J Am Pharm Assoc (2003). 2023 Nov-Dec;63(6):1678. doi: 10.1016/j.japh.2023.07.003.

NO ABSTRACT

PMID:37979996 | DOI:10.1016/j.japh.2023.07.003

Ann Rheum Dis. 2023 Nov 18:ard-2023-224540. doi: 10.1136/ard-2023-224540. Online ahead of print.

ABSTRACT

OBJECTIVE: Genome-wide association studies have successfully identified more than 100 loci associated with susceptibility to rheumatoid arthritis (RA). However, our understanding of the functional effects of genetic variants in causing RA and their effects on disease severity and response to treatment remains limited.

METHODS: In this study, we conducted expression quantitative trait locus (eQTL) analysis to dissect the link between genetic variants and gene expression comparing the disease tissue against blood using RNA-Sequencing of synovial biopsies (n=85) and blood samples (n=51) from treatment-naïve patients with RA from the Pathobiology of Early Arthritis Cohort.

RESULTS: This identified 898 eQTL genes in synovium and genes loci in blood, with 232 genes in common to both synovium and blood, although notably many eQTL were tissue specific. Examining the HLA region, we uncovered a specific eQTL at HLA-DPB2 with the critical triad of single-nucleotide polymorphisms (SNPs) rs3128921 driving synovial HLA-DPB2 expression, and both rs3128921 and HLA-DPB2 gene expression correlating with clinical severity and increasing probability of the lympho-myeloid pathotype.

CONCLUSIONS: This analysis highlights the need to explore functional consequences of genetic associations in disease tissue. HLA-DPB2 SNP rs3128921 could potentially be used to stratify patients to more aggressive treatment immediately at diagnosis.

PMID:37979960 | DOI:10.1136/ard-2023-224540

Clin Exp Med. 2023 Nov 18. doi: 10.1007/s10238-023-01244-5. Online ahead of print.

ABSTRACT

A panel of chronic lymphocytic leukemia (CLL) experts from Tuscany propose a real-life diagnostic and therapeutic approach CLL that considers the role of genomic and somatic prognostic factors in risk stratification and treatment decisions. Safety and efficacy of new agents has been demonstrated now not only in clinical trials but also in many real-world series. The BTK inhibitors, ibrutinib and acalabrutinib, and BH3 mimetic venetoclax are now indicated as first-line therapy and chemoimmunotherapy can be spared to the majority of CLL patients, thus preventing unnecessary hematological and non-hematological toxicity and second primary tumors. For treatment, FISH for 17 p and P53 mutational status are essential. IGHV mutation can be done at diagnosis or before treatment. Echography is the gold standard radiological investigation in CLL, at both diagnosis and response evaluation. Chemotherapy is virtually abandoned. Age, genetic risk, and patient comorbidities have to be carefully evaluated for treatment decision. With the availability of different drugs, there is a need for a uniform and shared approach in daily therapeutic choice. The proposed approach is based on current evidence and guidelines as well as results from clinical trials and daily clinical experience.

PMID:37979127 | DOI:10.1007/s10238-023-01244-5

Clin Rheumatol. 2023 Nov 17. doi: 10.1007/s10067-023-06814-2. Online ahead of print.

ABSTRACT

OBJECTIVES: To identify biomarkers at the gene expression level to predict response to methotrexate (MTX) in patients with rheumatoid arthritis (RA).

METHODS: MTX-naïve patients with RA were started on MTX and followed up over three months. The disease activity score 28 (DAS28) was used to classify patients into responders and non-responders. Genome-wide gene expression analysis was performed in CD4 + and CD14 + mononuclear cells sampled from whole blood at baseline to identify differentially expressed genes in responders versus non-responders. Gene selection methods and prediction modelling obtained the most relevant differentially expressed genes. A logistic regression prediction model was subsequently constructed and validated via bootstrapping. The area under the receiver operating characteristic (AUC) curve was calculated to judge model quality.

RESULTS: Seventy-nine patients with RA (53.4 ± 13.9 years, 74.7% females) were enrolled, and 70 finished the study with a documented treatment EULAR response (77.1% responders). Forty-six differentially expressed genes were found. The most promising genes were KRTAP4-11, LOC101927584, and PECAM1 in CD4 + cells and PSMD5 and ID1 in CD14 + cells. The final prediction model using these genes reached an AUC of 90%; the validation set's AUC was 82%.

