Am Health Drug Benefits. 2021 Mar;14(1):15-20.

ABSTRACT

BACKGROUND: The use of a novel strategy known as adaptive abiraterone therapy based on mathematical modeling of evolutionary dynamics of tumor subpopulations was shown in a clinical trial to extend the time to disease progression in patients with metastatic castration-resistant prostate cancer (CRPC) and reduced the use of abiraterone therapy. Although the clinical impact of adaptive abiraterone treatment is clear, the economic impact of this strategy has not been investigated.

OBJECTIVE: To compare the cost of care with adaptive abiraterone therapy versus standard continuous abiraterone therapy in patients with metastatic CRPC, using patient billing data.

METHODS: We performed a retrospective review of billing data for patients with metastatic CRPC who received abiraterone treatment at a large cancer center between June 1, 2012, and August 31, 2018. Patients were divided into 2 groups based on whether they received adaptive abiraterone therapy (N = 15) or continuous abiraterone therapy (N = 21). All patients with refractory, metastatic prostate cancer after castration that was indicated for abiraterone therapy were eligible for this study. Each patient in the adaptive abiraterone therapy cohort received abiraterone plus prednisone treatment until the patient reached a target threshold of 50% or more reduction in prostate-specific antigen (PSA) level compared with his PSA level before abiraterone therapy; treatment was then suspended until the PSA level rose above the 50% of PSA before abiraterone therapy target threshold. The continuous therapy cohort received abiraterone plus prednisone daily until radiographic progression. The primary outcomes were the mean annual cost of care per patient, including and excluding the cost of abiraterone, and the cost of care, by clinical category.

RESULTS: The median time to disease progression was 25.8 months for patients who received adaptive abiraterone therapy compared with 12.1 months for patients who received continuous abiraterone therapy. Overall, the mean total, including the cost of drug, annual cost per patient who received adaptive abiraterone therapy was $79,093 compared with $146,782 for patients who received continuous abiraterone therapy (P <.0001). The annual cost of care per patient, excluding the cost of abiraterone, was $13,883 for those who received adaptive therapy versus $22,322 for those who received continuous abiraterone therapy (P = .2757), which was not statistically significant.

CONCLUSION: Practical precision medicine strategies, such as adaptive abiraterone treatment or pharmacogenomics-targeted dosing, can use known biomarkers, such as PSA, to tailor therapy, generate improved outcomes, and reduce costs without the need for novel drug and diagnostic discovery and development. The results of this study suggest that a large clinical study of adaptive abiraterone therapy is warranted to validate the potential of this strategy to extend the time to disease progression and reduce costs of treatment of metastatic CRPC.

PMID:33841621 | PMC:PMC8025923

Front Pharmacol. 2021 Mar 25;12:621691. doi: 10.3389/fphar.2021.621691. eCollection 2021.

ABSTRACT

Objective: Antipsychotic compounds are known to induce sedation somnolence and have expanded clinical indications beyond schizophrenia to regulatory approval in bipolar disorder, treatment-resistant depression, and is being repurposed in infectious diseases and oncology. However, the medical sciences literature lacks a comprehensive association between sedation and somnolence among a wide-range of antipsychotic compounds. The objective of this study is to assess the disproportionality of sedation and somnolence among thirty-seven typical and atypical antipsychotics. Materials and Methods: Patient adverse drug reactions (ADR) cases were obtained from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) between January 01, 2004 and September 30, 2020 for a wide-array of clinical indications and off-label use of antipsychotics. An assessment of disproportionality were based on cases of sedation and somnolence and calculated using the case/non-case methodology. Statistical analysis resulting in the reporting odds-ratio (ROR) with corresponding 95% confidence intervals (95% CI) were conducted using the R statistical programming language. Results: Throughout the reporting period, there were a total of 9,373,236 cases with 99,251 specific ADRs reporting sedation and somnolence. Zuclopenthixol (n = 224) ROR = 13.3 (95% CI, 11.6-15.3) was most strongly associated of sedation and somnolence and haloperidol decanoate long-acting injection (LAI) was not statistically associated sedation and somnolence. Further, among atypical antipsychotic compounds, tiapride and asenapine were the top two compounds most strongly associated with sedation and somnolence. Comprehensively, the typical antipsychotics ROR = 5.05 (95%CI, 4.97-5.12) had a stronger association with sedation and somnolence when compared to atypical antipsychotics ROR = 4.65 (95%CI, 4.47-4.84). Conclusion: We conducted a head-to-head comparison of thirty-seven antipsychotics and ranked the compounds based on the association of sedation and somnolence from ADR data collected throughout 16 years from the FAERS. The results are informative and with recent interests in repurposing phenothiazine antipsychotics in infectious disease and oncology provides an informative assessment of the compounds during repurposing and in psychopharmacology.

