Pharmacol Rev. 2024 Aug 9:PHARMREV-AR-2022-000750. doi: 10.1124/pharmrev.123.000750. Online ahead of print.

ABSTRACT

Recent breakthroughs in human genetics and in information technologies have markedly expanded our understanding at the molecular level of the response to drugs, i.e. pharmacogenetics (PGx), across therapy areas. This review is restricted to PGx for cardiovascular (CV) drugs. First, we examined the PGx information in the labels approved by regulatory agencies in Europe, Japan and North America, and related recommendations from expert panels. Out of 221 marketed CV drugs, 36 had PGx information in their labels approved by one or more agencies. The level of annotations and recommendations varied markedly between agencies and expert panels. Clopidogrel is the only CV drug with consistent PGx recommendation (i.e., "actionable"). This situation prompted us to dissect the steps from discovery of a PGx association to clinical translation. We found 101 genome-wide association studies which investigated the response to CV drugs or drug classes. These studies reported significant associations for 48 PGx traits mapping to 306 genes. Six of these 306 genes are mentioned in the corresponding PGx labels or recommendations for CV drugs. Genomic analyses also highlighted the wide between-population differences in risk allele frequencies, and the individual load of actionable PGx variants. Given high attrition rate and the long road to clinical translation, additional work is warranted to identify and validate PGx variants for more CV drugs across diverse populations and to demonstrate the utility of PGx testing. To that end, pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV disease and beyond. Significance Statement Despite spectacular breakthroughs in human molecular genetics and information technologies, consistent evidence supporting pharmacogenetic (PGx) testing in the cardiovascular area is limited to few drugs. Additional work is warranted to discover and validate new PGx markers and demonstrate their utility. Pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for cardiovascular disease and beyond.

PMID:39122647 | DOI:10.1124/pharmrev.123.000750

Toxicol Appl Pharmacol. 2024 Aug 7:117064. doi: 10.1016/j.taap.2024.117064. Online ahead of print.

ABSTRACT

Propylthiouracil (PTU) and methimazole (MMI), two classical antithyroid agents possess risk of drug-induced liver injury (DILI) with unknown mechanism of action. This study aimed to examine and compare their hepatic toxicity using a quantitative system toxicology approach. The impact of PTU and MMI on hepatocyte survival, oxidative stress, mitochondria function and bile acid transporters were assessed in vitro. The physiologically based pharmacokinetic (PBPK) models of PTU and MMI were constructed while their risk of DILI was calculated by DILIsym, a quantitative systems toxicology (QST) model by integrating the results from in vitro toxicological studies and PBPK models. The simulated DILI (ALT >2 × ULN) incidence for PTU (300 mg/d) was 21.2%, which was within the range observed in clinical practice. Moreover, a threshold dose of 200 mg/d was predicted with oxidative stress proposed as an important toxic mechanism. However, DILIsym predicted a 0% incidence of hepatoxicity caused by MMI (30 mg/d), suggesting that the toxicity of MMI was not mediated through mechanism incorporated into DILIsym. In conclusion, DILIsym appears to be a practical tool to unveil hepatoxicity mechanism and predict clinical risk of DILI.

PMID:39122118 | DOI:10.1016/j.taap.2024.117064

EBioMedicine. 2024 Aug 8;107:105264. doi: 10.1016/j.ebiom.2024.105264. Online ahead of print.

ABSTRACT

BACKGROUND: The metabolic environment plays a crucial role in the development of heart failure (HF). Our prior research demonstrated that myo-inositol, a metabolite transported by the sodium-myo-inositol co-transporter 1 (SMIT-1), can induce oxidative stress and may be detrimental to heart function. However, plasmatic myo-inositol concentration has not been comprehensively assessed in large cohorts of patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF).

METHODS: Plasmatic myo-inositol levels were measured using mass spectrometry and correlated with clinical characteristics in no HF subjects and patients with HFrEF and HFpEF from Belgian (male, no HF, 53%; HFrEF, 84% and HFpEF, 40%) and Canadian cohorts (male, no HF, 51%; HFrEF, 92% and HFpEF, 62%).

