2.88, P=0.06). While comparing between patients with hepatotoxicity and healthy controls, the combined genotypes CCC and GCT have shown a susceptibility to hepatotoxicity severity (OR=2.89, P=0.05; OR=2.60, P=0.09). The miR196TT genotype was associated with the individuals of advanced HIV disease stage (OR=3.68, P=0.04). In HIV patients who consumed alcohol and did not have hepatotoxicity, the miR 196aCT genotype showed susceptibility to acquisition of hepatotoxicity with borderline significance (OR=2.36, P=0.06).
Discussion: The miR149TT and 196aTT genotypes showed a risk of acquisition of hepatotoxicity to nevirapine usage among HIV patients without hepatotoxicity (OR=4.19, P=0.07; OR=1.97, P=0.84). In HIV patients with and without hepatotoxicity, the miR 196aCT genotype showed a risk of acquisition of hepatotoxicity and its severity to the combined use of alcohol and nevirapine, respectively (OR=14.18, P=0.08; OR=2.29, P=0.08). In multivariate logistic regression, taking nevirapine, 196aCT genotype had an independent risk factor for hepatotoxicity severity (OR=5.98, P=0.005; OR=2.38, P=0.05).Conclusion: In conclusion, miR196aC/T polymorphism and combined genotypes GCT and CCC may facilitate the risk for acquisition of hepatotoxicity and its severity.

PMID: 31555064 [PubMed]

Pharmacogenomics and Placebo Response in a Randomized Clinical Trial in Asthma.

Clin Pharmacol Ther. 2019 Sep 26;:

Authors: Wang RS, Croteau-Chonka DC, Silverman EK, Loscalzo J, Weiss ST, Hall KT

Abstract
Genetic variation may differentially modify drug and placebo treatment effects in randomized trials (RCTs). In asthma, although lung function and asthma control improvements are commonplace with placebo, pharmacogenomics of placebo versus drug response remains unexamined. In a GWAS of subjective and objective outcomes with placebo treatment in Childhood Asthma Management Program (CAMP) of nedocromil/budesonide versus placebo (N=604), effect estimates for lead SNPs were compared across arms. The coughing/wheezing lead SNP, rs2392165 (β=0.94; P=1.10E-07) mapped to BBS9, a gene implicated in lung development which contains a lung function expression quantitative trait locus (eQTL). The effect was attenuated with budesonide (Pinteraction =1.48E-07), but not nedocromil (Pinteraction =0.06). The lead FVC SNP, rs12930749 (β=-5.80; P=1.47E-06), mapped to KIAA0556, a locus genome-wide associated with respiratory diseases. The rs12930749 effect was attenuated with budesonide (Pinteraction =1.32E-02) and nedocromil (Pinteraction =1.09E-02). Pharmacogenomic analysis revealed differential effects with placebo and drug treatment that could potentially guide precision drug development in asthma.

PMID: 31557306 [PubMed - as supplied by publisher]

The essential role of the transporter ABCG2 in the pathophysiology of erythropoietic protoporphyria.

Sci Adv. 2019 Sep;5(9):eaaw6127

Authors: Wang P, Sachar M, Lu J, Shehu AI, Zhu J, Chen J, Liu K, Anderson KE, Xie W, Gonzalez FJ, Klaassen CD, Ma X

Abstract
Erythropoietic protoporphyria (EPP) is an inherited disease caused by loss-of-function mutations of ferrochelatase, an enzyme in the heme biosynthesis pathway that converts protoporphyrin IX (PPIX) into heme. PPIX accumulation in patients with EPP leads to phototoxicity and hepatotoxicity, and there is no cure. Here, we demonstrated that the PPIX efflux transporter ABCG2 (also called BCRP) determines EPP-associated phototoxicity and hepatotoxicity. We found that ABCG2 deficiency decreases PPIX distribution to the skin and therefore prevents EPP-associated phototoxicity. We also found that ABCG2 deficiency protects against EPP-associated hepatotoxicity by modulating PPIX distribution, metabolism, and excretion. In summary, our work has uncovered an essential role of ABCG2 in the pathophysiology of EPP, which suggests the potential for novel strategies in the development of therapy for EPP.

PMID: 31555729 [PubMed - in process]

Potential Regulation of UGT2B10 and UGT2B7 by miR-485-5p in human liver.

