J Pers Med. 2022 Apr 1;12(4):557. doi: 10.3390/jpm12040557.

ABSTRACT

Precision medicine (PM), specifically genetic-based testing, is currently used in over 140,000 individual tests to inform the clinical management of disease. Though several databases (e.g., the NIH Genetic Testing Registry) demonstrate the availability of these sequencing-based tests, we do not currently understand the extent to which these tests are used. There exists a need to synthesize the body of real-world data (RWD) describing the use of sequencing-based tests to inform their appropriate use. To accomplish this, we performed a scoping review to examine what RWD sources have been used in studies of PM utilization between January 2015 and August 2021 to characterize the use of genome sequencing (GS), exome sequencing (ES), tumor sequencing (TS), next-generation sequencing-based panels (NGS), gene expression profiling (GEP), and pharmacogenomics (PGx) panels. We abstracted variables describing the use of these types of tests and performed a descriptive statistical analysis. We identified 440 articles in our search and included 72 articles in our study. Publications based on registry databases were the most common, followed by studies based on private insurer administrative claims. Slightly more than one-third (38%) used integrated datasets. Two thirds (67%) of the studies focused on the use of tests for oncological clinical applications. We summarize the RWD sources used in peer-reviewed literature on the use of PM. Our findings will help improve future study design by encouraging the use of centralized databases and registries to track the implementation and use of PM.

PMID:35455673 | DOI:10.3390/jpm12040557

J Pers Med. 2022 Mar 24;12(4):526. doi: 10.3390/jpm12040526.

ABSTRACT

Apixaban and rivaroxaban are the two most prescribed direct factor Xa inhibitors. With the increased use of DOACs in real-world settings, safety and efficacy concerns have emerged, particularly regarding their concomitant use with other drugs. Increasing evidence highlights drug-drug interactions with CYP3A/P-gp modulators leading to adverse events. However, current recommendations for dose adjustment do not consider CYP3A/P-gp genotype and phenotype. We aimed to determine their impact on apixaban and rivaroxaban blood exposure. Three-hundred hospitalized patients were included. CYP3A and P-gp phenotypic activities were assessed by the metabolic ratio of midazolam and AUC0-6h of fexofenadine, respectively. Relevant CYP3A and ABCB1 genetic polymorphisms were also tested. Capillary blood samples collected at four time-points after apixaban or rivaroxaban administration allowed the calculation of pharmacokinetic parameters. According to the developed multivariable linear regression models, P-gp activity (p < 0.001) and creatinine clearance (CrCl) (p = 0.01) significantly affected apixaban AUC0-6h. P-gp activity (p < 0.001) also significantly impacted rivaroxaban AUC0-6h. The phenotypic switch (from normal to poor metabolizer) of P-gp led to an increase of apixaban and rivaroxaban AUC0-6h by 16% and 25%, respectively, equivalent to a decrease of 38 mL/min in CrCl according to the apixaban model. CYP3A phenotype and tested SNPs of CYP3A/P-gp had no significant impact. In conclusion, P-gp phenotypic activity, rather than known CYP3A/P-gp polymorphisms, could be relevant for dose adjustment.

PMID:35455642 | DOI:10.3390/jpm12040526

J Pers Med. 2022 Mar 24;12(4):525. doi: 10.3390/jpm12040525.

ABSTRACT

BACKGROUND: The role of aberrant DNA methylation in allopurinol-induced severe cutaneous adverse reactions (SCARs) is incompletely understood. To fill the gap, we analyze the DNA methylation profiling in allopurinol-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) patients and identify the DNA methylation signature for predisposing allopurinol hypersensitivity.

METHODS: Genome-scale methylation analysis was conducted using the Illumina® HumanMethylation450 BeadChip. Weighted Gene Co-Expression Network Analysis (WGCNA) was utilized to analyze the data.