FINDINGS: Myo-inositol levels were significantly elevated in patients with HF, with a more pronounced increase observed in the HFpEF population of both cohorts. After adjusting for age, sex, body mass index, hypertension, diabetes, and atrial fibrillation, we observed that both HFpEF status and impaired kidney function were associated with elevated plasma myo-inositol. Unlike HFrEF, abnormally high myo-inositol (≥69.8 μM) was linked to unfavourable clinical outcomes (hazard ratio, 1.62; 95% confidence interval, [1.05-2.5]) in patients with HFpEF. These elevated levels were correlated with NTproBNP, troponin, and cardiac fibrosis in this subset of patients.

INTERPRETATION: Myo-inositol is a metabolite elevated in patients with HF and strongly correlated to kidney failure. In patients with HFpEF, high myo-inositol levels predict poor clinical outcomes and are linked to markers of cardiac adverse remodelling. This suggests that myo-inositol and its transporter SMIT1 may have a role in the pathophysiology of HFpEF.

FUNDING: BECAME-HF was supported by Collaborative Bilateral Research Program Québec - Wallonie-Brussels Federation.

PMID:39121579 | DOI:10.1016/j.ebiom.2024.105264

Crit Rev Clin Lab Sci. 2024 Aug 9:1-44. doi: 10.1080/10408363.2024.2358304. Online ahead of print.

ABSTRACT

The field of pharmacogenetics, the investigation of the influence of one or more sequence variants on drug response phenotypes, is a special case of pharmacogenomics, a discipline that takes a genome-wide approach. Massively parallel, next generation sequencing (NGS), has allowed pharmacogenetics to be subsumed by pharmacogenomics with respect to the identification of variants associated with responders and non-responders, optimal drug response, and adverse drug reactions. A plethora of rare and common naturally-occurring GPCR variants must be considered in the context of signals from across the genome. Many fundamentals of pharmacogenetics were established for G protein-coupled receptor (GPCR) genes because they are primary targets for a large number of therapeutic drugs. Functional studies, demonstrating likely-pathogenic and pathogenic GPCR variants, have been integral to establishing models used for in silico analysis. Variants in GPCR genes include both coding and non-coding single nucleotide variants and insertion or deletions (indels) that affect cell surface expression (trafficking, dimerization, and desensitization/downregulation), ligand binding and G protein coupling, and variants that result in alternate splicing encoding isoforms/variable expression. As the breadth of data on the GPCR genome increases, we may expect an increase in the use of drug labels that note variants that significantly impact the clinical use of GPCR-targeting agents. We discuss the implications of GPCR pharmacogenomic data derived from the genomes available from individuals who have been well-phenotyped for receptor structure and function and receptor-ligand interactions, and the potential benefits to patients of optimized drug selection. Examples discussed include the renin-angiotensin system in SARS-CoV-2 (COVID-19) infection, the probable role of chemokine receptors in the cytokine storm, and potential protease activating receptor (PAR) interventions. Resources dedicated to GPCRs, including publicly available computational tools, are also discussed.

PMID:39119983 | DOI:10.1080/10408363.2024.2358304

Postep Psychiatr Neurol. 2024 Jun;33(2):67-79. doi: 10.5114/ppn.2024.141056. Epub 2024 Jul 24.

ABSTRACT

PURPOSE: Stroke is the second leading cause of death worldwide with an annual mortality rate of 6.55 million, which accounts for 11.6% of the total number of deaths. Early diagnosis is crucial for improving treatment outcomes. Lean management is an approach originating in the car manufacturing process derived from the Toyota Production System, which healthcare providers have recently adapted. The objective is to examine the use of lean practices in managing AIS in hospital settings.

METHODS: A systematic literature search was performed using MEDLINE and SCOPUS databases, including publications from 1st January 2000 to 20th September 2022.

