Biochem Biophys Res Commun. 2022 May 18;615:75-80. doi: 10.1016/j.bbrc.2022.05.055. Online ahead of print.

ABSTRACT

Nuclear receptor Pregnane X Receptor (PXR; NR1I2) has transcriptional regulation functions for energy homeostasis in the liver. Mouse PXR has a conserved phosphorylation motif at serine 347 (serine 350 in humans) within the ligand-binding domain. PXR phosphorylated at this motif is expressed in mouse livers in response to fasting. Mice with a PXR∗Ser347Ala knockin mutation (PXR KI) were generated to block phosphorylation, and utilized to investigate the role of Ser347 phosphorylation in vivo. PXR KI mice had decreased body weight at 8-weeks of age and had much greater weight loss after fasting compared with PXR WT mice. The cDNA microarray analysis of hepatic mRNAs showed that cell death or apoptotic signaling was induced in fasting PXR KI mice. Moreover, increasing hepatic lipids, triglycerides and the development of hypertriglyceridemia were observed in fasting PXR KI mice. These findings are indicative that blocking phosphorylation prevents mice from maintaining hepatic energy homeostasis. Thus, phosphorylated PXR may be an essential factor to prevent the liver from developing damage caused by fasting.

PMID:35609418 | DOI:10.1016/j.bbrc.2022.05.055

Am J Health Syst Pharm. 2022 May 24:zxac147. doi: 10.1093/ajhp/zxac147. Online ahead of print.

ABSTRACT

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PURPOSE: Results of the 2021 ASHP National Survey of Pharmacy Practice in Hospital Settings are presented.

METHODS: Pharmacy directors at 1,498 general and children's medical/surgical hospitals in the United States were surveyed using a mixed-mode method of contact by email and mail. Survey completion was online. IQVIA supplied data on hospital characteristics; the survey sample was drawn from IQVIA's hospital database.

RESULTS: The response rate was 21.9%. Pharmacists are routinely assigned to a majority of patients at least 8 hours per day, 5 days per week in 70.4% of hospitals. This is an increase from 60.8% in 2018 and has steadily increased over the past decade. Pharmacists independently prescribe medications pursuant to a diagnosis in 30.9% of hospitals, an increase from 21.1% in 2020. Pharmacists have prescribing authority in 67% of health-system ambulatory clinics and can recommend or schedule pharmacogenomics testing for drug and dosage selection in 11.4% of hospitals, an increase from 5.4% in 2019. Pharmacists are using electronic methods in 82.5% of hospitals to collect information for monitoring medication therapy. Shortages of entry-level pharmacy technicians are acute, with 73.4% of survey respondents reporting a shortage. Technician shortages have affected pharmacy operations and have prompted new recruitment and retention strategies.

CONCLUSION: Despite workforce challenges, clinical pharmacy services continue to expand to cover increasing numbers of patients with medication management services in both the inpatient and outpatient settings. The use of data analytics and pharmacy technicians has contributed to this evolution. Addressing the workforce challenges will be critical to sustain this progress.

PMID:35609002 | DOI:10.1093/ajhp/zxac147

Pharmacogenomics. 2022 May 24. doi: 10.2217/pgs-2022-0014. Online ahead of print.

ABSTRACT

Background: Vitamin K antagonists (VKAs) are class I oral anticoagulants that are widely prescribed following surgical heart valve implantation. The objective of this study was to quantify the relative effects of VKORC1, CYP2C9 and CYP4F2 genotypes in predicting VKA dosing. Materials & methods: A total of 506 South Indian patients with mechanical prosthetic heart valves who were prescribed oral VKAs, such as warfarin or acenocoumarol, were genotyped. The discriminatory ability of mutant genotypes to predict dose categories and bleeding events was assessed using regression analysis. Results: The VKORC1 rs9923231, CYP2C9*3 and CYP4F2*3 mutant genotypes significantly influenced VKA-dose requirements and explained 27.47% of the observed dose variation. Conclusion: These results support pharmacogenetic screening for initial VKA dosing among South Indian patients with mechanical prosthetic heart valves.