RESULTS: A total of 21,497 annotated promoter regions were analyzed. Ten modules were identified between allopurinol hypersensitivity and tolerance, with turquoise and yellow modules being the most significant correlation. ATG13, EPM2AIP1, and SRSF11 were the top three hub genes in the turquoise module. MIR412, MIR369, and MIR409 were the top three hub genes in the yellow module. Gene Ontology (GO) analysis revealed that the turquoise module was related to the metabolic process in intracellular organelles and the binding of various compounds, proteins, or nucleotides. The yellow module, however, was related to stimulus sensory perception in cytoskeletal elements and the activity of the receptor or transducer.

CONCLUSION: DNA methylation plays a vital role in allopurinol-induced SCARs. DNA methylation profiling of SJS/TEN is significantly related to autophagy and microRNAs (miRNAs).

PMID:35455641 | DOI:10.3390/jpm12040525

J Pers Med. 2022 Mar 22;12(4):513. doi: 10.3390/jpm12040513.

ABSTRACT

Despite the rich armamentarium of available drugs against different forms of cardiovascular disease (CVD), major challenges persist in their safe and effective use. These include high rates of adverse drug reactions, increased heterogeneity in patient responses, suboptimal drug efficacy, and in some cases limited compliance. Dietary elements (including food, beverages, and supplements) can modulate drug absorption, distribution, metabolism, excretion, and action, with significant implications for drug efficacy and safety. Genetic variation can further modulate the response to diet, to a drug, and to the interaction of the two. These interactions represent a largely unexplored territory that holds considerable promise in the field of personalized medicine in CVD. Herein, we highlight examples of clinically relevant drug-nutrient-genome interactions, map the challenges faced to date, and discuss their future perspectives in personalized cardiovascular healthcare in light of the rapid technological advances.

PMID:35455629 | DOI:10.3390/jpm12040513

Medicina (Kaunas). 2022 Mar 29;58(4):491. doi: 10.3390/medicina58040491.

ABSTRACT

The genetic basis of migraine is rather complex. The rs2651899 in the PR/SET domain 16 (PRDM16) gene, the rs10166942 near the transient receptor potential cation channel subfamily M member 8 (TRPM8) gene, and the rs11172113 in the LDL receptor-related protein 1 (LRP1) gene, have been associated with migraine in a genome-wide association study (GWAS). However, data from subsequent studies examining the role of these variants and their relationship with migraine remain inconclusive. The aim of the present study was to meta-analyze the published data assessing the role of these polymorphisms in migraine, migraine with aura (MA), and migraine without aura (MO). We performed a search in the PubMed, Scopus, Web of Science, and Public Health Genomics and Precision Health Knowledge Base (v7.7) databases. In total, eight, six, and six studies were included in the quantitative analysis, for the rs2651899, rs10166942, and rs11172113, respectively. Cochran's Q and I2 tests were used to calculate the heterogeneity. The random effects (RE) model was applied when high heterogeneity was observed; otherwise, the fixed effects (FE) model was applied. The odds ratios (ORs) and the respective 95% confidence intervals (CIs) were calculated to estimate the effect of each variant on migraine. Funnel plots were created to graphically assess publication bias. A significant association was revealed for the CC genotype of the rs2651899, with the overall migraine group (RE model OR: 1.32; 95% CI: 1.02-1.73; p-value = 0.04) and the MA subgroup (FE model OR: 1.40; 95% CI: 1.12-1.74; p-value = 0.003). The rs10166942 CT genotype was associated with increased migraine risk (FE model OR: 1.36; 95% CI: 1.18-1.57; p-value < 0.0001) and increased MO risk (FE model OR: 1.41; 95% CI: 1.17-1.69; p-value = 0.0003). No association was detected for the rs11172113. The rs2651899 and the rs10166942 have an effect on migraine. Larger studies are needed to dissect the role of these variants in migraine.

PMID:35454329 | DOI:10.3390/medicina58040491

Biomolecules. 2022 Mar 30;12(4):520. doi: 10.3390/biom12040520.

ABSTRACT

Finding, exploring and filtering frequent sentence-based associations between a disease and a biomedical entity, co-mentioned in disease-related PubMed literature, is a challenge, as the volume of publications increases. Darling is a web application, which utilizes Name Entity Recognition to identify human-related biomedical terms in PubMed articles, mentioned in OMIM, DisGeNET and Human Phenotype Ontology (HPO) disease records, and generates an interactive biomedical entity association network. Nodes in this network represent genes, proteins, chemicals, functions, tissues, diseases, environments and phenotypes. Users can search by identifiers, terms/entities or free text and explore the relevant abstracts in an annotated format.

