Pharmacogenomics. 2023 Oct 17. doi: 10.2217/pgs-2023-0075. Online ahead of print.

ABSTRACT

Purpose: This work was designed to identify the pharmacogenetic profile of Brazilian psychiatric patients receiving psychoactive drug treatment according to ethnicity. Methods: Based on the GnTech® database, this cross-sectional study analyzed data from self-reported sociodemographic and genetic results from the next-generation sequencing panel composed of 26 pharmacogenes from 359 psychotropic drug users. Results: Variant frequencies of multiple pharmacogenes presented differences between ethnicities (CYP3A5, CYP2D6, CYP1A2, CYP2B6, CYP3A4, UGT1A4, UGT2B15, ABCB1 rs1045642, ADRA2A rs1800544, COMT rs4680, GRIK4 rs1954787, GSK3B rs334558, GSK3B rs6438552, HTR1A rs6295, HTR2A rs7997012, HTR2C rs1414334, MTHFR rs1801131, OPRM1 rs1799971 and 5-HTTLPR), endorsing the necessity of individual-level analyses in drug treatment. Conclusion: A discussion of pharmacogenomic test implementation in psychiatric clinical practice is needed to improve treatment choices, especially in Brazil, a multiethnic country.

PMID:37846556 | DOI:10.2217/pgs-2023-0075

Pharmacogenomics. 2023 Oct 17. doi: 10.2217/pgs-2023-0160. Online ahead of print.

NO ABSTRACT

PMID:37846553 | DOI:10.2217/pgs-2023-0160

Pharmacogenomics. 2023 Oct 17. doi: 10.2217/pgs-2023-0093. Online ahead of print.

ABSTRACT

Intravenous pentamidine is used for prophylaxis against Pneumocystis jirovecii pneumonia, an infection seen in hematopoietic stem cell transplant recipients. Pentamidine is partially metabolized by CYP2C19, which is vulnerable to pharmacogenetic variation. This retrospective study evaluated allogeneic hematopoietic stem cell transplant patients who received intravenous pentamidine as P. jirovecii pneumonia prophylaxis. The primary objective was the association between CYP2C19 phenotype and discontinuation of pentamidine due to drug-related side effects based on univariate logistic regression (N = 81). Ten patients (12.3%) discontinued pentamidine because of side effects. There was no difference in discontinuation between phenotype groups (p = 0.18) or discontinuation due to side effects (p = 0.76). Overall, no association was seen between phenotypes and pentamidine-related side effects (p = 0.475). Drug discontinuation rates and P. jirovecii pneumonia infection rates were low.

PMID:37846549 | DOI:10.2217/pgs-2023-0093

Pharmacogenomics. 2023 Oct 17. doi: 10.2217/pgs-2023-0124. Online ahead of print.

ABSTRACT

As substrates of CYP2C8, CYP3A4/5 and CYP2D6, chloroquine's (CQ) and hydroxychloroquine's (HCQ) efficacy and safety may be affected by variants in the genes encoding these enzymes. This paper aims to assimilate the current evidence on the pharmacogenomics of CQ/HCQ and to identify risk phenotypes affecting the safety or efficacy of these drugs. It has been found that some CYP3A5, CYP2D6 and CYP2C8 genetic variants may affect the safety or effectiveness of CQ/HCQ. The phenotypes predictively representing ultra-rapid and poor metabolizers have been considered high-risk phenotypes. After considering these high-risk phenotypes in different ethnic groups, it is predicted that a considerable proportion of patients taking CQ/HCQ may be at risk of either therapeutic failure or severe toxicities.

PMID:37846548 | DOI:10.2217/pgs-2023-0124

Br J Clin Pharmacol. 2023 Oct 16. doi: 10.1111/bcp.15930. Online ahead of print.

ABSTRACT

Artificial intelligence (AI) will impact many aspects of clinical pharmacology including drug discovery and development, clinical trials, personalised medicine, pharmacogenomics, pharmacovigilance and clinical toxicology. The rapid progress of AI in healthcare means clinical pharmacologists should have an understanding of AI and its implementation into clinical practice. As with any new therapy or health technology, it is imperative that AI tools are subject to robust and stringent evaluation to ensure that they enhance clinical practice in a safe and equitable manner. This review serves as an introduction to AI for the clinical pharmacologist, highlighting current applications, aspects of model development and issues surrounding evaluation and deployment. The aim of this article is to empower clinical pharmacologists to embrace and lead on the safe and effective use of AI within healthcare.