PMID:33841149 | PMC:PMC8027114 | DOI:10.3389/fphar.2021.621691

Drug Metab Rev. 2021 Apr 12:1-37. doi: 10.1080/03602532.2021.1910292. Online ahead of print.

ABSTRACT

Many drug candidates fail during preclinical and clinical trials due to variable or unexpected metabolism which may lead to variability in drug efficacy or adverse drug reactions. The drug metabolism field aims to address this important issue from many angles which range from the study of drug-drug interactions, pharmacogenomics, computational metabolic modeling, and others. This manuscript aims to provide brief but comprehensive manuscript summaries highlighting the conclusions and scientific importance of seven exceptional manuscripts published in recent years within the field of drug metabolism. Two main topics within the field are reviewed: novel computational metabolic modeling approaches which provide complex outputs beyond site of metabolism predictions, and experimental approaches designed to discern the impacts of interindividual variability and species differences on drug metabolism. The computational approaches discussed provide novel outputs in metabolite structure and formation likelihood and/or extend beyond the saturated field of drug phase I metabolism, while the experimental metabolic pathways assessments aim to highlight the impacts of genetic polymorphisms and clinical animal model metabolic differences on human metabolism and subsequent health outcomes.

PMID:33840322 | DOI:10.1080/03602532.2021.1910292

Infect Genet Evol. 2021 Apr 8:104856. doi: 10.1016/j.meegid.2021.104856. Online ahead of print.

ABSTRACT

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor that is used in the treatment of human immunodeficiency virus (HIV) infection in children younger than 3 years old. Identifying genetic predictors of NVP pharmacokinetics (PK) in young children is important because inter-individual variability in NVP concentrations contributes to variable treatment response and the information may be used to individualize dosing decisions. We examined the relationship between genetic variations in relevant drug disposition genes and NVP PK parameters in Ghanaian children living with HIV eligible to initiate NVP-based antiretroviral therapy. Participants received NVP plus zidovudine and lamivudine or abacavir and lamivudine twice daily, and those with tuberculosis (TB) coinfection received concurrent anti-TB therapy with NVP. Pharmacokinetic sampling was performed after at least 4 weeks of antiretroviral therapy. Nevirapine minimum concentration (Cmin), area under the concentration-time curve from time 0 to 12 h (AUC0-12h), and apparent clearance (CL/F) were calculated using non-compartmental analysis using Phoenix v8.0 software. Genotyping for CYP2B6, CYP2A6, CYP3A5, ABCB1, NR1I2, and NR1I3 single nucleotide polymorphism (SNPs) was performed by TaqMan® allelic discrimination method. The median (range) NVP dose received was 10 (7-14) mg/kg. Of the 53 participants, the median (range) Cmin was 3.3 (0.0-14.0) mg/L and AUC0-12h was 56.0 (16.7-202.6) mg.hr/L. Using step-wise regression, CYP2B6 rs3745274 and NR1I2 rs6785049 SNPs were independent as well as joint predictors NVP AUC0-12h, Cmin, and CL/F. We concluded that genotyping for CYP2B6 rs3745274, and the NR1I2 rs6785049 G > A SNP (which encodes the transcriptional factor, pregnane X receptor), could improve prediction of NVP PK for individualized therapy.

PMID:33839311 | DOI:10.1016/j.meegid.2021.104856

Drug Saf. 2021 Apr 10. doi: 10.1007/s40264-021-01063-1. Online ahead of print.

ABSTRACT

INTRODUCTION: Genetic variations of enzymes that affect the pharmacokinetics and hence effects of medications differ between ethnicities, resulting in variation in the risk of adverse drug reactions (ADR) between different populations. Previous work has demonstrated that risk-group considerations can be incorporated into approaches of statistical signal detection. It is unknown whether databases of individual case safety reports (ICSRs) are sensitive to pharmacogenomic differences between populations.

OBJECTIVE: The aim of this study was to explore the sensitivity of a global database of ICSRs to known pharmacogenomic risk variants common in Japan.