CONCLUSIONS: Our prediction model constructed via genome-wide gene expression analysis in CD4 + and CD14 + mononuclear cells yielded excellent predictions. Our findings necessitate confirmation in other cohorts of MTX-naïve RA patients. Especially if used in conjunction with previously identified clinical and laboratory (bio)markers, our results could help predict response to MTX in RA to guide treatment decisions. Key Points • Patients with rheumatoid arthritis may or may not respond to treatment with methotrexate, which is the recommended first-line drug in guidelines around the world. • In non-responders, valuable time is lost until second-line treatments are started. • This study aimed at predicting response to methotrexate by identifying differentially expressed genes from peripheral blood samples. • The final prediction model yielded excellent prognostic values, but validation in other cohorts is necessary to corroborate these findings.

PMID:37978145 | DOI:10.1007/s10067-023-06814-2

Int J Antimicrob Agents. 2023 Nov 15:107034. doi: 10.1016/j.ijantimicag.2023.107034. Online ahead of print.

ABSTRACT

BACKGROUND: Rifampicin exhibits high pharmacokinetic (PK) variability among individuals; a low plasma concentration might result in unfavorable treatment outcomes and drug resistance. This study evaluated the contributions of non- and genetic factors to the interindividual variability of RIF exposure, then suggested initial doses for patients with different weight bands.

METHODS: This multicenter prospective cohort study in Korea analyzed demographic and clinical data, the solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotypes, and rifampicin concentrations. Population PK modelling and simulations were conducted using nonlinear mixed-effect modelling.

RESULTS: In total, 879 tuberculosis (TB) patients were divided into a training dataset (510 patients) and a test dataset (359 patients). A one-compartment model with allometric scaling for effect of body size best described the RIF PKs. The apparent clearance (CL/F) was 16.6% higher among patients in the SLCO1B1 rs4149056 wild-type group than among patients in variant group, significantly decreasing RIF exposure in the wild-type group. The developed model showed better predictive performance compared with previously reported models. We also suggested that patients with body weights of < 40 kg, 40-55 kg, 55-70 kg, and > 70 kg patients receive rifampicin doses of 450, 600, 750, and 1050 mg/day, respectively.

CONCLUSIONS: Total body weight and SLCO1B1 rs4149056 genotypes were the most significant covariates that affected RIF CL/F variability in Korean TB patients. We suggest initial doses of RIF based on World Health Organization weight-band classifications. The model may be implemented in treatment monitoring for TB patients.

PMID:37977236 | DOI:10.1016/j.ijantimicag.2023.107034

J Pharm Biomed Anal. 2023 Nov 2;238:115839. doi: 10.1016/j.jpba.2023.115839. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: A high rate of interindividual variability in response to tamoxifen (TAM) in breast cancer patients with CYP2D6 polymorphism has been reported, which affects the patient's therapeutic outcome. The objective of this study was to investigate the pharmacogenomics of CYP2D6 genotyping in Iranian patients with breast cancer treated with adjuvant TAM.

METHODS: A peripheral blood sample was obtained to determine the steady-state plasma concentrations of TAM and its metabolites (Endoxifen (EN) and 4-Hydroxytamoxifen (4-OHT)) using high-performance liquid chromatography with fluorescence detection (HPLC-FLU) assay. We detected CYP2D6 * 3, * 4, * 10, and * 17 single nucleotide polymorphisms via polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method.

RESULTS: A total of 84 Iranian estrogen receptor‑positive breast cancer patients receiving the daily dose of 20 mg tamoxifen were recruited. Although a consequent decrease in the median EN and 4-OHT concentrations was observed by comparing poor or intermediate metabolizer patients with an extensive metabolizer population, this difference did not reach a significant level. The mean plasma EN concentrations in poor and intermediate metabolizers were 46.1% (95% CI, 7.4-27.8%) and 59.4% (95% CI, 11.9-37.3%) of extensive metabolizer subjects, respectively. Poor and intermediate metabolizers had the mean plasma 4-OHT concentrations that were 46.6% (95% CI, 0.9-61.7%) and 73.2% (95% CI, 2.7-93.1%) of those of subjects who were extensive metabolizer, respectively.