RESULTS: A total of 13 studies fulfilled the predefined inclusion criteria. The recombinant tissue plasminogen activator (rtPA) was used in 11 studies, in 2 studies in combination with mechanical thrombectomy (MT). MT alone was used in the other 2 studies. The value stream mapping was used in all included studies to analyze workflow in acute ischemic stroke (AIS) treatment. Outcome measures include mostly door-to-needle (DTN) time for rtPA treatment and door-to-puncture (DTP) time for mechanical thrombectomy. DTN time was assessed in nine studies and reached statistically significant results in five. DTP was examined in three studies; in two, statistically significant decreases in DTP were observed.

CONCLUSIONS: Lean management can be a useful method for achieving key performance indicators in AIS, consistent with current guidelines. The results of this systematic literature review show that value stream mapping may improve the process of AIS treatment by reducing in-hospital delays. The field of research that focuses on implementing lean management tools in healthcare is increasing, with more publications appearing in recent years.

PMID:39119549 | PMC:PMC11304223 | DOI:10.5114/ppn.2024.141056

Biol Cell. 2024 Aug 9:e2400073. doi: 10.1111/boc.202400073. Online ahead of print.

ABSTRACT

BACKGROUND INFORMATION: Arpin, an Arp2/3 inhibitory protein, inhibits lamellipodial protrusions and cell migration. Arpin expression is lost in tumor cells of several cancer types.

RESULTS: Here we analyzed expression levels of Arpin and various markers using Reverse Phase Protein Array (RPPA) in human mammary carcinomas. We found that Arpin protein levels were correlated with those of several DNA damage response markers. Arpin-null cells display enhanced clustering of double stand breaks (DSBs) when cells are treated with a DNA damaging agent, in line with a previously described role of the Arp2/3 complex in promoting DSB clustering for homologous DNA repair (HDR) in the nucleus. Using a specific HDR assay, we further showed that Arpin depletion increased HDR efficiency two-fold through its ability to inactivate the Arp2/3 complex.

CONCLUSIONS: Arpin regulates both cell migration in the cytosol and HDR in the nucleus.

SIGNIFICANCE: Loss of Arpin expression coordinates enhanced cell migration with up-regulated DNA repair, which is required when DNA damage is induced by active cell migration.

PMID:39118570 | DOI:10.1111/boc.202400073

Mol Genet Genomic Med. 2024 Aug;12(8):e2501. doi: 10.1002/mgg3.2501.

ABSTRACT

BACKGROUND: Non-photosensitive trichothiodystrophies (TTDs) are a diverse group of genodermatoses within the subset of conditions known as "sulphur-deficient brittle hair" syndromes. A part of them has only recently been identified, revealing novel causative genes and very rare phenotypes of these genetic skin disorders. At the same time, the molecular basis of previously published and unresolved cases has been revealed through the introduction of innovative genetic techniques. We have previously described the facial phenotype of patients with the Photosensitive form of TTD during childhood. This study marks the beginning of an effort to expand the analysis to include individuals of the same age who do not have photosensitivity.

METHODS: A total of 26 facial portraits of TTD paediatric patients with Non-photosensitivity from the literature were analysed using computer-aided technologies, and their facial features were examined through a detailed clinical review.

RESULTS: Distinct facial features were identified in both Photosensitive and Non-photosensitive TTDs.

CONCLUSION: The present study has comprehensively elucidated the facial features in TTDs, encompassing the Non-photosensitive clinical spectrum.

PMID:39118464 | DOI:10.1002/mgg3.2501

Clin Pharmacol Ther. 2024 Aug 8. doi: 10.1002/cpt.3401. Online ahead of print.

NO ABSTRACT

PMID:39115927 | DOI:10.1002/cpt.3401

JAMA Netw Open. 2024 Aug 1;7(8):e2425600. doi: 10.1001/jamanetworkopen.2024.25600.

NO ABSTRACT

PMID:39115850 | DOI:10.1001/jamanetworkopen.2024.25600

JAMA Netw Open. 2024 Aug 1;7(8):e2425593. doi: 10.1001/jamanetworkopen.2024.25593.

ABSTRACT

IMPORTANCE: Precise estimation of a patient's drug metabolism capacity is important for antiseizure dose personalization.

OBJECTIVE: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes.

DATA SOURCES: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions.