METHODS: The data source was VigiBase, the global database of ICSRs, including all reports entered in the version frozen on 5 January 2020. Subgroup disproportionality analysis was used to compare ICSRs of two subgroups, Japan and rest of world (RoW). Reports for UGT1A1-metabolized irinotecan and the CYP2C19-metabolized drugs voriconazole, escitalopram and clopidogrel were selected for comparison between the subgroups based upon known genetic polymorphisms with high prevalence in Japan. Contrast between the subgroups was quantified by IC delta [Formula: see text]), a robust shrinkage observed-to-expected (OE) ratio on a log scale. Harmonic mean p values (HMP) were calculated for each drug to evaluate whether a list of pre-specified ADRs were collectively significantly over- (or under-)reported as hypothesized. Daily drug dosages were calculated for ICSRs with sufficient information, and dose distributions were compared between Japan and RoW and related to differences in regionally approved doses.

RESULTS: The predictions of over-reporting patterns for specific ADRs were observed and confirmed in bootstrap HMP analyses (p = 0.004 for irinotecan and p < 0.001 for each of voriconazole, escitalopram and clopidogrel) and compared with similar drugs with different metabolic pathways. The impact of proactive regulatory action, such as recommended dosing and therapeutic drug monitoring (TDM), was also observable within the global database. For irinotecan and escitalopram, there was evidence of use of lower dosages as recommended in the Japanese labels; for voriconazole, there was evidence of use of TDM with an over-reporting of terms related to drug level measurements and an under-reporting of liver toxicity.

CONCLUSIONS: Pharmaco-ethnic vulnerabilities caused by pharmacogenomic differences between populations may contribute to differences in ADR reporting between countries in a global database of ICSRs. Regional analyses within a global database can inform on the effectiveness of local risk minimization measures and should be leveraged to catalyse the conversion of real-world usage into safer use of drugs in ethnically tailored ways.

PMID:33837924 | DOI:10.1007/s40264-021-01063-1

Pediatr Cardiol. 2021 Apr 10. doi: 10.1007/s00246-021-02585-2. Online ahead of print.

ABSTRACT

Warfarin is prescribed in patients with ventricular assist devices (VADs). Dosage depends on several factors including the underlying genotype. These include polymorphisms of genes encoding cytochrome P450 enzymes, the main ones being CYP2C9, VKORC1, and CYP4F2. The objectives of this study were to evaluate the prevalence of CY2CP9 1*2*3*, VKORC1, and CYP4F2 in children with VADs and the time to reach the target international normalized ratio. We performed a retrospective/prospective study in children with VADs. We recorded polymorphisms, disease, type of VAD, ethnicity, age, gender, height, weight, INR values, bleeding, and thromboembolic episodes. Informed consent was obtained. We enrolled 34 children (19 male, 15 female), with a median age of 2 years (range 0.3-17 years) and median weight of 6.9Kg. The Berlin Heart was the most commonly implanted VAD (22/34; 64%), and the most common diagnosis was dilated cardiomyopathy. Statistical analysis confirmed a significant partial correlation with VKORC1 CC (p = 0.019). The CYP2C9*2 CT genotype showed a late rise in target INR values (p = 0.06), while the CYP2C9*2 CC showed a tendency toward an early INR rise (p = 0.024). We provide new information on the contribution of the warfarin polymorphisms in children with VAD implantation. Pharmacogenomic dosing for children using warfarin has the potential to improve clinical care in VAD patients. Patients with the CYP2C9*2 CT genotype may need more time or higher doses to reach target INR, while clinicians may need to be aware of the potential for a rapid rise in INR in patients with the CYP2C9*2 CC genotype.

PMID:33837838 | DOI:10.1007/s00246-021-02585-2

Clin Pharmacol Ther. 2021 Apr 10. doi: 10.1002/cpt.2260. Online ahead of print.

ABSTRACT

Studying drug-metabolizing enzymes, encoded by pharmacogenes, may inform biological mechanisms underlying the diseases for which a medication is prescribed. Until recently, pharmacogenes could not be studied at biobank scale. In 7,649 unrelated African-ancestry (AFR) and 326,214 unrelated European-ancestry (EUR) participants from the UK Biobank, we associated pharmacogene haplotypes from 50 genes with 265 (EUR) and 17 (AFR) medication use phenotypes using generalized linear models. In EUR, N-acetyltransferase 2 (NAT2) metabolizer phenotype and activity score were associated with simvastatin use. The dose of NAT2*1 was associated with simvastatin use when compared to NAT2*5 (the most common haplotype). This association was robust to effects of low-density lipoprotein cholesterol (LDL-C) concentration (NAT2*1 OR=1.07, 95% CI:1.05-1.09, p=1.14x10-8 ) and polygenic risk for LDL-C concentration (NAT2*1 OR=1.09, 95% CI:1.04-1.14, p=2.26x10-4 ). Interactive effects between NAT2*1 and simvastatin use on LDL-C concentration (OR: 0.957, 95% CI:0.916-0.998, p=0.045) were replicated in eMERGE-PGx cohort (OR: 0.987, 95% CI:0.976-0.998, p=0.029). We used biobank-scale data to uncover and replicate an association between NAT2 locus variation and better response to statin therapy. Testing NAT2 alleles may be useful for making clinical decisions regarding the potential benefit (e.g., absolute risk reduction) in LDL-C concentration prior to statin treatment.