Mol Pharmacol. 2019 Sep 25;:

Authors: Sutliff AK, Shi J, Watson CJW, Hunt M, Chen G, Zhu HJ, Lazarus P

Abstract
The UDP-glucuronosyltransferase (UGT) family of enzymes are important in the metabolic elimination of a variety of endogenous compounds such as bile acids, steroids, and fat-soluble vitamins, as well as exogenous compounds including many pharmaceuticals. The UGT2B subfamily are the predominant isoforms expressed in human liver. The identification of novel mechanisms including post-transcriptional regulation by microRNA (miRNA) contribute to inter-individual variability in UGT2B expression and are crucial components in predicting patient drug response. In the present study, a high resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was employed to measure UGT2B protein levels in a panel of human liver microsomal samples. Concurrent in silico analysis identified eight candidate miRNA as potential regulators of UGT2B enzymes. Comparison of UGT2B protein expression and candidate miRNA levels from human liver samples demonstrated a significant (P<0.05) inverse correlation between UGT2B10 and one of these candidate miRNAs, miR-485-5p. In vitro analysis using luciferase-containing vectors suggested an interaction of miR-485-5p within the 3' untranslated region (UTR) of UGT2B10 (P=0.0073). A significant reduction in luciferase activity (P=0.022) was also observed for luciferase vectors containing the UGT2B7 3' UTR, an effect manifested by one of two potential miR-485-5p-binding sites. UGT2B10 and UGT2B7 activities were probed using nicotine and AZT, respectively, and significant decreases in glucuronidation activity were observed for both substrates in HuH-7 and Hep3B cells (P<0.0003 and P=0.016, and P=0.017 and P=0.030, respectively) upon over-expression of miR-485-5p mimic. This is the first study demonstrating a regulatory role for miR-485-5p for multiple UGT2B enzymes. SIGNIFICANCE STATEMENT: The purpose of this study was to identify novel epigenetic microRNA regulators of the UDP-glucuronosyltransferase (UGT) 2B drug-metabolizing enzymes in healthy human liver samples. Our results indicate that microRNA 485-5p is a novel regulator of UGTs 2B7 and 2B10, which play an important role in the metabolism of many commonly prescribed medications, carcinogens and endogenous compounds. This study identified potential miRNA-UGT2B mRNA interactions using a novel proteomic approach, with in vitro experiments undertaken to validate these interactions.

PMID: 31554697 [PubMed - as supplied by publisher]

Evaluation of Correlation Between the Pharmacogenetic Profiles of Risperidone Treated Psychiatry Patients with Plasma and Urine Concentration of Risperidone and its Active Moiety 9-OH Risperidone Determined with Optimized Bioanalytical LC Method.

Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2018 Dec 01;39(2-3):97-106

Authors: Filipce A, Naumovska Z, Nestorovska AK, Sterjev Z, Brezovska K, Tonic-Ribarska J, Grozdanova A, Suturkova L, Raleva M

Abstract
Atypical antipsychotic risperidone is widely used first-line monotherapy in schizophrenia and combined therapy in bipolar disorders. Therapeutic plasma concentrations of risperidone and its active moiety are directly influenced by genetic variations in metabolic CYP450 enzymes (CYP2D6 and CYP3A4/5) and transporter (ABCB1) protein and additional environmental factors. Since active metabolite 9-OH risperidone has a greater percentage of the pharmacologically active fraction and is equipotent to the parent drug risperidone, it is assumed that it contributes significantly to therapeutic and adverse effects. Unpredictable dose/concentration ratio, narrow therapeutic index, number of interactions, along with serious adverse reactions (ADR), raises the need for individualization of risperidone treatment and establishing of good therapeutic regime using TDM. A simple and reliable validated bioanalytical liquide-liquide extraction HPLC/UV method was applied for the simultaneous determination of risperidone and its active metabolite, 9-OH risperidone, in human plasma and urine of 52 hospitalized schizophrenia/bipolar disorder patients treated with risperidone as monotherapy and in polytherapy. All the patients were previously genotyped for CYP2D6 (EM=30, EM/IM=14, IM=4 IM/PM=1 and PM=3) and ABCB1 using Real-Time PCR methods with TaqMan SNP genotyping suitable assays according to the guidelines of the manufacturer (Life Technologies, USA).The influence of CYP2D6 phenotype on metabolic ratio MR (Ris/9-OHRis) in plasma (p=0.012) and in urine (p=0.048) was confirmed. Statistically significant correlation (R2=55.53%, Rho=0.844, p<0,0001) for MR in both plasma and urine indicates that urine may be utilized as appropriate media for initial CYP2D6 phenotype identification and selection of patients on risperidone treatment with high risk for ADR.