PMID:35454109 | DOI:10.3390/biom12040520

Diagnostics (Basel). 2022 Apr 11;12(4):950. doi: 10.3390/diagnostics12040950.

ABSTRACT

Dengue is a viral infection caused by the dengue virus (DENV). Dengue infection is a self-limited acute febrile illness caused by four serotypes of DENV (DENV-1~4). Early recognition of high-risk patients would be helpful to reduce mortality rates and prevent severe dengue. Our study aimed to identify factors related to dengue hemorrhagic fever (DHF) based on admission-day data, and further to understand the distribution of biochemical laboratory data in dengue patients. This retrospective study was conducted in hospitals in Yogyakarta city, Indonesia, and involved febrile patients who were admitted to the hospital with a diagnosis of dengue during 2018 and 2020. Logistic regression models were used to identify variables related to DHF. In this study, 1087 patients were included as suspected dengue patients, among them 468 had dengue fever (DF) and 619 had DHF. Over half of the DHF patients were males (55.9%) with an average age of 17.9 years, and with a secondary infection (71.3%). By a multivariate analysis, on-admission laboratory data of thrombocytopenia and hemoglobin showed significant association with DHF. Furthermore, DHF patients had significantly prolonged hospitalizations compared to DF patients. In conclusion, on-admission platelet counts and hemoglobin laboratory data are useful as predictors of DHF especially for suspected dengue patients with the limitations of diagnostic tests.

PMID:35453998 | DOI:10.3390/diagnostics12040950

Biology (Basel). 2022 Mar 22;11(4):481. doi: 10.3390/biology11040481.

ABSTRACT

More women are diagnosed with breast cancer (BC) than any other type of cancer. Although large-scale efforts have completely redefined cancer, a cure remains unattainable. In that respect, new molecular functions of the cell should be investigated, such as post-transcriptional regulation. RNA-binding proteins (RBPs) are emerging as critical post-transcriptional modulators of tumorigenesis, but only a few have clear roles in BC. To recognize new putative breast cancer RNA-binding proteins, we performed integrated in silico analyses of all human RBPs (n = 1392) in three major cancer databases and identified five putative BC RBPs (PUF60, TFRC, KPNB1, NSF, and SF3A3), which showed robust oncogenic features related to their genomic alterations, immunohistochemical changes, high interconnectivity with cancer driver genes (CDGs), and tumor vulnerabilities. Interestingly, some of these RBPs have never been studied in BC, but their oncogenic functions have been described in other cancer types. Subsequent analyses revealed PUF60 and SF3A3 as central elements of a spliceosome-related cluster involving RBPs and CDGs. Further research should focus on the mechanisms by which these proteins could promote breast tumorigenesis, with the potential to reveal new therapeutic pathways along with novel drug-development strategies.

PMID:35453681 | DOI:10.3390/biology11040481

Biomedicines. 2022 Apr 13;10(4):896. doi: 10.3390/biomedicines10040896.

ABSTRACT

Background: Presurgical treatment with an α-adrenergic receptor blocker is recommended to antagonize the catecholamine-induced α-adrenergic receptor mediated vasoconstriction in patients with pheochromocytoma or sympathetic paraganglioma (PPGL). There is, however, a considerable interindividual variation in the dose-response relationship regarding the magnitude of blood pressure reduction or the occurrence of side effects. We hypothesized that genetically determined differences in α-adrenergic receptor activity contribute to this variability in dose-response relationship. Methods: Thirty-one single-nucleotide polymorphisms (SNPs) of the α1A, α1B, α1D adrenoreceptor (ADRA1A, ADRA1B, ADRA1D) and α2A, α2B adrenoreceptor (ADRA2A, ADRA2B) genes were genotyped in a group of 116 participants of the PRESCRIPT study. Haplotypes were constructed after determining linkage disequilibrium blocks. Results: The ADRA1B SNP rs10515807 and the ADRA2A SNPs rs553668/rs521674 were associated with higher dosages of α-adrenergic receptor blocker (p < 0.05) and with a higher occurrence of side effects (rs10515807) (p = 0.005). Similar associations were found for haplotype block 6, which is predominantly defined by rs10515807. Conclusions: This study suggests that genetic variability of α-adrenergic receptor genes might be associated with the clinically observed variation in beneficial and adverse therapeutic drug responses to α-adrenergic receptor blockers. Further studies in larger cohorts are needed to confirm our observations.