PMID:33837531 | DOI:10.1002/cpt.2260

Adv Exp Med Biol. 2021;1305:231-255. doi: 10.1007/978-981-33-6044-0_13.

ABSTRACT

Genetic factors play a significant but complex role in antidepressant (AD) response and tolerability. During recent years, there is growing enthusiasm in the promise of pharmacogenetic/pharmacogenomic (PGx) tools for optimizing and personalizing treatment outcomes for patients with major depressive disorder (MDD). The influence of pharmacokinetic and pharmacodynamic genes on response and tolerability has been investigated, including those encoding the cytochrome P450 superfamily, P-glycoprotein, monoaminergic transporters and receptors, intracellular signal transduction pathways, and the stress hormone system. Genome-wide association studies are also identifying new genetic variants associated with AD response phenotypes, which, combined with methods such as polygenic risk scores (PRS), is opening up new avenues for novel personalized treatment approaches for MDD. This chapter describes the basic concepts in PGx of AD response, reviews the major pharmacokinetic and pharmacodynamic genes involved in AD outcome, discusses PRS as a promising approach for predicting AD efficacy and tolerability, and addresses key challenges to the development and application of PGx tests.

PMID:33834403 | DOI:10.1007/978-981-33-6044-0_13

Adv Exp Med Biol. 2021;1305:117-128. doi: 10.1007/978-981-33-6044-0_8.

ABSTRACT

Exposure to early life stress (ELS) represents a major risk factor for the development of psychiatric disorders, including depression. The susceptibility associated with ELS may result from persistent changes in gene transcription, which can occur through epigenetic mechanisms, such as DNA methylation, histone modifications, and microRNA expression. Animal models and reports in humans described that negative stimuli can alter the neurodevelopment of an individual, affecting their behavior and cognitive development. It is currently hypothesized that levels of environmental adversity in this early developmental period are able to shape the experience-dependent maturation of stress-regulating pathways leading to long-lasting alterations in stress responsivity during adulthood. Here, we review key findings from animal and clinical studies examining the effects of prenatal and postnatal environment in shaping development of the neuroendocrine regulation of stress and the role of epigenetic mechanisms in the predisposition of depression.

PMID:33834398 | DOI:10.1007/978-981-33-6044-0_8

Int J Anal Chem. 2021 Mar 25;2021:5590594. doi: 10.1155/2021/5590594. eCollection 2021.

ABSTRACT

A simple, rapid, and sensitive method of liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was developed and validated for the determination of vardenafil in rabbit plasma. A simple protein precipitation method with ice-cold acetonitrile was used for plasma extraction. The mass transitions m/z 489⟶151 and m/z 390⟶169 were used to measure vardenafil and tadalafil (internal standard), respectively, with a total assay run time of 6 min. The limit of detection was 0.2 ng/mL. The assay was reproducible with intra-assay and interassay precision ranging 1.17%-9.17% and 1.31%-5.86%, respectively. There was also good intra-assay and interassay accuracy between 89.3%-105.3% and 94%-102% of the expected value, respectively. The linearity range was 0.5-60 ng/mL in rabbit plasma (r 2 ≥ 0.99). The measured AUC from 0 to 24 h (AUC0 - 24t ) for the test and reference formulations were 174.38 ± 95.91 and 176.45 ± 76.88, respectively. For the test, C max and T max were 75.36 ± 59.53 ng/mL and 1.42 ± 0.19 h, whereas, for the reference, these were 58.22 ± 36.11 ng/mL and 2.04 ± 0.33 h, respectively. The test formulation achieved a slightly lower AUC0 - 24t value (p > 0.05), higher C max values (p > 0.05), faster T max (p < 0.05), and almost equal bioavailability compared with the reference formulation.

PMID:33833807 | PMC:PMC8018852 | DOI:10.1155/2021/5590594

J Oncol Pharm Pract. 2021 Apr 9:10781552211005525. doi: 10.1177/10781552211005525. Online ahead of print.