CONCLUSIONS: The possible role of genotyping in Iranian patients' response to treatment may explain inter-individual differences in the plasma concentrations of active metabolites of TAM.

PMID:37976989 | DOI:10.1016/j.jpba.2023.115839

Pharmacogenomics. 2023 Nov 17. doi: 10.2217/pgs-2023-0179. Online ahead of print.

ABSTRACT

Aim: To advance clinical adoption and implementation of pharmacogenomics (PGx) testing, barriers and facilitators to these efforts must be understood. This study identified and examined barriers and facilitators to active implementation of a PGx program across multiple clinic settings in an academic healthcare system. Materials & methods: 28 contributors to the PGx implementation (e.g., clinical providers, informatics specialists) completed an interview to elicit their perceptions of the implementation. Results: Qualitative analysis identified several barriers and facilitators that spanned different stages of the implementation process. Specifically, unclear test payment mechanisms, decision support tool development, rigid workflows and provider education were noted as barriers to the PGx implementation. A multidisciplinary implementation team and leadership support emerged as key facilitators. Furthermore, participants also suggested strategies to overcome or maintain these factors. Conclusion: Assessing real-world implementation perceptions and suggested strategies from a range of implementation contributors facilitates a more comprehensive framework and best-practice guidelines for PGx implementation.

PMID:37975236 | DOI:10.2217/pgs-2023-0179

Nat Commun. 2023 Nov 16;14(1):7421. doi: 10.1038/s41467-023-42997-7.

ABSTRACT

The gut microbiota may have an effect on the therapeutic resistance and toxicity of immune checkpoint inhibitors (ICIs). However, the associations between the highly variable genomes of gut bacteria and the effectiveness of ICIs remain unclear, despite the fact that merely a few gene mutations between similar bacterial strains may cause significant phenotypic variations. Here, using datasets from the gut microbiome of 996 patients from seven clinical trials, we systematically identify microbial genomic structural variants (SVs) using SGV-Finder. The associations between SVs and response, progression-free survival, overall survival, and immune-related adverse events are systematically explored by metagenome-wide association analysis and replicated in different cohorts. Associated SVs are located in multiple species, including Akkermansia muciniphila, Dorea formicigenerans, and Bacteroides caccae. We find genes that encode enzymes that participate in glucose metabolism be harbored in these associated regions. This work uncovers a nascent layer of gut microbiome heterogeneity that is correlated with hosts' prognosis following ICI treatment and represents an advance in our knowledge of the intricate relationships between microbiota and tumor immunotherapy.

PMID:37973916 | DOI:10.1038/s41467-023-42997-7

Drug Metab Dispos. 2023 Nov 16:DMD-AR-2023-001463. doi: 10.1124/dmd.123.001463. Online ahead of print.

ABSTRACT

Lung cancer is the leading cause of cancer deaths worldwide. We found that the cytochrome P450 isoform CYP4F11 is significantly overexpressed in patients with lung squamous cell carcinoma. CYP4F11 is a fatty acid w-hydroxylase and catalyzes the production of the lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. 20-HETE promotes cell proliferation and migration in cancer. An inhibition of 20-HETE-generating cytochrome P450 enzymes has been implicated as novel cancer therapy for more than a decade. However, the exact role of CYP4F11 and its potential as drug target for lung cancer therapy has not been established yet. Thus, we performed a transient knockdown of CYP4F11 in the lung cancer cell line NCI-H460. Knockdown of CYP4F11 significantly inhibits the lung cancer cell proliferation and migration while the 20-HETE production is significantly reduced. For biochemical characterization of CYP4F11-inhibitor interactions, we generated recombinant human CYP4F11. Spectroscopic ligand binding assays were conducted to evaluate CYP4F11 binding to the unselective CYP4A/F inhibitor HET0016. HET0016 shows high affinity to recombinant CYP4F11 and inhibits CYP4F11-mediated 20-HETE production in vitro with a nanomolar IC 50 Cross evaluation of HET0016 in NCI-H460 cells shows that lung cancer cell proliferation is significantly reduced together with 20-HETE production. However, HET0016 also displays antiproliferative effects which are not 20-HETE mediated. Future studies aim to establish the role of CYP4F11 in lung cancer and the underlying mechanism and investigate the potential of CYP4F11 as a therapeutic target for lung cancer. Significance Statement Lung cancer is a deadly cancer with limited treatment options. The cytochrome P450 4F11 (CYP4F11) is significantly upregulated in lung squamous cell carcinoma. A knockdown of CYP4F11 in a lung cancer cell line significantly attenuates cell proliferation and migration with reduced production of the lipid mediator 20-HETE. Studies with the unselective inhibitor HET0016 shows a high inhibitory potency of CYP4F11-mediated 20-HETE production using recombinant enzyme. Overall, our studies show the potential of targeting CYP4F11 for new transformative lung cancer treatment.