PMID:35608144 | DOI:10.2217/pgs-2022-0014

Anal Methods. 2022 May 24. doi: 10.1039/d2ay00129b. Online ahead of print.

ABSTRACT

Doxepin, a tricyclic antidepressant (TCA), is widely used in the treatment of depressive disorder and anxiety. There are some liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods that have been reported for detecting doxepin, but inadequacies in recovery and cumbersome sample preparation obstruct the pharmacokinetics study. Therefore, we aimed to develop and validate a rapid sample preparation method based on solid-phase extraction (SPE) for the precise quantification of doxepin and its metabolites. Chromatography separation was performed on a Waters ACQUITY UPLC BEH C18 column (2.1 × 100 mm, 1.7 μm) and a mobile phase consisting of 70% of mobile phase A (0.1% formic acid and 10 mM ammonium formate) and 30% mobile phase B (0.1% formic acid in acetonitrile) at a flow rate of 0.4 mL min-1 in the step gradient elution conditions. The lower limits of quantification for doxepin and N-nordoxepin were 4 pg mL-1 and 2 pg mL-1, respectively. This method was validated with satisfactory results including good precision and accuracy. A rapid, sensitive, and specific LC-MS/MS method was developed and validated for the determination of doxepin in human plasma. This method could be applied for determining doxepin and N-nordoxepin concentrations in plasma that could be useful for bioequivalence study of 3 mg doxepin.

PMID:35608048 | DOI:10.1039/d2ay00129b

Expert Rev Anti Infect Ther. 2022 May 24. doi: 10.1080/14787210.2022.2081546. Online ahead of print.

ABSTRACT

INTRODUCTION: Tuberculosis (TB) is a transnational public health concern, which requires more precise treatment strategies than the existing approaches. Vitamin D modulates the inflammatory and immune response to the disease. Robust evidence shows that vitamin D deficiency and its receptor gene polymorphism influence the susceptibility to TB and the outcome of the anti-tubercular treatment (ATT). However, in the different populations, these findings were inconsistent and even contradictory.

AREAS COVERED: The current review focuses on the association between vitamin D receptor (VDR) gene polymorphism with the risk of development of TB disease and response to the ATT. Additionally, it reviews various systematic reviews and meta-analyses on the impact of vitamin D supplements on both clinical and treatment outcomes in TB patients.

EXPERT OPINION: Although the majority of the findings rule out the benefits of the supplementation, sufficient evidence is available to warrant larger epidemiological research that should be aimed to generate possible interaction among the VDR polymorphism, vitamin D status, and the outcome in TB. We conclude that establishing such an association in different ethnic populations will help design nutrigenomics- or pharmacogenomics-based vitamin D supplementation to develop a personalized medicine approach to flatten the curve of TB disease.

PMID:35608034 | DOI:10.1080/14787210.2022.2081546

Pharmacogenomics. 2022 May 24. doi: 10.2217/pgs-2022-0011. Online ahead of print.

ABSTRACT

Talazoparib is an oral PARP inhibitor approved for locally advanced/metastatic breast cancer. There is no consensus, however, as to whether it is better used as a first-line treatment or after other therapies in patients with gBRCA mutations. In fact, talazoparib showed its superiority compared with chemotherapy in the survival and quality of life of patients with BRCA mutations, with an acceptable toxicity profile. While it's role in this indication is not debated, it's cost as well as the availability of other effective new agents, particularly immune checkpoint inhibitors, may encourage the movement of this drug to later treatment lines. Until more robust data are available, the best treatment sequence for BRCA-mutated breast cancer must be personalized on a case-by-case basis.

PMID:35607887 | DOI:10.2217/pgs-2022-0011

Ther Clin Risk Manag. 2022 May 17;18:579-591. doi: 10.2147/TCRM.S361936. eCollection 2022.

ABSTRACT

PURPOSE: To identify more objectively predictive factors of severe outcome among patients hospitalized for coronavirus disease 2019 (COVID-19).

PATIENTS AND METHODS: A retrospective cohort of 479 hospitalized patients diagnosed with COVID-19 in Hunan Province was selected. The prognostic effects of factors such as age and laboratory indicators were analyzed using the Kaplan-Meier method and Cox proportional hazards model. A prognostic nomogram model was established to predict the progression of patients with COVID-19.