STUDY SELECTION: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants.

DATA EXTRACTION AND SYNTHESIS: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis.

MAIN OUTCOMES AND MEASURES: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant.

RESULTS: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers.

CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.

PMID:39115847 | DOI:10.1001/jamanetworkopen.2024.25593

Pharmacogenomics. 2024 Aug 8:1-6. doi: 10.1080/14622416.2024.2375188. Online ahead of print.

ABSTRACT

In 2021, the Clinical Pharmacology Department of Hospital Universitario de La Princesa launched the PriME-PGx initiative (Multidisciplinary Initiative of the Hospital Universitario de La Princesa for the Implementation of Pharmacogenetics) to promote the expansion of pharmacogenetics in hospitalized patients. We establish seven pharmacogenetic profiles based on the specific needs of seven departments: Oncology, Pain Unit, Neuropsychiatry, Internal or Infectious Medicine, Cardiology, Gastroenterology and Immunosuppressants. The experience of the last 3 years reflects a total of 1421 reports (37.4% being oncology profiles), with a gradual increase in the number of requests each year. With this project, we aim to expand the availability and utility of pharmacogenetic biomarkers to achieve personalised therapy that avoids adverse drug reactions and therapeutic failure.

PMID:39115196 | DOI:10.1080/14622416.2024.2375188

Front Pharmacol. 2024 Jul 24;15:1463384. doi: 10.3389/fphar.2024.1463384. eCollection 2024.

NO ABSTRACT

PMID:39114360 | PMC:PMC11303329 | DOI:10.3389/fphar.2024.1463384

Pharmacogenomics J. 2024 Aug 7;24(5):24. doi: 10.1038/s41397-024-00346-x.

ABSTRACT

This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMG CoA reductase (HMGCR) inhibitors, specifically simvastatin, are significantly associated with reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several pathways associated with these processes. Higher expression of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and very low density lipoprotein (VLDL) cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA.

PMID:39112450 | DOI:10.1038/s41397-024-00346-x

Pharmacogenomics. 2024 Aug 7:1-13. doi: 10.1080/14622416.2024.2382078. Online ahead of print.

ABSTRACT

Aim: To explore general practitioners' (GPs) views on implementing pharmacogenomic testing in Australian general practice. Methods: Semi-structured interviews were conducted with nine GPs in Australia, recruited from primary care networks. Interviews were analyzed using thematic analysis. Themes were mapped onto the Consolidated Framework for Implementation Research domains. Results: Barriers to implementation included lack of knowledge, education, standardized pharmacogenomic reports and national clinical guidelines and financial inaccessibility. Facilitators included positive exposure to pharmacogenomics, peer influences, interdisciplinary collaboration and proven clinical utility. Current uptake was minimal; however, GPs shared positive perceptions of clinical use. Conclusion: Recommendations for successful implementation include building and disseminating clinical evidence, developing national guidelines and standardized reports, incorporation into formal education and increasing financial accessibility.

PMID:39109497 | DOI:10.1080/14622416.2024.2382078

Pharmacogenomics. 2024 Aug 7:1-13. doi: 10.1080/14622416.2024.2370761. Online ahead of print.

ABSTRACT

Calcineurin inhibitors (CNIs) are the mainstay of immunosuppression in kidney transplantation. Interpatient variability in the disposition of calcineurin inhibitors is a well-researched phenomenon and has a well-established genetic contribution. There is great diversity in the makeup of African genomes, but very little is known about the pharmacogenetics of CNIs and transplant outcomes. This review focuses on genetic variants of calcineurin inhibitors' metabolizing enzymes (CYP3A4, CYP3A5), related molecules (POR, PPARA) and membrane transporters involved in the metabolism of calcineurin inhibitors. Given the genetic diversity across the African continent, it is imperative to generate pharmacogenetic data, especially in the era of personalized medicine and emphasizes the need for studies specific to African populations. The study of allelic variants in populations where they have greater frequencies will help answer questions regarding their impact. We aim to fill the knowledge gaps by reviewing existing research and highlighting areas where African research can contribute.