PMID:37845024 | DOI:10.1111/bcp.15930

Annu Rev Pharmacol Toxicol. 2023 Oct 10. doi: 10.1146/annurev-pharmtox-090123-010552. Online ahead of print.

ABSTRACT

The reviews in Volume 64 of the Annual Review of Pharmacology and Toxicology cover diverse topics. A common theme in many of the reviews is the interindividual variability in the clinical response to drugs. Highlighted areas include emerging developments in pharmacogenomics that can predict the personal risk for drug inefficacy and/or adverse drug reactions. Other reviews focus on the use of circulating biomarkers to define drug metabolism phenotypes and the effect of circadian regulation on drug response. Another emerging technology, digital twins that model individual patients, is used to generate computational simulations of drug effects and identify optimal personalized treatments. Another variable that may affect clinical outcomes, the nocebo response (an adverse reaction to a placebo), complicates clinical trials. These reviews further document that pharmacological individuality is an essential component of the concepts of personalized medicine and precision medicine and will likely have an important impact on patient care. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:37844323 | DOI:10.1146/annurev-pharmtox-090123-010552

Naunyn Schmiedebergs Arch Pharmacol. 2023 Oct 16. doi: 10.1007/s00210-023-02751-8. Online ahead of print.

ABSTRACT

We have shown that in murine cardiomyopathy caused by overexpression of the β1-adrenoceptor, Gαi2-deficiency is detrimental. Given the growing evidence for isoform-specific Gαi-functions, we now examined the consequences of Gαi3 deficiency in the same heart-failure model. Mice overexpressing cardiac β1-adrenoceptors with (β1-tg) or without Gαi3-expression (β1-tg/Gαi3-/-) were compared to C57BL/6 wildtypes and global Gαi3-knockouts (Gαi3-/-). The life span of β1-tg mice was significantly shortened but improved when Gαi3 was lacking (95% CI: 592-655 vs. 644-747 days). At 300 days of age, left-ventricular function and survival rate were similar in all groups. At 550 days of age, β1-tg but not β1-tg/Gαi3-/- mice displayed impaired ejection fraction (35 ± 18% vs. 52 ± 16%) compared to wildtype (59 ± 4%) and Gαi3-/- mice (60 ± 5%). Diastolic dysfunction of β1-tg mice was prevented by Gαi3 deficiency, too. The increase of ANP mRNA levels and ventricular fibrosis observed in β1-tg hearts was significantly attenuated in β1-tg/Gαi3-/- mice. Transcript levels of phospholamban, ryanodine receptor 2, and cardiac troponin I were similar in all groups. However, Western blots and phospho-proteomic analyses showed that in β1-tg, but not β1-tg/Gαi3-/- ventricles, phospholamban protein was reduced while its phosphorylation increased. Here, we show that in mice overexpressing the cardiac β1-adrenoceptor, Gαi3 deficiency slows or even prevents cardiomyopathy and increases shortened life span. Previously, we found Gαi2 deficiency to aggravate cardiac dysfunction and mortality in the same heart-failure model. Our findings indicate isoform-specific interventions into Gi-dependent signaling to be promising cardio-protective strategies.

PMID:37843590 | DOI:10.1007/s00210-023-02751-8

Curr Diabetes Rev. 2023 Oct 12. doi: 10.2174/0115733998254570230923171449. Online ahead of print.

ABSTRACT

This study analysed pharmacogenomics studies on sulfonylurea research publications using the Pubmed and Scopus databases. In the end, 65 publications from the years 2015 to 2021 were noticed. The objective of this study was to analyse these studies using scientometric tools, such as frequency counts, percentages, relative growth rates, doubling times, and collectively. A maximum of 19 (29.23%) research publications were contributed during the 2020 research period. The relative growth rate tends to decrease from 2015 to 2020 and the doubling time tends to increase and decrease after 2020. Up to 2 (3.08%) research publications were contributed by Ewan R. Pearson and Chen each. The top authors have an average degree of collaboration of 0.90 and 41 (63.83%) of their research publications are articles. The United States is the major contributor with 19 (29.23%) pharmacogenomics research publications on sulfonylureas. Although the United States is the most prolific country in sulfonylurea pharmacogenomics research, there are few Indian institutions that are not listed among the most prolific institutions.

PMID:37842897 | DOI:10.2174/0115733998254570230923171449

Emerg Microbes Infect. 2023 Oct 16:2270074. doi: 10.1080/22221751.2023.2270074. Online ahead of print.