RESULTS: A total of 524 patients in Hunan province with COVID-19 from December 2019 to October 2020 were retrospectively recruited. Among them, 479 eligible patients were randomly assigned into the training cohort (n = 383) and validation cohort (n = 96), at a ratio of 8:2. Sixty-eight (17.8%) and 15 (15.6%) patients developed severe COVID-19 after admission in the training cohort and validation cohort, respectively. The differences in baseline characteristics were not statistically significant between the two cohorts with regard to age, sex, and comorbidities (P > 0.05). Multivariable analyses included age, C-reactive protein, fibrinogen, lactic dehydrogenase, neutrophil-to-lymphocyte ratio, urea, albumin-to-globulin ratio, and eosinophil count as predictive factors for patients with progression to severe COVID-19. A nomogram was constructed with sufficient discriminatory power (C index = 0.81), and proper consistency between the prediction and observation, with an area under the ROC curve of 0.81 and 0.86 in the training and validation cohort, respectively.

CONCLUSION: We proposed a simple nomogram for early detection of patients with non-severe COVID-19 but at high risk of progression to severe COVID-19, which could help optimize clinical care and personalized decision-making therapies.

PMID:35607424 | PMC:PMC9123913 | DOI:10.2147/TCRM.S361936

Support Care Cancer. 2022 May 24. doi: 10.1007/s00520-022-07118-y. Online ahead of print.

ABSTRACT

PURPOSE: Cyclophosphamide is a commonly used cancer agent that is metabolically activated by polymorphic enzymes. This study aims to investigate the association between predicted activity of candidate pharmacogenes with severe toxicity during cyclophosphamide treatment.

METHODS: Genome-wide genetic data was collected from an institutional genetic data repository for CYP2B6, CYP3A4, CYP2C9, CYP2C19, GSTA1, GSTP1, ALDH1A1, ALDH3A1, ABCC1, ABCB1, and ERCC1. Treatment and toxicity data were retrospectively collected from the patient's medical record. The a priori selected primary hypothesis was that patients who have CYP2B6 reduced metabolizer activity (poor or intermediate (PM/IM) vs. normal (NM) metabolizer) have lower risk of severe toxicity or cyclophosphamide treatment modification due to toxicity.

RESULTS: In the primary analysis of 510 cyclophosphamide-treated patients with available genetic data, there was no difference in the odds of severe toxicity or treatment modification due to toxicity in CYP2B6 PM/IM vs. NM (odds ratio = 0.97, 95% Confidence Interval: 0.62-1.50, p = 0.88). In an exploratory, statistically uncorrected secondary analysis, carriers of the ALDH1A1 rs8187996 variant had a lower risk of the primary toxicity endpoint compared with wild-type homozygous patients (odds ratio = 0.31, 95% Confidence Interval: 0.09-0.78, p = 0.028). None of the other tested phenotypes or genotypes was associated with the primary or secondary endpoints in unadjusted analysis (all p > 0.05).

CONCLUSION: The finding that patients who carry ALDH1A1 rs8187996 may have a lower risk of cyclophosphamide toxicity than wild-type patients contradicts a prior finding for this variant and should be viewed with skepticism. We found weak evidence that any of these candidate pharmacogenetic predictors of cyclophosphamide toxicity may be useful to personalize cyclophosphamide dosing to optimize therapeutic outcomes in patients with cancer.

PMID:35606478 | DOI:10.1007/s00520-022-07118-y

Commun Med (Lond). 2021 Nov 9;1:45. doi: 10.1038/s43856-021-00046-8. eCollection 2021.

ABSTRACT

BACKGROUND: Major depression is one of the most disabling health conditions internationally. In recent years, new generation antidepressant medicines have become very widely prescribed. While these medicines are efficacious, side effects are common and frequently result in discontinuation of treatment. Compared with specific pharmacological properties of the different medications, the relevance of individual vulnerability is understudied.

METHODS: We used data from the Australian Genetics of Depression Study to gain insights into the aetiology and genetic risk factors to antidepressant side effects. To this end, we employed structural equation modelling, polygenic risk scoring and regressions.