PMID:39109483 | DOI:10.1080/14622416.2024.2370761

J Endocr Soc. 2024 Jul 16;8(9):bvae135. doi: 10.1210/jendso/bvae135. eCollection 2024 Jul 26.

ABSTRACT

OBJECTIVE: Testosterone concentrations, albeit rarely, may be in the normal range (>3.0 ng/mL) in men with a prolactin-secreting pituitary adenoma (PSPA-nt). The evolution of total, bioavailable testosterone, gonadotropin levels, and that of graded symptoms of testosterone deficiency (TD) are uncertain in these patients.

DESIGN: Retrospective case-control longitudinal study at a tertiary referral center.

METHODS: From 287 men, we selected 25 PSPA-nt men undergoing prolactin normalization (<20.0 ng/mL) during the follow-up. Graded symptoms of TD were investigated by structured interviews. Biochemical changes and TD symptoms were compared to those of a matched cohort of 61 men with pituitary neoplasms and normal testosterone levels (PA-nt).

RESULTS: Baseline testosterone levels were similar between PSPA-nt and PA-nt subjects. The prevalence of specific and suggestive symptoms of TD was higher in PSPA-nt (20% and 68%) than in PAnt (3.3 and 29.5%; P = .02 and P = .0015, respectively). At the follow-up, total and bioavailable testosterone levels increased in PSPA-nt but not in PA-nt patients (Δ change: 1.28 ± 2.1 vs0.03 ± 1.5 ng/mL, + 0.33 ± 0.55 vs-0.26 ± 0.60 ng/mL; P = .0028 and P = .0088, respectively). LH and FSH levels also increased in PSPA-nt men (P < .05). Specific and suggestive, but not nonspecific symptoms of TD, improved only in PSPA-nt men (P < .05 for both). Baseline testosterone and LH were the strongest predictors of testosterone improvement in PSPA-nt patients.

CONCLUSION: Despite having normal testosterone levels at baseline, patients with PSPA-nt experience a relief of TD symptoms and an improvement of their pituitary-gonadal axis function following prolactin normalization, especially when baseline TT and LH levels are in the low-normal range.

PMID:39109291 | PMC:PMC11301044 | DOI:10.1210/jendso/bvae135

Front Pharmacol. 2024 Jul 23;15:1404370. doi: 10.3389/fphar.2024.1404370. eCollection 2024.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) is a well-established concept of how genes impact medication response, with many studies demonstrating reductions in medication side effects, improved efficacy and cost effectiveness. Despite these benefits, implementation of PGx in daily practice remains limited. Studies on the implementation of PGx in clinical practice have previously found that inadequate knowledge is one of the main barriers. Details regarding specifically which educational needs exist among family medicine clinicians requires further study.

OBJECTIVE: The aim of this study was to identify both the perceived role that pharmacogenomics (PGx) could play in primary care practice, the knowledge gaps that family medicine clinicians experience, and the skills they require to use PGx in their daily practice.

METHODS: To achieve this aim, the attitudes, knowledge, barriers, skills needed, and preferred educational program were explored in a family medicine clinician focus group study via a semi-structured interview and knowledge quiz. Second, multidisciplinary focus groups provided information on the level of knowledge and necessary skills to use PGx in patient care. After gathering key recorded information from both focus groups, the perceived role pharmacogenomics could possibly play in primary care, the predominant knowledge gaps, and the most appropriate educational program was determined by qualitative analysis.

RESULTS: Four themes emerged regarding the PGx educational needs and the role of PGx in family medicine: 1) need for PGx competences, 2) insight into the roles and responsibilities of PGx services, 3) optimization of PGx workflow through artificial intelligence integrated in the electronic health record, and 4) the ethical dilemmas and psychological effects related to PGx. These themes reflect a shift in the role of PGx in family medicine with implications for education.

CONCLUSION: The results obtained from this study will help improve the implementation of PGx in daily practice, and consequently, may result in increased utilization of PGx, thereby resulting in improved medication efficacy and reduced side effects.