PMID:37973374 | DOI:10.1124/dmd.123.001463

Acta Pharm Sin B. 2023 Nov;13(11):4502-4510. doi: 10.1016/j.apsb.2023.08.001. Epub 2023 Aug 7.

ABSTRACT

Paxlovid is a nirmatrelvir (NMV) and ritonavir (RTV) co-packaged medication used for the treatment of coronavirus disease 2019 (COVID-19). The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster. Our work aimed to investigate the drug/herb-drug interactions associated with Paxlovid and provide mechanism-based guidance for the clinical use of Paxlovid. By using recombinant human cytochrome P450s (CYPs), we confirmed that CYP3A4 and 3A5 are the major enzymes responsible for NMV metabolism. The role of CYP3A in Paxlovid metabolism were further verified in Cyp3a-null mice, which showed that the deficiency of CYP3A significantly suppressed the metabolism of NMV and RTV. Pregnane X receptor (PXR) is a ligand-dependent transcription factor that upregulates CYP3A4/5 expression. We next explored the impact of drug- and herb-mediated PXR activation on Paxlovid metabolism in a transgenic mouse model expressing human PXR and CYP3A4/5. We found that PXR activation increased CYP3A4/5 expression, accelerated NMV metabolism, and reduced the systemic exposure of NMV. In summary, our work demonstrated that PXR activation can cause drug interactions with Paxlovid, suggesting that PXR-activating drugs and herbs should be used cautiously in COVID-19 patients receiving Paxlovid.

PMID:37969744 | PMC:PMC10638548 | DOI:10.1016/j.apsb.2023.08.001

World J Clin Cases. 2023 Oct 26;11(30):7440-7449. doi: 10.12998/wjcc.v11.i30.7440.

ABSTRACT

BACKGROUND: Neonatal hypertension is a rare but potentially serious condition that requires careful monitoring and treatment. Pharmacogenomics can help guide individualized drug therapy and improve outcomes.

CASE SUMMARY: We report a case of a preterm infant with multiple complications, including bronchopulmonary dysplasia (BPD), sepsis, intracranial hemorrhage, and hypertension. The infant was treated with various drugs, including dexamethasone and amlodipine. The infant was diagnosed with neonatal hypertension based on blood pressure measurements exceeding the 95th percentile for his age and sex. The possible causes of hypertension included dexamethasone, hydrochlorothiazide, spironolactone, and BPD. The infant was treated with oral amlodipine to lower his blood pressure. A pharmacogenomic test was performed to evaluate the genetic polymorphisms of ABCB1 and CYP3A5, which are involved in the metabolism and transport of dexamethasone and amlodipine. The infant's blood pressure was well controlled after the dose of amlodipine was reduced according to the pharmacogenomic results. The infant had a stable general condition and was discharged on the 100th d after birth.

CONCLUSION: This case illustrates the importance of regular blood pressure monitoring and etiological investigation in preterm infants with hypertension. Pharmacogenomics can provide useful information for individualized drug therapy and safety in this population.

PMID:37969466 | PMC:PMC10643063 | DOI:10.12998/wjcc.v11.i30.7440

Am J Transl Res. 2023 Oct 15;15(10):6255-6263. eCollection 2023.