RESULTS: Here we show that participants reporting a specific side effect for one antidepressant are more likely to report the same side effect for other antidepressants, suggesting the presence of shared individual or pharmacological factors. Polygenic risk scores (PRS) for depression associated with side effects that overlapped with depressive symptoms, including suicidality and anxiety. Body Mass Index PRS are strongly associated with weight gain from all medications. PRS for headaches are associated with headaches from sertraline. Insomnia PRS show some evidence of predicting insomnia from amitriptyline and escitalopram.

CONCLUSIONS: Our results suggest a set of common factors underlying the risk for antidepressant side effects. These factors seem to be partly explained by genetic liability related to depression severity and the nature of the side effect. Future studies on the genetic aetiology of side effects will enable insights into their underlying mechanisms and the possibility of risk stratification and prophylaxis strategies.

PMID:35602235 | PMC:PMC9053224 | DOI:10.1038/s43856-021-00046-8

Front Pediatr. 2022 May 6;10:881612. doi: 10.3389/fped.2022.881612. eCollection 2022.

ABSTRACT

INTRODUCTION: EBV associated lymphoproliferative disorders (EBV LPD) are a known complication following solid organ or hematopoietic stem cell transplantation. The disturbance of the immune system leads to a lack of control of latent EBV-infected B-cells, as control by T-cells is mandatory to prevent uninhibited cell proliferation. EBV LPD in other settings is less frequent and etiology and pathogenesis are not completely understood.

CASE PRESENTATION: We present the case of an 18-year old adolescent suffering from lymphoblastic T-cell lymphoma who developed a life-threatening EBV associated B-cell lymphoma while he was under therapy with 6-MP (6- mercaptopurine). An underlying homozygous TPMT (thiopurine S-methyltransferase) deficiency with subsequent insufficient degradation of 6-MP was identified as contributory for the development of a distinct lymphopenia leading to EBV LPD. The patient was successfully treated by discontinuation of 6-MP and initiating rituximab monotherapy.

DISCUSSION: Rare cases of EBV LPD during therapy with 6-MP are reported in patients with leukemia, but no data about TPMT pharmacogenomics are available. In contrast the disease development in the presented case may be explained by the iatrogenic immunosuppression in the context of TPMT deficiency. While using 6-MP testing of genetic variations is not required for every protocol, although the use of thiopurines in patients with TPMT deficiency can cause severe immunosuppression. Our case suggests that insufficient degradation of 6-MP can have significant consequences despite dose reduction.

CONCLUSION: When using thiopurines, TPMT genetics should be initiated and strict drug monitoring and dose adjusting must be performed by a specialized center.

PMID:35601437 | PMC:PMC9120811 | DOI:10.3389/fped.2022.881612

Front Neurosci. 2022 May 5;16:858049. doi: 10.3389/fnins.2022.858049. eCollection 2022.

ABSTRACT

Persons with type 2 diabetes born in the regions of famine exposures have disproportionally elevated risk of vision-threatening proliferative diabetic retinopathy (PDR) in adulthood. However, the underlying mechanisms are not known. In the present study, we aimed to investigate the plausible molecular factors underlying progression to PDR. To study the association of genetic variants with PDR under the intrauterine famine exposure, we analyzed single nucleotide polymorphisms (SNPs) that were previously reported to be associated with type 2 diabetes, glucose, and pharmacogenetics. Analyses were performed in the population from northern Ukraine with a history of exposure to the Great Ukrainian Holodomor famine [the Diagnostic Optimization and Treatment of Diabetes and its Complications in the Chernihiv Region (DOLCE study), n = 3,583]. A validation of the top genetic findings was performed in the Hong Kong diabetes registry (HKDR, n = 730) with a history of famine as a consequence of the Japanese invasion during WWII. In DOLCE, the genetic risk for PDR was elevated for the variants in ADRA2A, PCSK9, and CYP2C19*2 loci, but reduced at PROX1 locus. The association of ADRA2A loci with the risk of advanced diabetic retinopathy in famine-exposed group was further replicated in HKDR. The exposure of embryonic retinal cells to starvation for glucose, mimicking the perinatal exposure to famine, resulted in sustained increased expression of Adra2a and Pcsk9, but decreased Prox1. The exposure to starvation exhibited a lasting inhibitory effects on neurite outgrowth, as determined by neurite length. In conclusion, a consistent genetic findings on the famine-linked risk of ADRA2A with PDR indicate that the nerves may likely to be responsible for communicating the effects of perinatal exposure to famine on the elevated risk of advanced stages of diabetic retinopathy in adults. These results suggest the possibility of utilizing neuroprotective drugs for the prevention and treatment of PDR.

