J Oncol Pharm Pract. 2021 Apr 15:10781552211005529. doi: 10.1177/10781552211005529. Online ahead of print.

ABSTRACT

INTRODUCTION: Pharmacogenetics, in hand with precision medicine in oncology, represents an opportunity to holistically tailor a patient's treatment regimen using both somatic and germline variants to improve efficacy and decrease toxicity. Colorectal cancer patients represent a population with frequent use of fluoropyrimidine and irinotecan and are an ideal opportunity for implementation of preemptive pharmacogenetics as evidence supports pharmacogenetic testing for DPYD and UGT1A1 to reduce fluoropyrimidine and irinotecan toxicities.

METHODS: This was a single arm proof-of-concept study at a large community-based health system. Participants provided samples for pharmacogenetic testing via an external vendor prior to chemotherapy initiation and an oncology pharmacist was responsible for pharmacogenetic interpretation and pharmacogenetic-guided therapeutic recommendation to the treating provider.

RESULTS: A total of 24 (60%) participants had a UGT1A1 variant. All participants (100%) were DPYD*1/*1. Results were available and interpreted for 29/40 (72.5%) participants prior to scheduled chemotherapy initiation (p value <0.014). Of the participants whose results were available in 5 weekdays or less (n = 23), 20 (87%) were communicated with the treating provider prior to scheduled chemotherapy administration. A total turnaround time of 5 days or less was significantly associated with PGx feasibility in a community-based oncology clinic (p = 0.03).

CONCLUSIONS: In conclusion, we were able to show that implementation of preemptive pharmacogenetic testing into a community oncology clinic with results interpretation available prior to scheduled initiation of chemotherapy was feasible. As pharmacogenetic testing in oncology expands, pharmacists should be prepared to optimize supportive medication regimens as well as chemotherapy with pharmacogenetic results.

PMID:33853470 | DOI:10.1177/10781552211005529

Pharmacogenet Genomics. 2021 Apr 12. doi: 10.1097/FPC.0000000000000434. Online ahead of print.

ABSTRACT

OBJECTIVE: Inhaled bronchodilators are the first-line treatment for asthma exacerbations, but individual bronchodilator response (BDR) varies by race and ethnicity. Studies have examined BDR's genetic underpinnings, but many did not include children or were not conducted during an asthma exacerbation. This pilot study tested single-nucleotide polymorphisms' (SNPs') association with pediatric African American BDR during an acute asthma exacerbation.

METHODS: This was a study of pediatric asthma patients in the age group 2-18 years treated in the emergency department for an asthma exacerbation. We measured BDR before and after inhaled bronchodilator treatments using both the Pediatric Asthma Severity Score (PASS) and asthma severity score. We collected genomic DNA and examined whether 21 candidate SNPs from a review of the literature were associated with BDR using crude odds ratios (OR) and adjusted analysis.

RESULTS: The final sample population was 53 children, with an average age of 7.2 years. The average initial PASS score (scale of ascending severity from 0 to 6) was 2.5. After adjusting for BMI, age category, gender and smoke exposure, rs912142 was associated with decreased odds of having low BDR (OR, 0.20; 95% confidence interval (CI), 0.02-0.92), and rs7081864 and rs7903366 were associated with decreased odds of having high BDR (OR, 0.097; 95% CI, 0.009-0.62).

CONCLUSIONS: We found three SNPs significantly associated with pediatric African American BDR that provide information regarding a child's potential response to emergency asthma exacerbation treatment. Once validated in larger studies, such information could guide pharmacogenomic evidence-based emergency asthma treatment to improve patient outcomes.

PMID:33851947 | DOI:10.1097/FPC.0000000000000434

Pharmacogenomics J. 2021 Apr 13. doi: 10.1038/s41397-021-00235-7. Online ahead of print.

ABSTRACT

Recently, the use of antiretroviral drug tenofovir disoproxil fumarate (TDF) is increased, thanks to the new co-formulation with doravirine, the availability of booster-free regimens, and its advantageous lipid-lowering effect. The aim of our study was to identify genetic markers that contribute to assess the risk of TDF-related renal toxicity. We have retrospectively investigated, in 179 HIV positive patients treated with TDF, the association between the main variants in ABCC2, ABCC4, and ABCC10 genes and four safety endpoints, three clinically relevant as renal outcomes and a higher tenofovir plasma concentration. In patients with an annual eGFR decline >5 mL/min/1.73 m2 a difference in genotype frequencies was observed for ABCC10 c.1875 + 526 G>A (3 subjects AA vs. 44 GG + GA, p = 0.045). In patients with an eGFR decrement >25%, plus a decline in GFR category and TDF discontinuation, a difference was observed for ABCC4 c.*38T>G (35 subjects TG + GG vs. 18 TT, p = 0.052). At univariate analysis OR was 1.39 [(95% CI 1.00-1.96) p = 0.054] and at multivariate analysis OR was 1.49 [(95% CI 1.00-2.22) p = 0.049]. The stronger associations were found between the tenofovir accumulation and ABCC4 c.*38T>G and c.3348G>A: the percentage of these patients was higher in the TG + GG (p = 0.011) and in the AA (p = 0.004) genotype, respectively. The logistic regression analysis confirmed these significant relationships. No significant association was observed in patients with eGFR < 60 mL/min/1.73m2 and with the studied ABCC2 polymorphisms. Our results show a major role for a combined determination of ABCC4/ABCC10 variants as an indicator of tenofovir toxicity in the clinical practice.