PMID:35453646 | DOI:10.3390/biomedicines10040896

J Mol Diagn. 2022 Apr 19:S1525-1578(22)00082-4. doi: 10.1016/j.jmoldx.2022.03.008. Online ahead of print.

ABSTRACT

Germline whole exome sequencing from molecular tumor boards has the potential to be repurposed to support clinical pharmacogenomics. However, accurately calling pharmacogenomics-relevant genotypes from exome sequencing data remains challenging. Accordingly, this study assessed the analytical validity of the computational tool, Aldy, in calling pharmacogenomics-relevant genotypes from exome sequencing data for 13 major pharmacogenes. Germline DNA from whole blood was obtained for 164 subjects seen at an institutional molecular solid tumor board. All subjects had whole exome sequencing from Ashion Analytics and panel-based genotyping from an institutional pharmacogenomics laboratory. Aldy v3.3 was operationalized on the LifeOmic Precision Health Cloud with copy number fixed to two copies per gene. Aldy results were compared to those from genotyping for 56 star-defining variants within CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP4F2, DPYD, G6PD, NUDT15, SLCO1B1, and TPMT. Read depth was >100x for all variants except CYP3A4*22. For 75 subjects in the validation cohort, all 3,393 Aldy variant calls were concordant with genotyping. Aldy calls for 736 diplotypes containing alleles assessed by both platforms were also concordant. Aldy identified additional star alleles not covered by targeted genotyping for 139 diplotypes. Aldy accurately called variants and diplotypes for 13 major pharmacogenes except for CYP2D6 variants involving copy number variations, thus allowing repurposing of whole exome sequencing to support clinical pharmacogenomics.

PMID:35452844 | DOI:10.1016/j.jmoldx.2022.03.008

Travel Med Infect Dis. 2022 Apr 19:102333. doi: 10.1016/j.tmaid.2022.102333. Online ahead of print.

ABSTRACT

OBJECTIVES: To elucidate the relationship between CYP2D6 polymorphisms and Plasmodium vivax recurrence in patients receiving primaquine-based treatment through systematic review and meta-analysis.

METHODS: We searched the PubMed, EMBASE, Cochrane Library, and Web of Science databases for eligible studies published up to August of 2021. We included studies investigating the associations between CYP2D6 polymorphisms and P. vivax recurrence. We evaluated the pooled odds ratio (OR) and 95% confidence interval (CI).

RESULTS: Data from nine studies, including 970 patients, were analyzed. We found that CYP2D6 poor metabolizers (PMs), intermediate metabolizers (IMs), or normal metabolizers slow (NM-Ss) were associated with a 1.8-fold (95% CI, 1.34-2.45; P = 0.0001) higher recurrence of P. vivax than normal metabolizers fast (NM-Fs), extensive metabolizers (EMs), or ultrarapid metabolizer (UMs). Subgroup analysis showed that studies on both Brazilian and Southeast or East Asian individuals had similar results to the main results. Sensitivity analysis by sequentially excluding individual studies also showed robust results (OR range: 1.63-2.01).

CONCLUSIONS: This meta-analysis confirmed that CYP2D6 PMs, IMs, or NM-Ss increased the risk of P. vivax recurrence compared to NM-Fs, EMs, or UMs. The results of this study could be used to predict P. vivax recurrence and suggest CYP2D6 genotype-based primaquine dosing.

PMID:35452835 | DOI:10.1016/j.tmaid.2022.102333

Clin Transl Med. 2022 Apr;12(4):e813. doi: 10.1002/ctm2.813.