PMID:35600617 | PMC:PMC9119187 | DOI:10.3389/fnins.2022.858049

Clin Transl Sci. 2022 May 22. doi: 10.1111/cts.13291. Online ahead of print.

ABSTRACT

Aggregated risk of carbamazepine (CBZ)-induced cutaneous adverse drug reactions (cADRs) with different HLA variants are unclear and limited in terms of the power of studies. This study aimed to assess the aggregated risk of CBZ-induced cADRs associated with carrying the following HLA variants: HLA-B*15:02, HLA-B*15:11, HLA-B*15:21, HLA-B*38:02, HLA-B*40:01, HLA-B*46:01, HLA-B*58:01, HLA-A*24:02, and HLA-A*31:01. Literature was searched in different databases following PRISMA guidelines. The outcomes were measured as odds ratio (OR) using RevMan software by a random/fixed effects model, where p < 0.05 was set as statistical significance. In total, 46 case-control studies met the inclusion criteria and were included in this analysis consisting of 1817 cases and 6614 controls. It was found that case-patients who carried the HLA-B*15:02 allele were associated with a significantly increased risk of CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) compared to controls (OR 26.01; 95% CI 15.88-42.60; p < 0.00001). The aggregated risk of cADRs was slightly higher in Asian compared to Caucasian patients (Asians: OR 14.84; 95% CI 8.95-24.61; p < 0.00001; Caucasians: OR 11.65; 95% CI 1.68-80.70; p = 0.01). Further, HLA-B*15:11, HLA-B*15:21, or HLA-A*31:01 allele was also associated with significantly increased risk of CBZ-induced cADRs (HLA-B*15:11: OR 6.08; 95% CI 2.28-16.23; p = 0.0003; HLA-B*15:21: OR 5.37; 95% CI 2.02-14.28; p = 0.0008; HLA-A*31:01: OR 5.92; 95% CI 4.35-8.05; p < 0.00001). Other HLA variants were not found to have any significant associations with CBZ-induced cADRs. Strong associations between the HLA-B*15:02, HLA-B*15:11, HLA-B*15:21, or HLA-A*31:01 allele with CBZ-induced cADRs have been established in this analysis. Pharmacogenetic testing of particular HLA alleles before initiation of CBZ therapy may be beneficial to patients and may help to eradicate cADRs substantially.

PMID:35599240 | DOI:10.1111/cts.13291

Metabolism. 2022 May 18:155219. doi: 10.1016/j.metabol.2022.155219. Online ahead of print.

NO ABSTRACT

PMID:35597274 | DOI:10.1016/j.metabol.2022.155219

ESMO Open. 2022 May 18;7(3):100459. doi: 10.1016/j.esmoop.2022.100459. Online ahead of print.