ABSTRACT

Recent decades have brought enormous progress in both genetics and genomics, as well as in information technology (IT). The sequence of the human genome is now known, and although our knowledge is far from complete, great progress has been made in understanding how the genome works. With the developments in storage capacity, artificial intelligence, and learning algorithms, we are now able to learn and interpret complex systems such as the human genome in a very short time. Perhaps the most important goal of learning about the human genome is to understand diseases better: how they develop; how their processes can be prevented or slowed down; and after diseases have developed, how they can be cured or their symptoms alleviated. The vast majority of diseases have a genetic background, i.e., genes, sequence variations, and gene-gene interactions play a role in most diseases to a greater or lesser extent. Accordingly, the first step is to discover which genes, or genomic variants, cause or contribute to the development of a particular disease in a given patient. Given that an individual's genome remains virtually unchanged throughout their life (with one or two exceptions, such as in the case of cancer, which is caused by somatic mutations), it might be considered advantageous to sequence the genome of every person at birth. In this paper, we set out to show the possible benefits of sequencing the entire genome of every human being at birth, while also discussing the main arguments against it.

PMID:37969196 | PMC:PMC10641337

Canine Med Genet. 2023 Nov 15;10(1):10. doi: 10.1186/s40575-023-00133-0.

ABSTRACT

BACKGROUND: Cortical folding is related to the functional organization of the brain. The TMF-1 regulated protein (TRNP1) regulates the expansion and folding of the mammalian cerebral cortex, a process that may have been accelerated by the domestication of dogs. The objectives of this study were to sequence the TRNP1 gene in dogs and related canid species, provide evidence of its expression in dog brain and compare the genetic variation within dogs and across the Canidae. The gene was located in silico to dog chromosome 2. The sequence was experimentally confirmed by amplifying and sequencing the TRNP1 exonic and promoter regions in 72 canids (36 purebred dogs, 20 Gy wolves and wolf-dog hybrids, 10 coyotes, 5 red foxes and 1 Gy fox).

RESULTS: A partial TRNP1 transcript was isolated from several regions in the dog brain. Thirty genetic polymorphisms were found in the Canis sp. with 17 common to both dogs and wolves, and only one unique to dogs. Seven polymorphisms were observed only in coyotes. An additional 9 variants were seen in red foxes. Dogs were the least genetically diverse. Several polymorphisms in the promoter and 3'untranslated region were predicted to alter TRNP1 function by interfering with the binding of transcriptional repressors and miRNAs expressed in neural precursors. A c.259_264 deletion variant that encodes a polyalanine expansion was polymorphic in all species studied except for dogs. A stretch of 15 nucleotides that is found in other mammalian sequences (corresponding to 5 amino acids located between Pro58 and Ala59 in the putative dog protein) was absent from the TRNP1 sequences of all 5 canid species sequenced. Both of these aforementioned coding sequence variations were predicted to affect the formation of alpha helices in the disordered region of the TRNP1 protein.

CONCLUSIONS: Potentially functionally important polymorphisms in the TRNP1 gene are found within and across various Canis species as well as the red fox, and unique differences in protein structure have evolved and been conserved in the Canidae compared to all other mammalian species.

PMID:37968761 | DOI:10.1186/s40575-023-00133-0

Brain Behav Immun. 2023 Nov 13:S0889-1591(23)00342-2. doi: 10.1016/j.bbi.2023.11.009. Online ahead of print.

ABSTRACT

Traumatic stress is associated with both accelerated epigenetic age and increased risk for dementia. Accelerated epigenetic age might link symptoms of traumatic stress to dementia-associated biomarkers, such as amyloid-beta (Aβ) proteins, neurofilament light (NFL), and inflammatory molecules. We tested this hypothesis using longitudinal data obtained from 214 trauma-exposed military veterans (85 % male, mean age at baseline: 53 years, 75 % White) who were assessed twice over the course of an average of 5.6 years. Cross-lagged panel mediation models evaluated measures of lifetime posttraumatic stress disorder and internalizing and externalizing comorbidity (assessed at Time 1; T1) in association with T1 epigenetic age (per the GrimAge algorithm) and T1 plasma markers of neuropathology along with bidirectional temporal paths between T1 and T2 epigenetic age and the plasma markers. Results revealed that a measure of externalizing comorbidity was associated with accelerated epigenetic age (β = 0.30, p <.01), which in turn, was associated with subsequent increases in Aβ-40 (β = 0.20, p <.001), Aβ-42 (β = 0.18, p <.001), and interleukin-6 (β = 0.18, p <.01). T1 advanced epigenetic age and the T1 neuropathology biomarkers NFL and glial fibrillary acidic protein predicted worse performance on T2 neurocognitive tasks assessing working memory, executive/attentional control, and/or verbal memory (ps = 0.03 to 0.009). Results suggest that advanced GrimAge is predictive of subsequent increases in neuropathology and inflammatory biomarkers as well as worse cognitive function, highlighting the clinical significance of this biomarker with respect to cognitive aging and brain health over time. The finding that advanced GrimAge mediated the association between psychiatric comorbidity and future neuropathology is important for understanding potential pathways to neurodegeneration and early identification of those at greatest risk.