PMID: 30864366 [PubMed - indexed for MEDLINE]

Amisulpride: Real-World Evidence of Dose Adaptation and Effect on Prolactin Concentrations and Body Weight Gain by Pharmacokinetic/Pharmacodynamic Analyses.

Clin Pharmacokinet. 2019 Sep 25;:

Authors: Glatard A, Guidi M, Delacrétaz A, Dubath C, Grosu C, Laaboub N, von Gunten A, Conus P, Csajka C, Eap CB

Abstract
BACKGROUND: Amisulpride is an antipsychotic used in a wide range of doses. One of the major adverse events of amisulpride is hyperprolactinemia, and the drug might also induce body weight gain.
OBJECTIVE: The aims of this work were to characterize the pharmacokinetics of amisulpride in order to suggest optimal dosage regimens to achieve the reference range of trough concentrations at steady-state (Cmin,ss) and to describe the relationship between drug pharmacokinetics and prolactin and body weight data.
METHODS: The influence of clinical and genetic characteristics on amisulpride pharmacokinetics was quantified using a population approach. The final model was used to simulate Cmin,ss under several dosage regimens, and was combined with a direct Emax model to describe the prolactin data. The effect of model-based average amisulpride concentrations over 24 h (Cav) on weight was estimated using a linear model.
RESULTS: A one-compartment model with first-order absorption and elimination best fitted the 513 concentrations provided by 242 patients. Amisulpride clearance significantly decreased with age and increased with lean body weight (LBW). Cmin,ss was higher than the reference range in 65% of the patients aged 60 years receiving 400 mg twice daily, and in 82% of the patients aged > 75 years with a LBW of 30 kg receiving 200 mg twice daily. The pharmacokinetic/pharmacodynamic model included 101 prolactin measurements from 68 patients. The Emax parameter was 53% lower in males compared with females. Model-predicted prolactin levels were above the normal values for Cmin,ss within the reference range. Weight gain did not depend on Cav.
CONCLUSIONS: Amisulpride treatment might be optimized when considering age and body weight. Hyperprolactinemia and weight gain do not depend on amisulpride concentrations. Modification of the amisulpride dosage regimen is not appropriate to reduce prolactin concentrations and alternative treatment should be considered.

PMID: 31552612 [PubMed - as supplied by publisher]

Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration.

Nat Neurosci. 2019 Oct;22(10):1635-1648

Authors: Joshi AU, Minhas PS, Liddelow SA, Haileselassie B, Andreasson KI, Dorn GW, Mochly-Rosen D

Abstract
In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration-one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.

PMID: 31551592 [PubMed - in process]

ITC Commentary on Metformin Clinical Drug-Drug Interaction Study Design That Enables an Efficacy- and Safety-Based Dose Adjustment Decision.

Clin Pharmacol Ther. 2018 11;104(5):781-784

Authors: Zamek-Gliszczynski MJ, Chu X, Cook JA, Custodio JM, Galetin A, Giacomini KM, Lee CA, Paine MF, Ray AS, Ware JA, Wittwer MB, Zhang L, International Transporter Consortium

Abstract
Metformin drug-drug interaction (DDI) studies are conducted during development of drugs that inhibit organic cation transporters and/or multidrug and toxin extrusion proteins (OCTs/MATEs). Monitoring solely changes in systemic exposure, the typical DDI study endpoint appears inadequate for metformin, which is metabolically stable, has poor passive membrane permeability, and undergoes transporter-mediated tissue distribution and clearance. Evaluation of renal clearance, antihyperglycemic effects, and potentially lactate as an exploratory safety marker, can support rational metformin dose adjustment. The proposed DDI study design aims to adequately inform metformin dosing during comedication.

PMID: 29761830 [PubMed - indexed for MEDLINE]

Worldwide prevalence of baseline resistance-associated polymorphisms and resistance mutations in HCV against current direct-acting antivirals.