PMID:39108762 | PMC:PMC11300371 | DOI:10.3389/fphar.2024.1404370

Iran J Pharm Res. 2024 May 14;23(1):e143898. doi: 10.5812/ijpr-143898. eCollection 2024 Jan-Dec.

ABSTRACT

BACKGROUND: Warfarin is the only approved anticoagulant for antithrombotic treatment in patients with mechanical prosthetic heart valves (MPHV). However, dosing warfarin is challenging due to its narrow therapeutic window and highly variable clinical outcomes. Both low and high doses of warfarin can lead to thrombotic and bleeding events, respectively, with these complications being more severe in individuals with sensitive genetic polymorphisms. Incorporating genetic testing could enhance the accuracy of warfarin dosing and minimize its adverse events.

OBJECTIVES: This study aims to evaluate the utilities and cost-effectiveness of pharmacogenomics-guided versus standard dosing of warfarin in patients with MPHV in Iran.

METHODS: In this economic evaluation study, a cost-effectiveness analysis was conducted to compare pharmacogenomics-guided versus standard warfarin dosing. Data related to quality of life (QoL) were collected through a cross-sectional study involving 105 randomly selected MPHV patients using the EuroQol-5D (EQ-5D) Questionnaire. Costs were calculated with input from clinical experts and a review of relevant guidelines. Additional clinical data were extracted from published literature. The pharmacoeconomic threshold set for medical interventions within Iran's healthcare system was $1,500. A decision tree model was designed from the perspective of Iran's healthcare system with a one-year study horizon. Sensitivity analyses were also performed to assess the uncertainty of input parameters.

RESULTS: The utility scores derived from the questionnaire for standard and pharmacogenomics-guided warfarin treatments were 0.68 and 0.76, respectively. Genotype-guided dosing of warfarin was more costly compared to the standard dosing ($246 vs $69), and the calculated incremental cost-effectiveness ratio (ICER) was $2474 per quality-adjusted life year (QALY) gained. One-way sensitivity analyses showed that our model is sensitive to the percentage of time in the therapeutic range (PTTR), the cost of genetic tests, and the utility of both pharmacogenomics-guided and standard dosing arms. However, the probabilistic sensitivity analysis demonstrates the robustness of our model.

CONCLUSIONS: Warfarin dosing with pharmacogenomics testing is currently not cost-effective. However, if the cost of genotyping tests decreases to $118, the ICER would become cost-effective.

PMID:39108643 | PMC:PMC11302438 | DOI:10.5812/ijpr-143898

Acta Anaesthesiol Scand. 2024 Aug 6. doi: 10.1111/aas.14508. Online ahead of print.

ABSTRACT

BACKGROUND: Treatment with opioids is a mainstay in perioperative pain management. While the leading treatment paradigm has been procedure-specific pain management, efforts regarding personalized pain treatment are increasing. The OPI•AID project aims to develop personalized algorithms for perioperative pain management, taking demographic, surgical, and anaesthesiologic factors into account. We will undertake five parallel reviews to illuminate current evidence on different aspects of individual responses to perioperative opioid treatment.

METHODS: Inclusion of adult populations in English-written studies. Review-specific searches are developed for the following databases: CENTRAL, MEDLINE, Embase, clinicaltrials.gov, and clinicaltrial.eu. Two authors will independently screen citations, extract data, and assess the risks of bias in each review (QUIPS, PROBAST and RoB2, as relevant).

CONCLUSION: These reviews will evaluate various aspects of perioperative opioid treatment, including individualized treatment strategies, selection of specific opioids, and individual patient responses. These will guide future development of a personalized perioperative opioid treatment algorithm (OPI•AID) that will be validated and tested clinically against standard of care.

PMID:39107975 | DOI:10.1111/aas.14508

Br J Clin Pharmacol. 2024 Aug 6. doi: 10.1111/bcp.16196. Online ahead of print.

ABSTRACT

AIMS: Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5 ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5 ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib.

METHODS: This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive.

RESULTS: Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P ≤ 5 × 10-6).

CONCLUSIONS: While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.

PMID:39107874 | DOI:10.1111/bcp.16196