PMID:37967663 | DOI:10.1016/j.bbi.2023.11.009

Curr Heart Fail Rep. 2023 Nov 15. doi: 10.1007/s11897-023-00631-z. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Heart transplantation (HT) remains the optimal therapy for patients living with end-stage heart disease. Despite recent improvements in peri-transplant management, the median survival after HT has remained relatively static, and complications of HT, including infection, rejection, and allograft dysfunction, continue to impact quality of life and long-term survival.

RECENT FINDINGS: Omics technologies are becoming increasingly accessible and can identify novel biomarkers for, and reveal the underlying biology of, several disease states. While some technologies, such as gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA), are routinely used in the clinical care of HT recipients, a number of emerging platforms, including pharmacogenomics, proteomics, and metabolomics, hold great potential for identifying biomarkers to aid in the diagnosis and management of post-transplant complications. Omics-based assays can improve patient and allograft longevity by facilitating a personalized and precision approach to post-HT care. The following article is a contemporary review of the current and future opportunities to leverage omics technologies, including genomics, transcriptomics, proteomics, and metabolomics in the field of HT.

PMID:37966542 | DOI:10.1007/s11897-023-00631-z

Pharmacogenomics. 2023 Nov 15. doi: 10.2217/pgs-2023-0185. Online ahead of print.

ABSTRACT

Aim: Pre-emptive testing of pharmacogenomic (PGx) variations has potential to improve medication safety and effectiveness; however, testing is not routine. Given the newfound payor coverage of multigene testing and the potential value of testing within aging patients, it is imperative to test local PGx testing capabilities, report results to patients and providers, and determine the value of testing. Materials & methods: We designed a randomized clinical pilot of a pre-emptive PGx testing process using the electronic health record compared with usual care among an aging primary care population. Results & conclusion: The impact of the program on prescribing patterns, healthcare utilization and costs of care will be evaluated. We hypothesize that implementation of a pre-emptive multigene PGx panel is feasible among elderly, polypharmacy, primary care patients, measured by the number of enrolled patients with PGx results entered in the medical record. Health system wide PGx implementation, including capacity needed to integrate these valuable results, is also described.

PMID:37965783 | DOI:10.2217/pgs-2023-0185

Front Genet. 2023 Oct 27;14:1308169. doi: 10.3389/fgene.2023.1308169. eCollection 2023.

NO ABSTRACT

PMID:37964778 | PMC:PMC10641871 | DOI:10.3389/fgene.2023.1308169

CMAJ. 2023 Nov 14;195(44):E1499-E1508. doi: 10.1503/cmaj.221785.

ABSTRACT

BACKGROUND: Pharmacogenomic testing to identify variations in genes that influence metabolism of antidepressant medications can enhance efficacy and reduce adverse effects of pharmacotherapy for major depressive disorder. We sought to establish the cost-effectiveness of implementing pharmacogenomic testing to guide prescription of antidepressants.

METHODS: We developed a discrete-time microsimulation model of care pathways for major depressive disorder in British Columbia, Canada, to evaluate the effectiveness and cost-effectiveness of pharmacogenomic testing from the public payer's perspective over 20 years. The model included unique patient characteristics (e.g., metabolizer phenotypes) and used estimates derived from systematic reviews, analyses of administrative data (2015-2020) and expert judgment. We estimated incremental costs, life-years and quality-adjusted life-years (QALYs) for a representative cohort of patients with major depressive disorder in BC.