Antivir Ther. 2018;23(6):485-493

Authors: Palanisamy N, Kalaghatgi P, Akaberi D, Lundkvist Å, Chen ZW, Hu P, Lennerstrand J

Abstract
BACKGROUND: HCV infections can now be completely cured, thanks to the currently marketed direct-acting antivirals (DAAs). It is known that HCV patients carry viral populations with baseline polymorphisms and/or mutations that make them resistant against some of these DAAs, which can negatively impact the patient's treatment outcome. Using complete HCV coding sequences isolated from 1,306 treatment-naive patients of genotypes (GTs) 1, 2, 3, 4 and 6 from around the globe, we studied the prevalence of baseline resistance-associated polymorphisms (RAPs) and resistance mutations (RMs) against DAAs that are currently on the market or in clinical trials.
METHODS: The HCV genome sequences used in this study were retrieved from the NCBI database. RAPs and RMs, with reference to HCV GT1a, were identified using the HCV Geno2pheno web server.
RESULTS: Nearly 50% of the total amino acid positions (including NS3 protease, NS5A and NS5B) studied are baseline polymorphisms that differentiated one GT from the rest. A proportion of these baseline polymorphisms and baseline non-polymorphic RMs could confer a significant increase in resistance against DAAs.
CONCLUSIONS: In this study, we show the presence and prevalence of RAPs and RMs in DAA treatment-naive patients against currently used DAAs or DAAs in clinical trials. Our study suggests that RAPs and RMs profiling of HCV patients should be performed before the start of the therapy. Our results should be relevant especially in low- and middle-income countries, where the patients have a large variation of GTs and subtypes, and where the generic HCV treatment is now increasingly available.

PMID: 29745936 [PubMed - indexed for MEDLINE]

Population pharmacokinetics of tacrolimus in children with nephrotic syndrome.

Br J Clin Pharmacol. 2018 08;84(8):1748-1756

Authors: Hao GX, Huang X, Zhang DF, Zheng Y, Shi HY, Li Y, Jacqz-Aigrain E, Zhao W

Abstract
AIMS: Nephrotic syndrome (NS) is the most common clinical manifestation of glomerular disease in children. Currently, tacrolimus (TAC) is widely used in children with NS. However, pharmacokinetic data in children with nephrotic syndrome is limited. This study was intended to evaluate the population pharmacokinetics (PPK) of TAC in paediatric NS and to optimize dosing regimen.
METHODS: Blood samples from NS children treated with TAC were collected and the blood concentrations of TAC were detected using HPLC-MS/MS. A PPK model was developed using NONMEM software. Pharmacogenetic analysis was carried out in the CYP3A5 gene.
RESULTS: The data from 28 children were used for PPK analysis. A one-compartment model and first-order elimination were accorded with the TAC data in paediatric NS. A covariate analysis showed that body weight and CYP3A5 genotype significantly affected TAC pharmacokinetics. Monte Carlo simulation indicated that NS children with CYP3A5*3/*3 receiving 0.10 mg kg-1  dose-1 twice daily and NS children with CYP3A5*1 receiving 0.25 mg kg-1  dose-1 twice daily TAC could achieve the target concentrations of 5-10 ng ml-1 .
CONCLUSION: The PPK of TAC was estimated in children with NS and a CYP3A5 genotype-based dosing regimen was set up based on simulations.

PMID: 29637588 [PubMed - indexed for MEDLINE]

CYP2D6 Protein Level Is the Major Contributor to Interindividual Variability in CYP2D6-Mediated Drug Metabolism in Healthy Human Liver Tissue.

Clin Pharmacol Ther. 2018 11;104(5):974-982

Authors: Ning M, Duarte JD, Rubin LH, Jeong H

Abstract
CYP2D6 genetic polymorphisms are considered a major contributor to the large interindividual variability in CYP2D6-mediated drug metabolism, but fail to explain a significant portion of the variability. The aim of this study was to assess the ability of the CYP2D6 activity score (AS) estimated from CYP2D6 genotype to predict CYP2D6 expression and enzyme activity. The CYP2D6 gene region was sequenced in 115 healthy human liver tissue samples to determine their CYP2D6 AS. Additionally, CYP2D6 enzyme activity, protein, and mRNA levels were estimated. CYP2D6 AS explained 23% of the interindividual variability in CYP2D6 activity, but only 7.5% in tissues assigned AS 1-2. The CYP2D6 protein level was found to be the major determinant of CYP2D6 activity, explaining 59% of variability. These findings suggest that while CYP2D6 AS is a good predictor of poor metabolizer phenotype, additional nongenetic factors may govern the rate of CYP2D6-mediated metabolism in those without the poor metabolizer phenotype.