ABSTRACT

Chikungunya virus is a re-emerging arbovirus that has caused epidemic outbreaks in recent decades. Patients in older age groups with high viral load and severe immunologic response during acute infection are likely to develop chronic arthritis and severe joint pain. Currently, no antiviral drug is available. Previous studies suggested that a flavone derivative, 8-bromobaicalein, was a potential dengue and Zika replication inhibitor in a cell-based system targeting flaviviral polymerase. Here we characterized that 8-bromobaicalein inhibited chikungunya virus replication with EC50 of 0.49 ± 0.11 µM in Vero cells. The molecular target predicted at viral nsP1 methyltransferase using molecular binding and fragment molecular orbital calculation. Additionally, oral administration of 250 mg/kg twice daily treatment alleviated chikungunya-induced musculoskeletal inflammation and reduced viral load in healthy adult mice. Pharmacokinetic analysis indicated that the 250 mg/kg administration maintained the compound level above EC99.9 for 12 h. Therefore, 8-bromobaicalein should be a potential candidate for further development as a pan-arboviral drug.

PMID:37842770 | DOI:10.1080/22221751.2023.2270074

EClinicalMedicine. 2023 Oct 5;64:102249. doi: 10.1016/j.eclinm.2023.102249. eCollection 2023 Oct.

ABSTRACT

BACKGROUND: Patients with inflammatory bowel disease (IBD) receiving anti-TNF and JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the Omicron BA.4/5 variant.

METHODS: In this multicentre cohort study, we prospectively recruited 340 adults (69 healthy controls and 271 IBD) at nine UK hospitals between May 28, 2021 and March 29, 2022. The IBD study population was established (>12 weeks therapy) on either thiopurine (n = 63), infliximab (n = 45), thiopurine and infliximab combination therapy (n = 48), ustekinumab (n = 45), vedolizumab (n = 46) or tofacitinib (n = 24). Patients were excluded if they were being treated with any other immunosuppressive therapies. Participants had two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccines, followed by a third dose of either BNT162b2 or mRNA1273. Pseudo-neutralisation assays against SARS-CoV-2 wild-type and BA.4/5 were performed. The half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARS-CoV-2 neutralising response against wild-type virus and Omicron BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, vaccine type, age, and interval between vaccination and blood collection. This study is registered with ISRCTN (No. 13495664).

FINDINGS: Both heterologous (first two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both wild-type SARS-CoV-2 virus and the Omicron BA.4/5 variant in healthy participants and patients with IBD. Antibody titres against BA.4/5 were significantly lower than antibodies against wild-type virus in both healthy participants and patients with IBD (p < 0.0001). Multivariable models demonstrated that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in patients with IBD on infliximab (Geometric Mean Ratio (GMR) 0.19 [0.10, 0.36], p < 0.0001), infliximab and thiopurine combination (GMR 0.25 [0.13, 0.49], p < 0.0001) or tofacitinib (GMR 0.43 [0.20, 0.91], p = 0.028), but not in patients on thiopurine monotherapy, ustekinumab, or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against wild-type (p = 0.037) and BA.4/5 (p = 0.045).

INTERPRETATION: A third dose of a COVID-19 mRNA vaccine based on the wild-type spike glycoprotein significantly boosts neutralising antibody titres in patients with IBD. However, responses are lower against the Omicron variant BA.4/5, particularly in patients taking anti-TNF and JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed patients with IBD may receive additional benefit from bivalent vaccine boosters which target Omicron variants.

FUNDING: Pfizer.

PMID:37842172 | PMC:PMC10570718 | DOI:10.1016/j.eclinm.2023.102249

Front Oncol. 2023 Sep 29;13:1238464. doi: 10.3389/fonc.2023.1238464. eCollection 2023.

ABSTRACT

BACKGROUND: Tumor invasion and metastasis are responsible for the majority of cancer-related deaths. The identification of molecules involved in these processes is crucial to design effective treatments that can halt the progression of cancer. To spread and metastasize, tumor cells must restructure their cytoskeleton and emit protrusions. A key molecule in this process of creating these invading structures is Fascin1, the main protein involved in the formation of actin cytoskeleton bundles and a consistent marker of bad prognosis in several types of cancer. Recent studies have shown that imipramine, an FDA- and EMA-approved antidepressant, can block Fascin1and prevent the formation of actin bundles, making it a promising candidate for the treatment of Fascin1-expressing cancers. As a result, a clinical trial will be conducted to assess the efficacy of imipramine being the first experimental clinical study selecting patients based on Fascin1 expression.