ABSTRACT

Constitutional BRCA1/BRCA2 pathogenic or likely pathogenic variants (PVs) are associated with an increased risk for developing breast and ovarian cancers. Current evidence indicates that BRCA1/2 PVs are also associated with pancreatic cancer, and that BRCA2 PVs are associated with prostate cancer risk. The identification of carriers of constitutional PVs in the BRCA1/2 genes allows the implementation of individual and family prevention pathways, through validated screening programs and risk-reducing strategies. According to the relevant and increasing therapeutic predictive implications, the inclusion of BRCA testing in the routine management of patients with breast, ovarian, pancreatic and prostate cancers represent a key requirement to optimize medical or surgical therapeutic and prevention decision-making, and access to specific anticancer therapies. Therefore, accurate patient selection, the use of standardized and harmonized procedures, and adherence to homogeneous testing criteria, are essential elements to implement BRCA testing in clinical practice. This consensus position paper has been developed and approved by a multidisciplinary Expert Panel of 64 professionals on behalf of the AIOM-AIRO-AISP-ANISC-AURO-Fondazione AIOM-SIAPEC/IAP-SIBioC-SICO-SIF-SIGE-SIGU-SIU-SIURO-UROP Italian Scientific Societies, and a patient association (aBRCAdaBRA Onlus). The working group included medical, surgical and radiation oncologists, medical and molecular geneticists, clinical molecular biologists, surgical and molecular pathologists, organ specialists such as gynecologists, gastroenterologists and urologists, and pharmacologists. The manuscript is based on the expert consensus and reports the best available evidence, according to the current eligibility criteria for BRCA testing and counseling, it also harmonizes with current Italian National Guidelines and Clinical Recommendations.

PMID:35597177 | DOI:10.1016/j.esmoop.2022.100459

Gastroenterol Clin North Am. 2022 Jun;51(2):299-317. doi: 10.1016/j.gtc.2021.12.007. Epub 2022 Apr 27.

ABSTRACT

Reactive therapeutic drug monitoring (TDM) is considered the standard of care for optimizing biologics in inflammatory bowel disease (IBD) including Crohn's disease (CD). Preliminary data show that proactive TDM is associated with positive outcomes in IBD and can be also used to efficiently guide therapeutic decisions in specific clinical scenarios. Higher biological drug concentrations are associated with favorable therapeutic outcomes in specific IBD populations or phenotypes including pediatric CD, perianal fistulizing CD, small bowel CD, and following an ileocolonic resection for CD. Future perspectives of TDM include the use of rapid testing, pharmacogenomics, and pharmacokinetic dashboards toward individualized therapy.

PMID:35595416 | DOI:10.1016/j.gtc.2021.12.007

Neurologia (Engl Ed). 2022 May;37(4):287-303. doi: 10.1016/j.nrleng.2018.03.022. Epub 2020 Jun 1.

ABSTRACT

INTRODUCTION: Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response.

DEVELOPMENT: We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial.

CONCLUSIONS: Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as ageing.

PMID:35595404 | DOI:10.1016/j.nrleng.2018.03.022

Zhonghua Liu Xing Bing Xue Za Zhi. 2022 May 10;43(5):747-754. doi: 10.3760/cma.j.cn112338-20210402-00276.

ABSTRACT

Pharmacogenetic studies are designed to investigate the associations between genetic variation and treatment response for a particular drug in terms of both efficacy and adverse events and have high sample size requirements. To improve the quality of pharmacogenetic studies and facilitate the Meta-analyses to investigate statistically significant associations, Strengthening the Reporting of Pharmacogenetic Studies (STROPS) guideline was developed in 2020 based on the Strengthening the Reporting of Genetic Association Studies (STREGA) statement. The objective of this article is to present a brief introduction to the STROPS guideline and an interpretation of the key points in some items with examples for the better understanding and application.

PMID:35589583 | DOI:10.3760/cma.j.cn112338-20210402-00276

Pharmacogenomics J. 2022 May 19. doi: 10.1038/s41397-022-00280-w. Online ahead of print.

ABSTRACT

Beyond the identification of causal genetic variants in the diagnosis of Mendelian disorders, exome sequencing can detect numerous variants with potential relevance for clinical care. Clinical interventions can thus be conducted to improve future health outcomes for patients and their at-risk relatives, such as predicting late-onset genetic disorders accessible to prevention, treatment or identifying differential drug efficacy and safety. To evaluate the interest of such pharmacogenetic information, we designed an "in house" pipeline to determine the status of 122 PharmGKB (Pharmacogenomics Knowledgebase) variant-drug combinations in 31 genes. This pipeline was applied to a cohort of 90 epileptic patients who had previously an exome sequencing (ES) analysis, to determine the frequency of pharmacogenetic variants. We performed a retrospective analysis of drug plasma concentrations and treatment efficacy in patients bearing at least one relevant PharmGKB variant. For PharmGKB level 1A variants, CYP2C9 status for phenytoin prescription was the only relevant information. Nineteen patients were treated with phenytoin, among phenytoin-treated patients, none were poor metabolizers and four were intermediate metabolizers. While being treated with a standard protocol (10-23 mg/kg/30 min loading dose followed by 5 mg/kg/8 h maintenance dose), all identified intermediate metabolizers had toxic plasma concentrations (20 mg/L). In epileptic patients, pangenomic sequencing can provide information about common pharmacogenetic variants likely to be useful to guide therapeutic drug monitoring, and in the case of phenytoin, to prevent clinical toxicity caused by high plasma levels.