ABSTRACT

Although therapeutically actionable molecular alterations are widely distributed across many cancer types, only a handful of them show evidence of clinical utility and are recommended for routine clinical practice in the management of cancers of colon and rectum (CRC). This 2021 update aims to provide a succinct summary on the use of prognostic and/or predictive biomarkers (expanded RAS, BRAF, microsatellite-high [MSI-H] or deficient mismatch repair [dMMR], neurotrophic tyrosine receptor kinase [NTRK] fusion genes, and human epidermal growth factor receptor type II [HER2] gene amplification) associated with CRC. Therapeutic implications of each relevant predictive or prognostic biomarker for patients with CRC are described, along with discussion on new developments on (1) biomarker-driven therapies such as testing of BRAF, MLH1 promoter methylation and MMR germline genes in differentiating sporadic CRC or hereditary conditions such as Lynch syndrome; (2) first-line use of immune checkpoint inhibitors in metastatic CRC; (3) risk stratification and therapy selection based on primary tumor location (left-sided vs. right-sided colon cancer); (3) atypical BRAF mutations; (4) use of EGFR directed therapy in the perioperative oligometastatic disease setting; (5) re-challenge of EGFR directed therapy and (6) personalizing therapy of fluoropyrimidine and irinotecan based on new evidence in pharmacogenomic testing. Data are collected and analyzed from available systematic reviews and meta-analyses of treatments with known therapeutic targets in CRC, which may be associated with predictive and/or prognostic biomarkers. Discussions are presented in an application-based format, with goal to empower pharmacists or other clinicians to gain awareness and understanding in biomarker-driven cancer therapy issues.

PMID:33832365 | DOI:10.1177/10781552211005525

Pharmacogenomics. 2021 Apr 8. doi: 10.2217/pgs-2020-0181. Online ahead of print.

ABSTRACT

Pharmacogenetic (PGx) literature has shown beneficial outcomes in safety, efficacy and cost when evidence-based gene-drug decision making is incorporated into clinical practice. PGx programs with successfully implemented clinical services have been published in a variety of settings including academic health centers and community practice. The primary objective was to systematically scope the literature to characterize the current trends, extent, range and nature of clinical PGx programs. Forty articles representing 19 clinical PGx programs were included in analysis. Most programs are in urban, academic institutions. Education, governance and workflow were commonly described while billing/reimbursement and consent were not. This review provides an overview of current PGx models that can be used as a reference for institutions beginning the implementation process.

PMID:33829852 | DOI:10.2217/pgs-2020-0181

J Pharm Bioallied Sci. 2020 Nov;12(Suppl 2):S787-S803. doi: 10.4103/jpbs.JPBS_248_19. Epub 2020 Nov 5.

ABSTRACT

INTRODUCTION: Dopamine receptor D2 (DRD2) is one of the dopamine receptors that have been studied in relation to opioid dependence. It is possible, therefore, that DRD2 gene (DRD2) polymorphisms influence treatment outcomes of patients with opioid dependence. The objective of this study was to investigate the influence of DRD2 polymorphisms on the clinical outcomes of opioid-dependent patients on methadone maintenance therapy (MMT).

MATERIALS AND METHODS: Patients with opioid dependence (n = 148) were recruited from MMT clinics. Pain sensitivity, severity of the opiate withdrawal syndrome, and sleep quality were assessed using cold pressor test (CPT), Subjective Opiate Withdrawal Scale (SOWS-M), and Pittsburgh Sleep Quality Index (PSQI)-Malay, respectively. Deoxyribonucleic acid (DNA) was extracted from whole blood, and then was used for genotyping of Val96Ala, Leu141Leu, Val154Ile, Pro310Ser, Ser311Cys, TaqI A, -141C Ins/Del, and A-241G polymorphisms.

RESULTS: Among 148 patients, 8.1% (n = 12), 60.8% (n = 90), 27.7% (n = 41), and 29.1% (n = 43) had at least one risk allele for Ser311Cys, TaqI A, -141C Ins/Del, and A-241G polymorphisms, respectively. There were no significant differences in pain responses (pain threshold, tolerance, and intensity), SOWS, and PSQI scores between DRD2 polymorphisms.

CONCLUSION: The common DRD2 polymorphisms are not associated with pain sensitivity, severity of the opiate withdrawal syndrome, and sleep quality in patients with opioid dependence on MMT. However, this may be unique for Malays. Additional research should focus on investigating these findings in larger samples and different ethnicity.

PMID:33828379 | PMC:PMC8021064 | DOI:10.4103/jpbs.JPBS_248_19

Mol Psychiatry. 2021 Apr 8. doi: 10.1038/s41380-021-01061-w. Online ahead of print.