METHODS: The HITCLIF trial is a multicenter, double-blind, placebo-controlled, randomized and non-commercial phase II clinical trial conducted in parallel groups to evaluate the effectiveness of the tricyclic antidepressant imipramine as anti-invasive agent in the treatment of localized colon, rectal and triple negative breast cancer patients with overexpression of Fascin1. Eligible patients will be randomly assigned, in a 1:1 ratio, to receive imipramine or placebo. Patients will be stratified into 2 groups according to whether administration of imipramine is concomitant with neoadjuvant chemotherapy regimen. Group A will receive imipramine alone without neoadjuvant chemotherapy, while Group B will receive imipramine treatment along with the standard neoadjuvant chemotherapy regimen. The primary endpoint of the trial is the grade of alteration in the prognostic histopathological features at invasive margins (tumor budding, cytoplasmic pseudo-fragments, tumor growth pattern, and peritumoral lymphocytic infiltration).

DISCUSSION: Fascin1 is an interesting therapeutical target as it plays a causative role in the invasion and metastasis of cancer cells. Moreover, its expression is virtually absent in normal epithelia but highly expressed in cancer with bad prognosis. In silico, in vitro and in vivo studies by our group have demonstrated that the antidepressant imipramine has Fascin1-dependant anti-invasive and anti-metastatic effects in colorectal cancer cells. Now we are recruiting patients in a clinical trial based on Fascin1 over-expression in which administration of imipramine will be carried out during the period between the diagnosis biopsy and surgical resection to explore the drug effects on tumor invasive front.

CLINICAL TRIAL REGISTRATION: https:///www.clinicaltrialsregister.eu/ctr-search/trial/2021-001328-17/ES, identifier 2021-001328-17.

PMID:37841433 | PMC:PMC10570506 | DOI:10.3389/fonc.2023.1238464

Clin Exp Pharmacol Physiol. 2023 Oct 15. doi: 10.1111/1440-1681.13830. Online ahead of print.

ABSTRACT

Children, as a special group, have their own peculiarities in terms of individualized medication use compared to adults. Adverse drug reactions have been an important issue that needs to be addressed in the hope of safe medication use in children, and the occurrence of adverse drug reactions is partly due to genetic factors. Anti-infective drugs are widely used in children, and they have always been an important cause of the occurrence of adverse reactions in children. Pharmacogenomic technologies are becoming increasingly sophisticated, and there are now many guidelines describing the pharmacogenomics of anti-infective drugs. However, data from paediatric-based studies are scarce. This review provides a systematic review of the pharmacogenomics of anti-infective drugs recommended for gene-guided use in CPIC guidelines by exploring the relationship between pharmacogenetic frequencies and the incidence of adverse reactions, which will help inform future studies of individualized medication use in children.

PMID:37840030 | DOI:10.1111/1440-1681.13830

Biochem Pharmacol. 2023 Oct 13:115857. doi: 10.1016/j.bcp.2023.115857. Online ahead of print.

ABSTRACT

Ovarian cancer stands as the prevailing gynecologic malignancy, afflicting over 313,959 individuals annually worldwide, accompanied by more than 207,252 fatalities. Perturbations in calcium signaling contribute significantly to the pathogenesis of numerous cancers, including ovarian cancer, wherein alterations in calcium transporter expression have been reported. Overexpression of TRPM7, a prominent calcium transporter, has been linked to adverse prognostic outcomes in various cancer types. The focus of this comprehensive review centers around delineating the oncogenic role of TRPM7 in cancer development and exploring its therapeutic potential as a target in combating this disease. Notably, TRPM7 fosters cancer invasion, metastasis, and uncontrolled cell proliferation, thereby perpetuating the expansion and reinforcement of these malignant entities. Furthermore, this review takes ovarian cancer as an example and summarizes the "dual-mode" regulatory role of TRPM7 in cancer. Within the domain of ovarian cancer, TRPM7 assumes the role of a harsh tyrant, firmly controlling the calcium ion signaling pathway and metabolic reprogramming pathways.

PMID:37839677 | DOI:10.1016/j.bcp.2023.115857

Epigenetics. 2023 Dec;18(1):2268814. doi: 10.1080/15592294.2023.2268814. Epub 2023 Oct 15.