PMID: 29349771 [PubMed - indexed for MEDLINE]

Optimization of Voriconazole Therapy for the Treatment of Invasive Fungal Infections in Adults.

Clin Pharmacol Ther. 2018 11;104(5):957-965

Authors: Mangal N, Hamadeh IS, Arwood MJ, Cavallari LH, Samant TS, Klinker KP, Bulitta J, Schmidt S

Abstract
Therapeutic concentrations of voriconazole in invasive fungal infections (IFIs) are ensured using a drug monitoring approach, which relies on attainment of steady-state pharmacokinetics. For voriconazole, time to reach steady state can vary from 5-7 days, not optimal for critically ill patients. We developed a population pharmacokinetic/pharmacodynamic model-based approach to predict doses that can maximize the net benefit (probability of efficacy-probability of adverse events) and ensure therapeutic concentrations, early on during treatment. The label-recommended 200 mg voriconazole dose resulted in attainment of targeted concentrations in ≥80% patients in the case of Candida spp. infections, as compared to only 40-50% patients, with net benefit ranging from 5.8-61.8%, in the case of Aspergillus spp. infections. Voriconazole doses of 300-600 mg were found to maximize the net benefit up to 51-66.7%, depending on the clinical phenotype (due to CYP2C19 status and pantoprazole use) of the patient and type of Aspergillus infection.

PMID: 29315506 [PubMed - indexed for MEDLINE]

Single nucleotide polymorphisms in treatment of polycystic ovary syndrome: a systematic review.

Drug Metab Rev. 2019 Sep 24;:1-11

Authors: Deswal R, Nanda S, Dang AS

Abstract
As 15-20% of reproductive aged females are suffering from polycystic ovary syndrome (PCOS), a large number of pharmacological preparations are frequently available in the market for the treatment of PCOS; however, they seem to be ineffective and cause undesirable side effects. This has emphasized the need to optimize dosage regimens for individualized treatment. The objective of this systematic review is to review single nucleotide polymorphisms (SNPs) associated with drugs used for the treatment of PCOS to understand pharmacogenetics variability of patients to drug response there by helping clinicians in designing tailored treatments and possibly reducing adverse drug reactions. A comprehensive electronic literature search was conducted to highlight some clinically relevant SNPs that act to influence PCOS and associated co-morbidities. A total of 16 studies were included in this review. These genetic variations can be used as a potential target for pharmacotherapy and pharmacogenetic clinical trials for better diagnosis, management, and treatment planning.

PMID: 31549867 [PubMed - as supplied by publisher]

Prospective CYP2C19-Guided Voriconazole Prophylaxis in Neutropenic AML Patients Reduces the Incidence of Subtherapeutic Antifungal Plasma Concentrations.

Clin Pharmacol Ther. 2019 Sep 24;:

Authors: Hicks JK, Quilitz RE, Komrokji RS, Kubal TE, Lancet JE, Pasikhova Y, Qin D, So W, Caceres G, Kelly K, Salchert YS, Shahbazian K, Abbas-Aghababazadeh F, Fridley BL, Velez AP, McLeod HL, Greene JN

Abstract
A risk mitigation strategy was implemented to determine if a higher prophylactic voriconazole dosage in CYP2C19 rapid metabolizer neutropenic AML patients reduces the incidence of subtherapeutic trough concentrations. AML patients (n=263) were preemptively genotyped for CYP2C19*2, *3, and *17 alleles as part of a single-center prospective, interventional, quality improvement study. CYP2C19 rapid metabolizers (CYP2C19*1/*17) were recommended to receive interventional voriconazole 300 mg twice daily, ultrarapid metabolizers (CYP2C19*17/*17) were recommended to avoid voriconazole, and all others received the standard prophylactic dosage of 200 mg twice daily. In this real-world setting, 202 patients (76.8%) were prescribed prophylactic voriconazole and of these patients 176 (87.1%) received CYP2C19-guided prophylactic dosing. Voriconazole trough concentrations were obtained for 41 of the 58 (70.7%) CYP2C19 rapid metabolizers prescribed prophylactic voriconazole. Interventional voriconazole resulted in higher plasma trough concentrations (median 2.7 μg/mL) compared to the standard prophylactic dosage (median 0.6 μg/mL, P=0.001). Subtherapeutic concentrations were avoided in 83.8% of CYP2C19 rapid metabolizers receiving interventional dosage compared to 46.2% receiving standard dosage (P=0.02). CYP2C19 genotyping to preemptively guide prophylactic voriconazole dosing is feasible and may be a potential strategy for reducing the risk of subtherapeutic trough concentrations that potentiate breakthrough fungal infections.