PMID:33850298 | DOI:10.1038/s41397-021-00235-7

Pharmacogenomics J. 2021 Apr 13. doi: 10.1038/s41397-021-00236-6. Online ahead of print.

ABSTRACT

The aim of this study was to perform a systematic overview of the pharmacogenetic studies conducted in Jordan. A structured search of Medline was conducted for articles over the last decade (January 2010-July 2020). Studies were classified by design, sample size, drug-gene combination, and the significance of the results. Thirty-two studies met the criteria for review. Most pharmacogenomic studies had a case-only design (n = 23). Only five studies included >500 participants. The total number of genetic variants in all studies was one hundred fifteen, which were found in forty genes, including dynamic (n = 27), and kinetic (n = 9) genes. The most commonly studied drugs were within the hematology and cardiology therapeutic areas and included statins, warfarin, aspirin, and clopidogrel. Most studies (n = 18) reported results with mixed p values [<0.05 and >0.05]. Pharmacogenomic research in Jordan is still in its infancy and is limited mainly to replication attempts. The need for standardization is imperative, especially in developing countries with scarce funding resources.

PMID:33850297 | DOI:10.1038/s41397-021-00236-6

Sci Rep. 2021 Apr 13;11(1):8478. doi: 10.1038/s41598-021-88212-9.

NO ABSTRACT

PMID:33850257 | DOI:10.1038/s41598-021-88212-9

Pharmacogenomics. 2021 Apr 14. doi: 10.2217/pgs-2020-0177. Online ahead of print.

ABSTRACT

Background: Despite the expansion of pharmacogenetics (PGx), the views of pediatric patients remain unknown. This study explores adolescents' understanding and perceptions of PGx testing. Methods: Adolescents who had PGx testing were interviewed and their electronic health records were reviewed. Results: Adolescents accurately described reason for testing and most felt the results impacted their current and future care. None perceived risks to securing future employment or insurance. All felt PGx would benefit their peers. Conclusion: Adolescents understand the reasons for PGx and perceive testing to be useful, low risk and applicable to peers. Findings from this study advocate for the inclusion of adolescents in shared decision-making regarding testing and for active engagement in the discussion of results.

PMID:33849282 | DOI:10.2217/pgs-2020-0177

Pharmacogenomics. 2021 Apr 14. doi: 10.2217/pgs-2021-0036. Online ahead of print.

NO ABSTRACT

PMID:33849279 | DOI:10.2217/pgs-2021-0036

J Clin Pharmacol. 2021 Apr 13. doi: 10.1002/jcph.1873. Online ahead of print.

ABSTRACT

Morphine is an opioid analgesic indicated in the treatment of acute and chronic moderate to severe pain. From a pharmacodynamic standpoint, morphine exerts its effects by agonizing mu-opioid receptors (OPRM1) predominantly, resulting in analgesia and sedation. Pharmacokinetically, morphine is primarily metabolized in the liver via glucuronidation by the enzyme uridine diphosphate glucuronosyltransferase family 2-member B7 (UGT2B7) and encounters the transporter proteins organic cation transporter isoform 1 (OCT1) and p-glycoprotein (ABCB1) as it is being distributed throughout the body. The genes coding for the proteins impacting either the pharmacokinetics or pharmacodynamics of morphine may bear genetic variations, also known as polymorphisms, which may alter the function of the proteins in such a manner that an individual may have disparate treatment outcomes. The purpose of this review is to highlight some of the genes coding for proteins that impact morphine pharmacokinetics and pharmacodynamics and present some treatment considerations. This article is protected by copyright. All rights reserved.

PMID:33847389 | DOI:10.1002/jcph.1873

Acta Derm Venereol. 2021 Apr 13. doi: 10.2340/00015555-3794. Online ahead of print.