NO ABSTRACT

PMID:35452191 | DOI:10.1002/ctm2.813

Neuropsychopharmacol Hung. 2022 Mar 1;24(1):17-28.

ABSTRACT

Prescribing antidepressant medication is currently the most effective way of treating major depression, but only very few patients achieve permanent improvement. Therefore, it is important to identify objectively measurable markers for effective, personalized therapy. The aim of this review article is to collect all the markers that are robustly predictive of the outcome of therapy. We searched for systematic review articles that have simultaneously investigated the effects of as many different markers as possible on the response to antidepressant therapy in major depressive patients. From these we extracted markers that have been found to be significant by at least two independent review studies and that have proven replicable also within each of these reviews. A separate search was performed for meta-analyses of pharmacogenetic genome-wide association studies. Based on our results, onset time, symptom severity, presence of anhedonia, early treatment response, comorbid anxiety, alcohol consumption, frontal EEG theta activity, hippocampal volume, activity of anterior cingulate cortex, as well as a peripheral marker, serum BDNF levels have proven replicable predictors of antidepressant response. Pharmacogenomic studies to date have not yielded replicable results. Predictors identified as robust by our study may provide a starting point for future machine learning models within a 'big data' database of major depressive patients. (Neuropsychopharmacol Hung 2022; 24(1): 17-28).

PMID:35451589

Front Pharmacol. 2022 Apr 5;13:866903. doi: 10.3389/fphar.2022.866903. eCollection 2022.

ABSTRACT

Background: The HLA-B is the most polymorphic gene, play a crucial role in drug-induced hypersensitivity reactions. There is a lot of evidence associating several risk alleles to life-threatening adverse drug reactions, and a few of them have been approved as valid biomarkers for predicting life-threatening hypersensitivity reactions. Objectives: The objective of this present study is to present the progression of HLA-B pharmacogenomics (PGx) testing in the Thai population during a 10-year period, from 2011 to 2020. Methods: This was a retrospective observational cohort study conducted at the Faculty of Medicine Ramathibodi Hospital. Overall, 13,985 eligible patients who were tested for HLA-B risk alleles between periods of 2011-2020 at the study site were included in this study. Results: The HLA PGx testing has been increasing year by year tremendously, 94 HLA-B testing was done in 2011; this has been raised to 2,880 in 2020. Carbamazepine (n = 4,069, 33%), allopurinol (n = 4,675, 38%), and abacavir (n = 3,246, 26%) were the most common drugs for which the HLA-B genotyping was performed. HLA-B*13:01, HLA-B*15:02 and HLA-B*58:01 are highly frequent, HLA-B*51:01 and HLA-B*57:01 are moderately frequent alleles that are being associated with drug induced hypersensitivity. HLA-B*59:01 and HLA-B*38:01 theses alleles are rare but has been reported with drug induced toxicity. Most of the samples were from state hospital (50%), 36% from private clinical laboratories and 14% from private hospitals. Conclusion: According to this study, HLA-B PGx testing is increasing substantially in Thailand year after year. The advancement of research in this field, increased physician awareness of PGx, and government and insurance scheme reimbursement assistance could all be factors. Incorporating PGx data, along with other clinical and non-clinical data, into clinical decision support systems (CDS) and national formularies, on the other hand, would assist prescribers in prioritizing therapy for their patients. This will also aid in the prediction and prevention of serious adverse drug reactions.

PMID:35450046 | PMC:PMC9016335 | DOI:10.3389/fphar.2022.866903

Pharmacogenomics J. 2022 Apr 21. doi: 10.1038/s41397-022-00278-4. Online ahead of print.