ABSTRACT

Mood disorders (depression, bipolar disorders) are prevalent and disabling. They are also highly co-morbid with other psychiatric disorders. Currently there are no objective measures, such as blood tests, used in clinical practice, and available treatments do not work in everybody. The development of blood tests, as well as matching of patients with existing and new treatments, in a precise, personalized and preventive fashion, would make a significant difference at an individual and societal level. Early pilot studies by us to discover blood biomarkers for mood state were promising [1], and validated by others [2]. Recent work by us has identified blood gene expression biomarkers that track suicidality, a tragic behavioral outcome of mood disorders, using powerful longitudinal within-subject designs, validated them in suicide completers, and tested them in independent cohorts for ability to assess state (suicidal ideation), and ability to predict trait (future hospitalizations for suicidality) [3-6]. These studies showed good reproducibility with subsequent independent genetic studies [7]. More recently, we have conducted such studies also for pain [8], for stress disorders [9], and for memory/Alzheimer's Disease [10]. We endeavored to use a similar comprehensive approach to identify more definitive biomarkers for mood disorders, that are transdiagnostic, by studying mood in psychiatric disorders patients. First, we used a longitudinal within-subject design and whole-genome gene expression approach to discover biomarkers which track mood state in subjects who had diametric changes in mood state from low to high, from visit to visit, as measured by a simple visual analog scale that we had previously developed (SMS-7). Second, we prioritized these biomarkers using a convergent functional genomics (CFG) approach encompassing in a comprehensive fashion prior published evidence in the field. Third, we validated the biomarkers in an independent cohort of subjects with clinically severe depression (as measured by Hamilton Depression Scale, (HAMD)) and with clinically severe mania (as measured by the Young Mania Rating Scale (YMRS)). Adding the scores from the first three steps into an overall convergent functional evidence (CFE) score, we ended up with 26 top candidate blood gene expression biomarkers that had a CFE score as good as or better than SLC6A4, an empirical finding which we used as a de facto positive control and cutoff. Notably, there was among them an enrichment in genes involved in circadian mechanisms. We further analyzed the biological pathways and networks for the top candidate biomarkers, showing that circadian, neurotrophic, and cell differentiation functions are involved, along with serotonergic and glutamatergic signaling, supporting a view of mood as reflecting energy, activity and growth. Fourth, we tested in independent cohorts of psychiatric patients the ability of each of these 26 top candidate biomarkers to assess state (mood (SMS-7), depression (HAMD), mania (YMRS)), and to predict clinical course (future hospitalizations for depression, future hospitalizations for mania). We conducted our analyses across all patients, as well as personalized by gender and diagnosis, showing increased accuracy with the personalized approach, particularly in women. Again, using SLC6A4 as the cutoff, twelve top biomarkers had the strongest overall evidence for tracking and predicting depression after all four steps: NRG1, DOCK10, GLS, PRPS1, TMEM161B, GLO1, FANCF, HNRNPDL, CD47, OLFM1, SMAD7, and SLC6A4. Of them, six had the strongest overall evidence for tracking and predicting both depression and mania, hence bipolar mood disorders. There were also two biomarkers (RLP3 and SLC6A4) with the strongest overall evidence for mania. These panels of biomarkers have practical implications for distinguishing between depression and bipolar disorder. Next, we evaluated the evidence for our top biomarkers being targets of existing psychiatric drugs, which permits matching patients to medications in a targeted fashion, and the measuring of response to treatment. We also used the biomarker signatures to bioinformatically identify new/repurposed candidate drugs. Top drugs of interest as potential new antidepressants were pindolol, ciprofibrate, pioglitazone and adiphenine, as well as the natural compounds asiaticoside and chlorogenic acid. The last 3 had also been identified by our previous suicidality studies. Finally, we provide an example of how a report to doctors would look for a patient with depression, based on the panel of top biomarkers (12 for depression and bipolar, one for mania), with an objective depression score, risk for future depression, and risk for bipolar switching, as well as personalized lists of targeted prioritized existing psychiatric medications and new potential medications. Overall, our studies provide objective assessments, targeted therapeutics, and monitoring of response to treatment, that enable precision medicine for mood disorders.

PMID:33828235 | DOI:10.1038/s41380-021-01061-w

Sci Rep. 2021 Apr 7;11(1):7570. doi: 10.1038/s41598-021-87130-0.