RESULTS: Pharmacogenomic testing, if implemented in BC for adult patients with moderate-severe major depressive disorder, was predicted to save the health system $956 million ($4926 per patient) and bring health gains of 0.064 life-years and 0.381 QALYs per patient (12 436 life-years and 74 023 QALYs overall over 20 yr). These savings were mainly driven by slowing or avoiding the transition to refractory (treatment-resistant) depression. Pharmacogenomic-guided care was associated with 37% fewer patients with refractory depression over 20 years. Sensitivity analyses estimated that costs of pharmacogenomic testing would be offset within about 2 years of implementation.

INTERPRETATION: Pharmacogenomic testing to guide antidepressant use was estimated to yield population health gains while substantially reducing health system costs. These findings suggest that pharmacogenomic testing offers health systems an opportunity for a major value-promoting investment.

PMID:37963621 | DOI:10.1503/cmaj.221785

Clin Genet. 2023 Nov 14. doi: 10.1111/cge.14452. Online ahead of print.

ABSTRACT

Anthracyclines remain the cornerstone of numerous chemotherapeutic protocols, with beneficial effects against haematological malignancies and solid tumours. Unfortunately, the clinical usefulness of anthracyclines is compromised by the development of cardiotoxic side effects, leading to dose limitations or treatment discontinuation. There is no absolute linear correlation between the incidence of cardiotoxicity and the threshold dose, suggesting that genetic factors may modify the association between anthracyclines and cardiotoxicity risk. And the majority of single nucleotide polymorphisms (SNPs) associated with anthracycline pharmacogenomics were identified in the ATP-binding cassette (ABC) and solute carrier (SLC) transporters, generating increasing interest in the pharmacogenetic implications of their genetic variations for anthracycline-induced cardiotoxicity (AIC). This review focuses on the influence of SLC and ABC polymorphisms on AIC and highlights the prospects and clinical significance of pharmacogenetics for individualised preventive approaches.

PMID:37961936 | DOI:10.1111/cge.14452

JACC Adv. 2022 Jun;1(2):100039. doi: 10.1016/j.jacadv.2022.100039. Epub 2022 May 23.

ABSTRACT

BACKGROUND: Direct-acting oral anticoagulants are first-line agents for prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF), but data are limited for the oldest patients, and with reduced dosing.

OBJECTIVES: To determine steady-state apixaban peak and trough concentrations during routine care of older adults with NVAF, compare concentrations to clinical trial concentrations, and explore factors associated with concentrations.

METHODS: A cross-sectional study of medically stable older adults with NVAF (≥75 years or ≥70 years if Black) receiving apixaban. Peak (2-4.4 hours post-dose) and trough (before next dose) concentrations were determined by anti-Xa activity calibrated chromogenic assay. Patient characteristics associated with concentrations were determined by multivariate modeling.

RESULTS: The median age of patients (n = 115) was 80 (interquartile range: 77-84) years. The cohort comprised 46 women and 69 men; of which 98 are White, 11 Black, and 6 Asian. With 5 mg twice daily per labelling (n = 88), peak concentrations were higher in women: 248 ± 105 vs 174 ± 67 ng/mL in men (P < 0.001) and exceeded expected 95% range in 6 of 30 vs 0 of 55 men (P = 0.002). With 2.5 mg twice daily per label (n = 11), concentrations were <5 mg twice daily (peak: 136 ± 87 vs 201 ± 90 ng/mL, P = 0.026; trough: 65 ± 28 vs 109 ± 56 ng/mL, P < 0.001), but not different than 2.5 mg twice daily without reduction criteria (n = 13; peak: 132 ± 88; trough: 65 ± 31 ng/mL). Covariates associated with concentrations included sex, number of daily medications, and creatinine clearance.

CONCLUSIONS: Older women had higher than expected peak apixaban concentrations, and 2.5 mg twice daily produced lower concentrations than standard dosing. Factors not currently included in dosing recommendations affected concentrations. The impact of apixaban concentrations on outcomes needs evaluation.

PMID:37961076 | PMC:PMC10643025 | DOI:10.1016/j.jacadv.2022.100039