ABSTRACT

Loss-of-function CYP2C19 variants are associated with increased cumulative ischemic outcomes warranting CYP2C19 genotyping prior to clopidogrel administration. TAILOR-PCI was an international, multicenter (40 sites), prospective, randomized trial comparing rapid point of care (POC) genotype-guided vs. conventional anti-platelet therapy. The performance of buccal-based rapid CYP2C19 genotyping performed by non-laboratory-trained staff in TAILOR-PCI was assessed. Pre-trial training and evaluation involved rapid genotyping of 373 oral samples, with 99.5% (371/373) concordance with Sanger sequencing. During TAILOR-PCI, 5302 patients undergoing PCI were randomized to POC rapid CYP2C19 *2, *3, and *17 genotyping versus no genotyping. At 12 months post-PCI, TaqMan genotyping determined 99.1% (2,364/2,385) concordance with the POC results, with 90.7-98.8% sensitivity and 99.2-99.6% specificity. In conclusion, non-laboratory personnel can be successfully trained for on-site instrument operation and POC rapid genotyping with analytical accuracy and precision across multiple international centers, thereby supporting POC genotyping in patient-care settings, such as the cardiac catheterization laboratory.Clinical Trial Registration: https://www.clinicalTrials.gov (Identifier: NCT01742117).

PMID:35449399 | DOI:10.1038/s41397-022-00278-4

Sci Rep. 2022 Apr 21;12(1):6548. doi: 10.1038/s41598-022-10311-y.

ABSTRACT

Long-term treatment of cancer with chemotherapeutics leads to the development of resistant forms that reduce treatment options. The main associated mechanism is the overexpression of transport proteins, particularly P-glycoprotein (P-gp, ABCB1). In this study, we have tested the anticancer and multidrug resistance (MDR) modulation activity of 15 selenocompounds. Out of the tested compounds, K3, K4, and K7 achieved the highest sensitization rate in ovarian carcinoma cells (HOC/ADR) that are resistant to the action of the Adriamycin. These compounds induced oxidation stress, inhibited P-gp transport activity and altered ABC gene expression. To verify the effect of compounds, 3D cell models were used to better mimic in vivo conditions. K4 and K7 triggered the most significant ROS release. All selected selenoesters inhibited P-gp efflux in a dose-dependent manner while simultaneously altering the expression of the ABC genes, especially P-gp in paclitaxel-resistant breast carcinoma cells (MCF-7/PAX). K4, and K7 demonstrated sensitization potential in resistant ovarian spheroids. Additionally, all selected selenoesters achieved a high cytotoxic effect in 3D breast and ovarian models, which was comparable to that in 2D cultures. K7 was the only non-competitive P-gp inhibitor, and therefore appears to have considerable potential for the treatment of drug-resistant cancer.

PMID:35449387 | DOI:10.1038/s41598-022-10311-y

Toxics. 2022 Mar 22;10(4):151. doi: 10.3390/toxics10040151.

ABSTRACT

The effectiveness of thiopurine drugs in inflammatory bowel disease (IBD) was confirmed more than a half-century ago. It was proven that these can be essential immunomodulatory medications. Since then, they have been used routinely to maintain remission of Crohn's disease (CD) and ulcerative colitis (UC). The cytotoxic properties of thiopurines and the numerous adverse effects of the treatment are controversial. However, the research subject of their pharmacology, therapy monitoring, and the search for predictive markers are still very relevant. In this article, we provide an overview of the current knowledge and findings in the field of thiopurines in IBD, focusing on the aspect of their cytotoxicity. Due to thiopurines' benefits in IBD therapy, it is expected that they will still constitute an essential part of the CD and UC treatment algorithm. More studies are still required on the modulation of the action of thiopurines in combination therapy and their interaction with the gut microbiota.

PMID:35448412 | DOI:10.3390/toxics10040151

Bioengineering (Basel). 2022 Mar 25;9(4):137. doi: 10.3390/bioengineering9040137.

ABSTRACT

BACKGROUND: Degenerative disc disease is a progressive and chronic disorder with many open questions regarding its pathomorphological mechanisms. In related studies, in vitro organ culture systems are becoming increasingly essential as a replacement option for laboratory animals. Live disc cells are highly appealing to study the possible mechanisms of intervertebral disc (IVD) degeneration. To study the degenerative processes of the endplate chondrocytes in vitro, we established a relatively quick and easy protocol for isolating human chondrocytes from the vertebral endplates.