ABSTRACT

Asparaginase is an important agent for the treatment of acute lymphoblastic leukaemia (ALL), but it is occasionally associated with severe adverse events. Thus, for safer and more efficacious therapy, a clinical biomarker predicting asparaginase sensitivity is highly anticipated. Asparaginase depletes serum asparagine by deaminating asparagine into aspartic acid, and ALL cells are thought to be sensitive to asparaginase due to reduced asparagine synthetase (ASNS) activity. We have recently shown that allele-specific methylation of the ASNS gene is highly involved in asparaginase sensitivity in B-precursor ALL (BCP-ALL) by using next-generation sequence (NGS) analysis of bisulphite PCR products of the genomic DNA. Here, we sought to confirm the utility of methylation status of the ASNS gene evaluated with high-performance liquid chromatography (HPLC) analysis of bisulphite PCR products for future clinical applications. In the global methylation status of 23 CpG sites at the boundary region of promoter and exon 1 of the ASNS gene, a strong positive correlation was confirmed between the mean percent methylation evaluated with the HPLC method and that with the NGS method in 79 BCP-ALL cell lines (R2 = 0.85, p = 1.3 × 10-33) and in 63 BCP-ALL clinical samples (R2 = 0.84, p = 5.0 × 10-26). Moreover, methylation status of the ASNS gene evaluated with the HPLC method was significantly associated with in vitro asparaginase sensitivities as well as gene and protein expression levels of ASNS. These observations indicated that the ASNS gene methylation status evaluated with the HPLC method is a reliable biomarker for predicting the asparaginase sensitivity of BCP-ALL.

PMID:37839090 | DOI:10.1080/15592294.2023.2268814

Crit Care Nurs Clin North Am. 2023 Dec;35(4):425-451. doi: 10.1016/j.cnc.2023.07.001. Epub 2023 Aug 19.

ABSTRACT

Elderly critical care patients are one of the largest growing patient population groups according to Medicare data. More than 51% of elderly patients are discharged on inappropriate medications that have the potential to cause harm or interact adversely with other medications. Precision health has the potential to prevent adverse drug events and prescription of inappropriate medications. The purpose of this literature review was to define the concept of precision health and determine the state of science regarding interprofessional models of precision health for assessment of caregiver impact on polypharmacy in elderly intensive care unit patients.

PMID:37838417 | DOI:10.1016/j.cnc.2023.07.001

Am J Med Sci. 2023 Oct 12:S0002-9629(23)01375-7. doi: 10.1016/j.amjms.2023.10.004. Online ahead of print.

ABSTRACT

Adverse drug reactions can be either dose-dependent (Type A) or idiosyncratic (Type B). Type B adverse drug reactions tend to be extremely rare and difficult to predict. They are usually immune-mediated. Examples include severe skin reactions and drug-induced liver injury. For many commonly prescribed drugs (such as antibiotics), the risk of developing an idiosyncratic adverse drug reaction is influenced by variability in the human leukocyte antigen (HLA) genes. Because these HLA-mediated adverse drug reactions can be lethal, there is growing interest in defining which specific drug-gene relationships might benefit from pre-emptive HLA genotyping and automated clinical decision support. This review summarizes the literature for HLA-mediated adverse reactions linked to common drugs.

PMID:37838157 | DOI:10.1016/j.amjms.2023.10.004

J Pharm Biomed Anal. 2023 Oct 11;237:115786. doi: 10.1016/j.jpba.2023.115786. Online ahead of print.

ABSTRACT

Ginsenosides in Panax ginseng are regarded to be functional ingredients for diverse pharmacological effects and orally administrated with very low absorption in the gastrointestinal tract to be metabolized by gut microbiota. However, in vivo metabolic characteristics of ginsenosides mediated by gut microbiota are not well-known. This study aimed to explore the metabolic profiles of ginsenosides in rat feces mediated by gut microbiota. Ginsenosides and metabolites were identified and relatively quantified by ultra-performance liquid chromatography tandem/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS). As a result, eighty-four metabolites were identified in the normal control rat feces, while only thirty intermediates were found with very low yields in the pseudo-germ-free (GF) group. Similarly, the main bioconversion pathways of ginsenosides in vivo were the same deglycosylation reaction mediated by gut microbiota in vitro. The findings demonstrated significant differences in metabolic profiles between the normal control and pseudo-GF rats, which implied gut microbiota played an important role in the metabolism of ginsenosides.

PMID:37837893 | DOI:10.1016/j.jpba.2023.115786

Int J Mol Sci. 2023 Sep 30;24(19):14767. doi: 10.3390/ijms241914767.