PMID: 31549389 [PubMed - as supplied by publisher]

Evaluation of CYP2C19 Genotype-guided Voriconazole Prophylaxis After Allogeneic Hematopoietic Cell Transplant.

Clin Pharmacol Ther. 2019 Sep 24;:

Authors: Patel JN, Hamadeh IS, Robinson M, Shahid Z, Symanowski J, Steuerwald N, Hamilton A, Reese ES, Plesca DC, Arnall J, Taylor M, Trivedi J, Grunwald MR, Gerber J, Ghosh N, Avalos B, Copelan E

Abstract
There is a high risk of voriconazole failure in those with subtherapeutic drug concentrations, which is more common in CYP2C19 rapid/ultrarapid metabolizers (RM/UMs). We evaluated CYP2C19 genotype-guided voriconazole dosing on drug concentrations and clinical outcomes in adult allogeneic hematopoietic cell transplant (HCT) recipients. Poor (PMs), intermediate (IMs), and normal metabolizers (NMs) received voriconazole 200 mg twice daily; RM/UMs received 300 mg twice daily. Steady state trough concentrations were obtained after five days targeting 1.0 - 5.5 mg/L. Of 89 evaluable patients, 29% had subtherapeutic concentrations compared to 50% in historical controls (p<0.001). Zero, 26%, 50%, and 16% of PMs, IMs, NMs, and RM/UMs were subtherapeutic. Voriconazole success rate was 78% compared to 54% in historical controls (p<0.001). No patients experienced an invasive fungal infection (IFI). Genotype-guided dosing resulted in $4,700 estimated per patient savings as compared with simulated controls. CYP2C19 genotype-guided voriconazole dosing reduced subtherapeutic drug concentrations and effectively prevented IFIs.

PMID: 31549386 [PubMed - as supplied by publisher]

Discovering long noncoding RNA predictors of anticancer drug sensitivity beyond protein-coding genes.

Proc Natl Acad Sci U S A. 2019 Sep 23;:

Authors: Nath A, Lau EYT, Lee AM, Geeleher P, Cho WCS, Huang RS

Abstract
Large-scale cancer cell line screens have identified thousands of protein-coding genes (PCGs) as biomarkers of anticancer drug response. However, systematic evaluation of long noncoding RNAs (lncRNAs) as pharmacogenomic biomarkers has so far proven challenging. Here, we study the contribution of lncRNAs as drug response predictors beyond spurious associations driven by correlations with proximal PCGs, tissue lineage, or established biomarkers. We show that, as a whole, the lncRNA transcriptome is equally potent as the PCG transcriptome at predicting response to hundreds of anticancer drugs. Analysis of individual lncRNAs transcripts associated with drug response reveals nearly half of the significant associations are in fact attributable to proximal cis-PCGs. However, adjusting for effects of cis-PCGs revealed significant lncRNAs that augment drug response predictions for most drugs, including those with well-established clinical biomarkers. In addition, we identify lncRNA-specific somatic alterations associated with drug response by adopting a statistical approach to determine lncRNAs carrying somatic mutations that undergo positive selection in cancer cells. Lastly, we experimentally demonstrate that 2 lncRNAs, EGFR-AS1 and MIR205HG, are functionally relevant predictors of anti-epidermal growth factor receptor (EGFR) drug response.

PMID: 31548386 [PubMed - as supplied by publisher]

Cytogenetics and Cytogenomics Evaluation in Cancer.

Int J Mol Sci. 2019 Sep 23;20(19):