ABSTRACT

Although pancreatic ductal adenocarcinoma (PDAC) survival is poor, there are differences in patients' response to the treatments. Detection of predictive biomarkers explaining these differences is of the utmost importance. In a recent study two genetic markers (CD44-rs353630 and CHI3L2-rs684559) were reported to be associated with survival after PDAC resection. We attempted to replicate the associations in 1856 PDAC patients (685 resected with stage I/II) from the PANcreatic Disease ReseArch (PANDoRA) consortium. We also analysed the combined effect of the two genotypes in order to compare our results with what was previously reported. Additional stratified analyses considering TNM stage of the disease and whether the patients received surgery were also performed. We observed no statistically significant associations, except for the heterozygous carriers of CD44-rs353630, who were associated with worse OS (HR = 5.01; 95% CI 1.58-15.88; p = 0.006) among patients with stage I disease. This association is in the opposite direction of those reported previously, suggesting that data obtained in such small subgroups are hardly replicable and should be considered cautiously. The two polymorphisms combined did not show any statistically significant association. Our results suggest that the effect of CD44-rs353630 and CHI3L2-rs684559 cannot be generalized to all PDAC patients.

PMID:33828170 | DOI:10.1038/s41598-021-87130-0

Arterioscler Thromb Vasc Biol. 2021 Apr 8:ATVBAHA121314689. doi: 10.1161/ATVBAHA.121.314689. Online ahead of print.

ABSTRACT

OBJECTIVE: Smyd3 (SET and MYND domain-containing protein 3) is an H3K4 (histone H3 lysine 4) dimethyltransferase and trimethyltransferase that activates the transcription of oncogenes and cell cycle genes in human cancer cells. We discovered its overexpression in proliferative vascular smooth muscle cells (VSMCs). However, whether Smyd3 plays a role in vascular remodeling remains unanswered. The objective of this study is to investigate the role and underlying mechanism of Smyd3 in phenotypic transition of VSMCs (such as proliferation and migration) and vascular remodeling (such as neointima formation). Approach and Results: We discovered upregulation of Smyd3 in both PDGF (platelet-derived growth factor) BB-induced vascular cell proliferation model and balloon injury-induced neointima formation model. Knockdown of Smyd3 or blockade of its enzymatic activity suppressed VSMCs proliferation and migration ability, whereas Smyd3 overexpression promoted VSMC migration and proliferation. Mechanistically, RNA-seq and ChIP-seq analysis revealed Smyd3 promoted neointimal formation by directly binding and increasing H3K4me3 to the promoter regions of target genes that are associated with cell proliferation and migration, cell cycle control. Furthermore, knockout of Smyd3 in mice profoundly suppressed carotid artery ligation-induced neointimal hyperplasia, consistently, local knocking down Smyd3 in rats relieved balloon injury-induced neointimal formation, while restored VSMC contractile protein expression, suggesting that Smyd3 plays a critical role in vivo.

CONCLUSIONS: Our results demonstrate that Smyd3 promotes VSMC proliferation and migration during injury-induced vascular remodeling, which provide a potential therapeutic target for preventing neointimal hyperplasia in proliferative vascular diseases.

PMID:33827259 | DOI:10.1161/ATVBAHA.121.314689

Pediatr Res. 2021 Apr 6. doi: 10.1038/s41390-021-01499-2. Online ahead of print.

ABSTRACT

This review evaluates the pediatric evidence for pharmacogenetic associations for drugs that are commonly prescribed by or encountered by pediatric clinicians across multiple subspecialties, organized from most to least pediatric evidence. We begin with the pharmacogenetic research that led to the warning of increased risk of death in certain pediatric populations ("ultrarapid metabolizers") who are prescribed codeine after tonsillectomy or adenoidectomy. We review the evidence for genetic testing for thiopurine metabolism, which has become routine in multiple pediatric subspecialties. We discuss the pharmacogenetic research in proton pump inhibitors, for which clinical guidelines have recently been made available. With an increase in the prevalence of behavioral health disorders including attention deficit hyperactivity disorder (ADHD), we review the pharmacogenetic literature on selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and ADHD medications. We will conclude this section on the current pharmacogenetic data on ondansetron. We also provide our perspective on how to integrate the current research on pharmacogenetics into clinical care and what further research is needed. We discuss how institutions are managing pharmacogenetic test results and implementing them clinically, and how the electronic health record can be leveraged to ensure testing results are available and taken into consideration when prescribing medications. IMPACT: While many reviews of pharmacogenetics literature are available, there are few focused on pediatrics. Pediatricians across subspecialties will become more comfortable with pharmacogenetics terminology, know resources they can use to help inform their prescribing habits for drugs with known pharmacogenetic associations, and understand the limitations of testing and where further research is needed.

PMID:33824446 | DOI:10.1038/s41390-021-01499-2

Pharmacogenomics J. 2021 Apr 6. doi: 10.1038/s41397-021-00225-9. Online ahead of print.