ABSTRACT

Osteoarthritis is a multifactorial joint disease characterized by degeneration, and aging stands as a significant risk factor. Autophagy, a crucial cellular homeostasis mechanism, is influenced by aging and closely linked to cartilage health. This correlation between autophagy, cell death, and OA underscores its relevance in disease progression. MicroRNAs have emerged as autophagy regulators, with miRNA-based interventions showing promise in preclinical models. Remarkably, the ethanolic extract of propolis exhibits positive effects on autophagy-related proteins and healthy cartilage markers in an in vitro osteoarthritis model. The aim of this brief report was to evaluate through in silico analysis and postulate five microRNAs that could regulate autophagy proteins (AKT1, ATG5, and LC3) and assess whether the ethanolic extract of propolis could regulate the expression of these microRNAs. Among the examined miRNAs (miR-19a, miR-125b, miR-181a, miR-185, and miR-335), the ethanolic extract of propolis induced significant changes in four of them. Specifically, miR-125b responded to EEP by counteracting IL-1β-induced effects, while miR-181a, miR-185, and miR-335 exhibited distinct patterns of expression under EEP treatment. These findings unveil a potential link between miRNAs, EEP, and autophagy modulation in OA, offering promising therapeutic insights. Nevertheless, further validation and clinical translation are warranted to substantiate these promising observations.

PMID:37834215 | DOI:10.3390/ijms241914767

J Med Econ. 2023 Oct 13:1-17. doi: 10.1080/13696998.2023.2270868. Online ahead of print.

ABSTRACT

Studies found a strong association between HLA-B*13:01 allele and co-trimoxazole-induced severe cutaneous adverse reactions (SCARs). Genetic screening before initiation of co-trimoxazole may decrease the incidence of co-trimoxazole-induced SCARs. This study aims to evaluate the cost-effectiveness of HLA-B*13:01 screening before co-trimoxazole initiation in HIV-infected patients in Thailand. A combination of a decision tree model and a Markov model was used to estimate lifetime costs and outcomes of two strategies including 1) HLA-B*13:01 screening before co-trimoxazole initiation and 2) usual practice from a societal perspective. Alternative drugs are not considered because dapsone (the second-line drug) also presents a genetic risk. Input parameters were obtained from literature, government documents, and part of the TREAT Asia HIV Observational Database (TAHOD). One-way sensitivity analyses and probabilistic analyses were performed to determine robustness of the findings. HLA-B*13:01 screening resulted in 0.0061 quality-adjusted life years (QALYs) loss with an additional cost of 370 THB ($11.84). At the cost-effectiveness threshold of 160,000 THB ($5,112.85), the probability of the genetic screening strategy being cost-effective is 9.54%. This analysis demonstrated that HLA-B*13:01 allele screening before initiation of co-trimoxazole among HIV-infected patients is unlikely to be cost-effective in Thailand. Our findings will help policymakers make an evidence-informed decision making.

PMID:37830976 | DOI:10.1080/13696998.2023.2270868

Pharmacogenet Genomics. 2023 Oct 13. doi: 10.1097/FPC.0000000000000510. Online ahead of print.

ABSTRACT

Extensive scientific evidence consistently demonstrates the clinical validity and utility of HLA-B*15:02 pre-screening in averting severe cutaneous adverse reactions (SCARs), namely Stevens-Johnson syndrome and toxic epidermal necrolysis, associated with carbamazepine or oxcarbazepine usage. Current practice guidelines and drug labeling actively advocate for pharmacogenetic pre-screening before initiating these antiepileptic drugs (AED), with particular emphasis on patients of Asian descent. However, there is a potential need to strengthen compliance with these recommendations. This retrospective study aimed to describe the pharmacogenetic pre-screening, documentation, and SCARs incidence for patients of Asian ancestry initiated on carbamazepine or oxcarbazepine at a large Northeastern USA healthcare system. Between 1 July 2016 and August 1, 2021, 27 patients with documented Asian heritage in the electronic health record (EHR) were included. The overall rate of HLA-B*15:02 pre-screening before carbamazepine or oxcarbazepine initiation was 4%. None who underwent pharmacogenetic pre-screening carried the associated HLA-B risk allele, and no SCARs were reported. Notably, pharmacogenetic results were not discretely entered into the EHR, and the results were only found as attached documents in the miscellaneous section of the EHR. There remains a significant opportunity for improving HLA-B*15:02 pre-screening for patients starting carbamazepine and oxcarbazepine to prevent SCARs in the USA.

PMID:37830946 | DOI:10.1097/FPC.0000000000000510