PMID:35590072 | DOI:10.1038/s41397-022-00280-w

Pharmgenomics Pers Med. 2022 May 9;15:465-475. doi: 10.2147/PGPM.S354011. eCollection 2022.

ABSTRACT

PURPOSE: Pharmacogenetic (PGx) panel testing could help to determine the heritable component of a rheumatoid arthritis (RA) patient's susceptibility for therapy failure and/or adverse drug reactions (ADRs) from methotrexate (MTX). Considering the literature mentioning the potential applicability of PGx panel testing within MTX regimens, we discuss the case of a patient who was treated with MTX, suffered from ADRs, and obtained a reactive PGx panel testing.

GENOTYPING: We used a commercial PGx panel test involving the ABC-transporters P-glycoprotein (P-gp; gene: ABCB1), and breast cancer resistance protein (BCRP; gene: ABCG2), the solute carriers reduced folate carrier 1 (RFC1; gene: SLC19A1), and organic anion transporting polypeptide 1B1 (OATP1B1; gene: SLCO1B1), and the enzymes inosine triphosphatase (ITPA), and glutathione transferase P1 (GSTP1). In addition, we genotyped the patient for the enzymes 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICAR)/inosine monophosphate (IMP) cyclohydrolase (gene name: ATIC), gamma-glutamyl hydrolase (gene name: GGH) and methylenetetrahydrofolate reductase (gene name: MTHFR).

RESULTS: The PGx profile of the patient revealed genetic variants in SLC19A1, ABCB1, and MTHFR, which may explain the ADRs experienced during the treatment with MTX and a potentially lower efficacy of MTX. Based on our interpretation of the PGx profile, we recommended the patient to avoid MTX in the future.

CONCLUSION: The MTX pathway is complex, which makes the interpretation of genetic variants affecting metabolism challenging. A reactive PGx panel test was applicable to explain ADRs experienced during MTX treatment for a patient with RA. However, the clinical utility of PGx-guided MTX treatment in a primary care setting is still limited. In order to base a recommendation for MTX on PGx data, we need genome-wide association studies, large prospective multicenter studies and PGx studies, which analyze different multi-gene haplotypes and gene-drug-drug interactions for MTX.

PMID:35586477 | PMC:PMC9109898 | DOI:10.2147/PGPM.S354011

BMC Bioinformatics. 2022 May 18;23(1):188. doi: 10.1186/s12859-022-04693-z.

ABSTRACT

BACKGROUND: Identifying associations among biological variables is a major challenge in modern quantitative biological research, particularly given the systemic and statistical noise endemic to biological systems. Drug sensitivity data has proven to be a particularly challenging field for identifying associations to inform patient treatment.

RESULTS: To address this, we introduce two semi-parametric variations on the commonly used concordance index: the robust concordance index and the kernelized concordance index (rCI, kCI), which incorporate measurements about the noise distribution from the data. We demonstrate that common statistical tests applied to the concordance index and its variations fail to control for false positives, and introduce efficient implementations to compute p-values using adaptive permutation testing. We then evaluate the statistical power of these coefficients under simulation and compare with Pearson and Spearman correlation coefficients. Finally, we evaluate the various statistics in matching drugs across pharmacogenomic datasets.

CONCLUSIONS: We observe that the rCI and kCI are better powered than the concordance index in simulation and show some improvement on real data. Surprisingly, we observe that the Pearson correlation was the most robust to measurement noise among the different metrics.

PMID:35585485 | DOI:10.1186/s12859-022-04693-z