ABSTRACT

Carbamazepine (CBZ)-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are strongly associated with the HLA-B*15:02 allele. Screening HLA-B*15:02 before CBZ administration might prevent CBZ-induced SJS/TEN by enabling clinicians to prescribe alternative therapy for positive patients. Similar to other Southeastern Asian countries, HLA-B*15:02 is highly prevalent in Indonesia. Therefore, we assessed the economic value of HLA-B*15:02 screening before CBZ prescription to patients with epilepsy in Indonesia. A generic cost-effectiveness model and decision support tool, developed to enable users to perform an initial cost-effectiveness analysis from a healthcare provider/payer perspective, were used to assess the value of HLA-B*15:02 genotyping. The incremental cost-effectiveness ratio of adopting universal HLA-B*15:02 screening was 656,444,671 Indonesian Rupiah (IDR)/quality-adjusted life year (QALY) gained for patients compared with 2,634,975,574 IDR/QALY gained for providing valproic acid (alternative drug) without screening. Thus, neither HLA-B*15:02 screening nor substitution with VPA meets the Indonesian threshold for cost effectiveness. However, the improved outcomes with this test in other Asian countries may inform the desirability of implementation in Indonesia even with suboptimal cost-effectiveness.

PMID:33824430 | DOI:10.1038/s41397-021-00225-9

Pharmacogenomics J. 2021 Apr 6. doi: 10.1038/s41397-021-00234-8. Online ahead of print.

ABSTRACT

Selective serotonin reuptake inhibitors (SSRIs) are prescribed both to patients with schizophrenia and bipolar disorder. Previous studies have shown associations between SSRI treatment and cardiometabolic alterations. The aim of the present study was to investigate genetic variants associated with cardiometabolic adverse effects in patients treated with SSRIs in a naturalistic setting, using a genome-wide cross-sectional approach in a genetically homogeneous sample. We included and genotyped 1981 individuals with schizophrenia or bipolar disorder, of whom 1180 had information available on the outcomes low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein cholesterol (HDL-cholesterol), triglycerides, and body mass index (BMI) and investigated interactions between SNPs and SSRI use (N = 246) by conducting a genome-wide GxE analysis. We report 13 genome-wide significant interaction effects of SNPs and SSRI serum concentrations on LDL-cholesterol, HDL-cholesterol, and BMI, located in four distinct genomic loci. This study provides new insight into the pharmacogenetics of SSRI but warrants replication in independent populations.

PMID:33824429 | DOI:10.1038/s41397-021-00234-8

Drug Metab Dispos. 2021 Apr 6:DMD-AR-2021-000367. doi: 10.1124/dmd.121.000367. Online ahead of print.

ABSTRACT

About 30% of approved drugs are cleared predominantly by renal clearance (CLr). Of these, many are secreted by transporters. For these drugs, in vitro-to-in vivo extrapolation of transporter-mediated renal secretory clearance (CLsec,plasma) is important to prospectively predict their renal clearance and to assess the impact of drug-drug interactions and pharmacogenetics on their pharmacokinetics. Here we compared the ability of the relative expression factor (REF) and the relative activity factor (RAF) approaches to quantitatively predict the in vivo CLsec,plasma of 26 Organic Anion Transporter (OAT) substrates assuming that OAT-mediated uptake is the rate-determining step in the CLsec,plasma of the drugs. The REF approach requires protein quantification of each transporter in the tissue (e.g. kidney) and transporter-expressing cells (TEC) while the RAF approach requires the use of a transporter-selective probe substrate (both in vitro and in vivo) for each transporter of interest. For the REF approach, 50% and 69% of the CLsec,plasma predictions were within 2- and 3-fold of the observed values, respectively; the corresponding values for the RAF approach were 65% and 81%. We found no significant difference between the two approaches in their predictive capability (as measured by accuracy and bias) of the CLsec,plasma or CLr of OAT drugs. We recommend that the REF and RAF approaches can be used interchangeably to predict OAT-mediated CLsec,plasma Further research is warranted to evaluate the ability of the REF or RAF approach to predict CLsec,plasma of drugs when uptake is not the rate-determining step. Significance Statement This is the first direct comparison of the REF and RAF approaches to predict transporter-mediated CLr The RAF, but not REF, approach requires transporter-selective probes and that the basolateral uptake is the rate-determining step in the CLr of drugs. Given that there is no difference in predictive capability of the REF and RAF approach for OAT-mediated CLr, the REF approach should be explored further to assess its ability to predict CLr when basolateral uptake is not the sole rate-determining step.

PMID:33824168 | DOI:10.1124/dmd.121.000367