METHODS: The fragments of human lumbar endplates following lumbar fusion were collected, cut, ground and partially digested with collagenase I in Advanced DMEM/F12 with 5% foetal bovine serum. The sediment was harvested, and cells were seeded in suspension, supplemented with special media containing high nutrient levels. Morphology was determined with phalloidin staining and the characterisation for collagen I, collagen II and aggrecan with immunostaining.

RESULTS: The isolated cells retained viability in appropriate laboratory conditions and proliferated quickly. The confluent culture was obtained after 14 days. Six to 8 h after seeding, attachments were observed, and proliferation of the isolated cells followed after 12 h. The cartilaginous endplate chondrocytes were stable with a viability of up to 95%. Pheno- and geno-typic analysis showed chondrocyte-specific expression, which decreased with passages.

CONCLUSIONS: The reported cell isolation process is simple, economical and quick, allowing establishment of a viable long-term cell culture. The availability of a vertebral endplate cell model will permit the study of cell properties, biochemical aspects, the potential of therapeutic candidates for the treatment of disc degeneration, and toxicology studies in a well-controlled environment.

PMID:35447697 | DOI:10.3390/bioengineering9040137

Xenobiotica. 2022 Apr 21:1-22. doi: 10.1080/00498254.2022.2069060. Online ahead of print.

ABSTRACT

1. This study aimed to identify physiological and pharmacogenomic covariates and develop a population pharmacokinetic model of high-dose methotrexate (HD-MTX) in Chinese pediatric patients with acute lymphoblastic leukemia (ALL) and malignant lymphoma.2. A total 731 MTX courses and 1658 MTX plasm concentration from 205 pediatric patients with ALL and malignant lymphoma were analyzing using a nonlinear mixed-effects model technique. 47 SNPs in 16 MTX-related gene were genotyped and screened as covariates. A PPK model was established to determine the influence of covariates such as body surface area (BSA), age, laboratory test value, and SNPs on the pharmacokinetic process of HD-MTX.3. Two-compartmental model with allometric scaling using BSA could nicely characterize the in vivo behavior of HD-MTX. After accounting for body size, rs17004785 and rs4148416 were the covariates that influence MTX clearance (CL). The PPK model obtained was: CL =9.33 * (BSA/1.73) 0.75 * e0.13*rs17004785 * e0.39*rs4148416 * eηCL, Vc =24.98 * (BSA/1.73) * eηvc, Q = 0.18 * (BSA/1.73) 0.75 * eηQ and Vp =4.70 * (BSA/1.73) * eηvp.4. The established model combined with Bayesian approach could estimate individual pharmacokinetic parameters and optimize personalized HD-MTX therapy for pediatric patients with ALL and malignant lymphoma.

PMID:35446233 | DOI:10.1080/00498254.2022.2069060

Front Pharmacol. 2022 Apr 4;13:866058. doi: 10.3389/fphar.2022.866058. eCollection 2022.

ABSTRACT

Warfarin has remained the most commonly prescribed vitamin K oral anticoagulant worldwide since its approval in 1954. Dosing challenges including having a narrow therapeutic window and a wide interpatient variability in dosing requirements have contributed to making it the most studied drug in terms of genotype-phenotype relationships. However, most of these studies have been conducted in Whites or Asians which means the current pharmacogenomics evidence-base does not reflect ethnic diversity. Due to differences in minor allele frequencies of key genetic variants, studies conducted in Whites/Asians may not be applicable to underrepresented populations such as Blacks, Hispanics/Latinos, American Indians/Alaska Natives and Native Hawaiians/other Pacific Islanders. This may exacerbate health inequalities when Whites/Asians have better anticoagulation profiles due to the existence of validated pharmacogenomic dosing algorithms which fail to perform similarly in the underrepresented populations. To examine the extent to which individual races/ethnicities are represented in the existing body of pharmacogenomic evidence, we review evidence pertaining to published pharmacogenomic dosing algorithms, including clinical utility studies, cost-effectiveness studies and clinical implementation guidelines that have been published in the warfarin field.

PMID:35444556 | PMC:PMC9014219 | DOI:10.3389/fphar.2022.866058