ABSTRACT

Biological drugs targeting tumour necrosis factor are effective for psoriasis. However, 30-50% of patients do not respond to these drugs and may even develop paradoxical psoriasiform reactions. This study search-ed for DNA copy number variations that could predict anti-tumour necrotic factor drug response or the appearance of anti-tumour necrotic factor induced psoriasiform reactions. Peripheral blood samples were collected from 70 patients with anti-tumour necrotic factor drug-treated moderate-to-severe plaque psoriasis. Samples were analysed with an Illumina 450K methylation microarray. Copy number variations were obtained from raw methylation data using conumee and Chip Analysis Methylation Pipeline (ChAMP) R packages. One copy number variation was found, harbouring 1 gene (CPM) that was significantly associated with adalimumab response (Bonferroni-adjusted p-value < 0.05). Moreover, 1 copy number variation was identified harbouring 3 genes (ARNT2, LOC101929586 and MIR5572) related to the development of paradoxical psoriasiform reactions. In conclusion, this study has identified DNA copy number variations that could be good candidate markers to predict response to adalimumab and the development of anti-tumour necrotic factor paradoxical psoriasiform reactions.

PMID:33846759 | DOI:10.2340/00015555-3794

Scand J Public Health. 2021 Apr 12:14034948211004421. doi: 10.1177/14034948211004421. Online ahead of print.

ABSTRACT

Aim: This case study aimed to investigate the process of integrating resources of multiple biobanks and health-care registers, especially addressing data permit application, time schedules, co-operation of stakeholders, data exchange and data quality. Methods: We investigated the process in the context of a retrospective study: Pharmacogenomics of antithrombotic drugs (PreMed study). The study involved linking the genotype data of three Finnish biobanks (Auria Biobank, Helsinki Biobank and THL Biobank) with register data on medicine dispensations, health-care encounters and laboratory results. Results: We managed to collect a cohort of 7005 genotyped individuals, thereby achieving the statistical power requirements of the study. The data collection process took 16 months, exceeding our original estimate by seven months. The main delays were caused by the congested data permit approval service to access national register data on health-care encounters. Comparison of hospital data lakes and national registers revealed differences, especially concerning medication data. Genetic variant frequencies were in line with earlier data reported for the European population. The yearly number of international normalised ratio (INR) tests showed stable behaviour over time. Conclusions: A large cohort, consisting of versatile individual-level phenotype and genotype data, can be constructed by integrating data from several biobanks and health data registers in Finland. Co-operation with biobanks is straightforward. However, long time periods need to be reserved when biobank resources are linked with national register data. There is a need for efforts to define general, harmonised co-operation practices and data exchange methods for enabling efficient collection of data from multiple sources.

PMID:33845693 | DOI:10.1177/14034948211004421

Diagn Cytopathol. 2021 Apr 12. doi: 10.1002/dc.24749. Online ahead of print.

ABSTRACT

BACKGROUND: The increase in immunohistochemical and molecular predictive tests in lung cancer requires new strategies for managing small samples taken during bronchoscopic procedures. The value of Rapid On Site Evaluation (ROSE) during conventional bronchoscopic procedures on endobronchial neoplasms in optimizing small biopsies and cytologlogical tissue specimens for diagnostic testing, and ancillary studies was evaluated.

METHOD: ROSE on touch imprint cytology (TIC) and brushing was performed on 690 consecutive cases of patients undergoing biopsies, using fiber optic bronchoscopy. Immunohistochemical assay for PD-L1, ALK, and ROS1 and molecular testing, via next generation technique for EGFR, KRAS, and BRAF, were performed.

RESULTS: The concordance between ROSE and final diagnoses was almost perfect for brushing (sensitivity: 0.84; specificity: 0.96), and less so for touch preparations (sensitivity: 0.77; specificity: 0.89). Immunohistochemical assay for PD-L1 was evaluated on 256 bioptic cases with only six unsuitable samples. Material available for immunohistochemistry for ALK was sufficient in 151 biopsies with no inadequate cases. ROS1 was evaluated in 132 biopsies, with only two unsuitable samples. Molecular analysis was performed on 128 biopsies, 29 TIC, and 17 brushing. Out of these, only ten were considered to be unsuitable.

CONCLUSIONS: ROSE is an effective procedure for monitoring the quality and quantity of material taken during conventional bronchoscopic procedures for evaluating the suitability of small samples that must undergo immunohistochemical and molecular assay.

PMID:33844889 | DOI:10.1002/dc.24749

Front Med (Lausanne). 2021 Mar 24;8:644154. doi: 10.3389/fmed.2021.644154. eCollection 2021.

ABSTRACT

Drug-related Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare but severe adverse drug reactions, termed as idiosyncratic reactions; however, predicting their onset remains challenging. Pharmacogenomic information associated with SJS/TEN has accumulated on several drugs in the last 15 years, with clinically useful information now included on drug labels in several countries/regions or guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC) for implementation. However, label information might be different among countries. This mini-review summarizes pharmacogenomic information on drug labels of five drugs in six countries and compared descriptions of drug labels and CPIC guidelines. Finally, we discuss future perspectives of this issue. Pharmacogenomic information on drug labels is not well-harmonized across countries/regions, but CPIC guidelines are a scientifically sound goal for future pharmacogenomic implementation.

PMID:33842507 | PMC:PMC8024462 | DOI:10.3389/fmed.2021.644154

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