Authors: Ribeiro IP, Melo JB, Carreira IM

Abstract
The availability of cytogenetics and cytogenomics technologies improved the detection and identification of tumor molecular signatures as well as the understanding of cancer initiation and progression. The use of large-scale and high-throughput cytogenomics technologies has led to a fast identification of several cancer candidate biomarkers associated with diagnosis, prognosis, and therapeutics. The advent of array comparative genomic hybridization and next-generation sequencing technologies has significantly improved the knowledge about cancer biology, underlining driver genes to guide targeted therapy development, drug-resistance prediction, and pharmacogenetics. However, few of these candidate biomarkers have made the transition to the clinic with a clear benefit for the patients. Technological progress helped to demonstrate that cellular heterogeneity plays a significant role in tumor progression and resistance/sensitivity to cancer therapies, representing the major challenge of precision cancer therapy. A paradigm shift has been introduced in cancer genomics with the recent advent of single-cell sequencing, since it presents a lot of applications with a clear benefit to oncological patients, namely, detection of intra-tumoral heterogeneity, mapping clonal evolution, monitoring the development of therapy resistance, and detection of rare tumor cell populations. It seems now evident that no single biomarker could provide the whole information necessary to early detect and predict the behavior and prognosis of tumors. The promise of precision medicine is based on the molecular profiling of tumors being vital the continuous progress of high-throughput technologies and the multidisciplinary efforts to catalogue chromosomal rearrangements and genomic alterations of human cancers and to do a good interpretation of the relation genotype-phenotype.

PMID: 31547595 [PubMed - in process]

CYP2D6 Genotype Predicts Plasma Concentrations of Tamoxifen Metabolites in Ethiopian Breast Cancer Patients.

Cancers (Basel). 2019 Sep 12;11(9):

Authors: Ahmed JH, Makonnen E, Fotoohi A, Aseffa A, Howe R, Aklillu E

Abstract
Tamoxifen displays wide inter-individual variability (IIV) in its pharmacokinetics and treatment outcome. Data on tamoxifen pharmacokinetics and pharmacogenetics from black African breast cancer patient populations is lacking. We investigated the pharmacokinetic and pharmacogenetic profile of tamoxifen and its major active metabolite, endoxifen, in Ethiopian breast cancer patients. A total of 81 female breast cancer patients on adjuvant tamoxifen therapy were enrolled. Tamoxifen (Tam) and its major metabolites, N-desmethyltamoxifen (NDM), 4-hydroxy-tamoxifen (4-HT), and (Z)-endoxifen (E) were quantified using LC-MS/MS. Genotyping for CYP2D6, CYP2C9, CYP2C19, CYP3A5, POR, and ABCB1 and UGT2B15 and copy number variation for CYP2D6 were done. The proportion of patients with low endoxifen level (<5.9 ng/mL) was 35.8% (median concentration 7.94 ng/mL). The allele frequency of CYP2D6 gene deletion (*5) and duplication (*1×N or *2×N) was 4.3% and 14.8%, respectively. Twenty-six percent of the patients carried duplicated or multiplicated CYP2D6 gene. An increase in CYP2D6 activity score was associated with increased endoxifen concentration and MRE/NDM (p < 0.001). The IIV in endoxifen concentration and MRE/NDM was 74.6% and 59%, respectively. CYP2D6 diplotype explained 28.2% and 44% of the variability in absolute endoxifen concentration and MRE/NDM, respectively. The explanatory power of CYP2D6 diplotype was improved among ABCB1c.4036G carriers (43% and 65.2%, respectively for endoxifen concentration and MRE/NDM) compared to A/A genotype. CYP2C9, CYP2C19, and CYP3A5 genotypes had no significant influence on endoxifen concentration or MRE/NDM. In conclusion, we report a high rate of low endoxifen level as well as large IIV in tamoxifen and its metabolite concentrations. CYP2D6 is significant predictor of plasma endoxifen level in a gene-dose dependent manner.

PMID: 31547390 [PubMed]

From the Origins of Pharmacogenetics to First Applications in Psychiatry.

Pharmacopsychiatry. 2019 Sep 23;:

Authors: Müller DJ, Rizhanovsky Z

Abstract
Pharmacogenetics is the division of science addressing how genetic factors contribute to the metabolism, response, and side effects of a given medication. What was once regarded as a subdivision of genetics and pharmacology is now recognized as its own field and has its own unique story of origin. While the term "pharmacogenetics" was coined by Friedrich Vogel in 1959, the relevance of inherited genetic traits in affecting the clinical outcome to xenobiotics has been observed long before. In fact, there is much hope that pharmacogenetics can help unravel the "mysteries" as to why different people may display variable responses to the same medication as well as identify new drug targets. This article will highlight the conceptual framework for pharmacogenetics advanced by pioneer scientists Arno Motulsky and Friedrich Vogel (both human geneticists), as well as Werner Kalow (clinical pharmacologist), leading up to the creation of modern pharmacogenetics. Finally, the practical implications and first steps toward implementation for current psychiatric treatment are reviewed followed by an outlook on future studies.

PMID: 31546266 [PubMed - as supplied by publisher]