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Genetics in Medicine : Official Journal... Mar 2020To examine the evidence on the cost-effectiveness of implementing pharmacogenomics (PGx) in cardiovascular disease (CVD) care.
PURPOSE
To examine the evidence on the cost-effectiveness of implementing pharmacogenomics (PGx) in cardiovascular disease (CVD) care.
METHODS
We conducted a systematic review using multiple databases from inception to 2018. The titles and abstracts of cost-effectiveness studies on PGx-guided treatment in CVD care were screened, and full texts were extracted.
RESULTS
We screened 909 studies and included 46 to synthesize. Acute coronary syndrome and atrial fibrillation were the predominantly studied conditions (59%). Most studies (78%) examined warfarin-CYP2C9/VKORC1 or clopidogrel-CYP2C19. A payer's perspective was commonly used (39%) for cost calculations, and most studies (46%) were US-based. The majority (67%) of the studies found PGx testing to be cost-effective in CVD care, but cost-effectiveness varied across drugs and conditions. Two studies examined PGx panel testing, of which one examined pre-emptive testing strategies.
CONCLUSION
We found mixed evidence on the cost-effectiveness of PGx in CVD care. Supportive evidence exists for clopidogrel-CYP2C19 and warfarin-CYP2C9/VKORC1, but evidence is limited in other drug-gene combinations. Gaps persist, including unclear explanation of perspective and cost inputs, underreporting of study design elements critical to economic evaluations, and limited examination of PGx panel and pre-emptive testing for their cost-effectiveness. This review identifies the need for further research on economic evaluations of PGx implementation.
Topics: Cardiovascular Diseases; Clopidogrel; Cost-Benefit Analysis; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Humans; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine; Vitamin K Epoxide Reductases; Warfarin
PubMed: 31591509
DOI: 10.1038/s41436-019-0667-y -
Clinical and Translational Science Jun 2024For the same age, sex, and dosage, there can be significant variation in fertility outcomes in childhood cancer survivors. Genetics may explain this variation. This...
For the same age, sex, and dosage, there can be significant variation in fertility outcomes in childhood cancer survivors. Genetics may explain this variation. This study aims to: (i) review the genetic contributions to infertility, (ii) search for pharmacogenomic studies looking at interactions of cancer treatment, genetic predisposition and fertility-related outcomes. Systematic searches in MEDLINE Ovid, Embase Classic+Embase, and PubMed were conducted using the following selection criteria: (i) pediatric, adolescent, and young adult cancer survivors, below 25 years old at the time of diagnosis, (ii) fertility outcome measures after cancer therapy, (iii) genetic considerations. Studies were excluded if they were (i) conducted in animal models, (ii) were not published in English, (iii) editorial letters, (iv) theses. Articles were screened in Covidence by at least two independent reviewers, followed by data extraction and a risk of bias assessment using the Quality in Prognostic Studies tool. Eight articles were reviewed with a total of 29 genes. Outcome measures included sperm concentration, azoospermia, AMH levels, assessment of premature menopause, ever being pregnant or siring a pregnancy. Three studies included replication cohorts, which attempted replication of SNP findings for NPY2R, BRSK1, FANCI, CYP2C19, CYP3A4, and CYP2B6. Six studies were rated with a high risk of bias. Differing methods may explain a lack of replication, and small cohorts may have contributed to few significant findings. Larger, prospective longitudinal studies with an unbiased genome-wide focus will be important to replicate significant results, which can be applied clinically.
Topics: Adolescent; Child; Female; Humans; Male; Young Adult; Antineoplastic Agents; Cancer Survivors; Fertility; Infertility; Neoplasms; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 38924306
DOI: 10.1111/cts.13827 -
Clinical Pharmacology and Therapeutics Aug 2019Demonstrated improvements in patient outcomes will facilitate the clinical implementation of pharmacogenetic testing. Using the association between solute carrier...
Demonstrated improvements in patient outcomes will facilitate the clinical implementation of pharmacogenetic testing. Using the association between solute carrier organic anion transporter family member 1B1 (SLCO1B1) and statin-associated muscle symptoms (SAMSs) as a model, we conducted a systematic review of patient outcomes after delivery of SLCO1B1 results. Using PubMed and Embase searches through December 19, 2017, we identified 37 eligible records reporting preliminary or final outcomes, including six studies delivering only SLCO1B1 results and five large healthcare system-based implementation projects of multipharmacogene panels. Two small trials have demonstrated at least short-term improvements in low-density lipoprotein cholesterol after SLCO1B1 testing among previously statin intolerant patients. Evidence from large implementation projects suggests that SLCO1B1 results may change prescribing patterns for some high-risk patients. No study has reported improvements in SAMSs or cardiovascular events or tracked the economic outcomes of SLCO1B1 testing. Ongoing studies should collect and report outcomes relevant to pharmacogenetics stakeholders.
Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver-Specific Organic Anion Transporter 1; Muscular Diseases; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 30137643
DOI: 10.1002/cpt.1223 -
The Pharmacogenomics Journal Dec 2021Despite the known contributions of genes, genetic-guided pharmacotherapy has not been routinely implemented for venous thromboembolism (VTE). To examine evidence on...
Despite the known contributions of genes, genetic-guided pharmacotherapy has not been routinely implemented for venous thromboembolism (VTE). To examine evidence on cost-effectiveness of genetic-guided pharmacotherapy for VTE, we searched six databases, websites of four HTA agencies and citations, with independent double-reviewers in screening, data extraction, and quality rating. The ten eligible studies, all model-based, examined heterogeneous interventions and comparators. Findings varied widely; testing was cost-saving in two base-cases, cost-effective in four, not cost-effective in three, dominated in one. Of 22 model variables that changed decisions about cost-effectiveness, effectiveness/relative effectiveness of the intervention was the most frequent, albeit of poor quality. Studies consistently lacked details on the provision of interventions and comparators as well as on model development and validation. Besides improving the reporting of interventions, comparators, and methodological details, future economic evaluations should examine strategies recommended in guidelines and testing key model variables for decision uncertainty, to advise clinical implementations.
Topics: Adolescent; Adult; Child; Child, Preschool; Clinical Decision-Making; Cost-Benefit Analysis; Drug Costs; Female; Fibrinolytic Agents; Genetic Predisposition to Disease; Hemorrhage; Humans; Male; Middle Aged; Pharmacogenomic Testing; Pharmacogenomic Variants; Phenotype; Precision Medicine; Predictive Value of Tests; Recurrence; Risk Assessment; Risk Factors; Treatment Outcome; Venous Thromboembolism; Young Adult
PubMed: 34131314
DOI: 10.1038/s41397-021-00243-7 -
The Pharmacogenomics Journal Dec 2021Variable responses to medications complicates perioperative care. As a potential solution, we evaluated and synthesized pharmacogenomic evidence that may inform...
Variable responses to medications complicates perioperative care. As a potential solution, we evaluated and synthesized pharmacogenomic evidence that may inform anesthesia and pain prescribing to identify clinically actionable drug/gene pairs. Clinical decision-support (CDS) summaries were developed and were evaluated using Appraisal of Guidelines for Research and Evaluation (AGREE) II. We found that 93/180 (51%) of commonly-used perioperative medications had some published pharmacogenomic information, with 18 having actionable evidence: celecoxib/diclofenac/flurbiprofen/ibuprofen/piroxicam/CYP2C9, codeine/oxycodone/tramadol CYP2D6, desflurane/enflurane/halothane/isoflurane/sevoflurane/succinylcholine/RYR1/CACNA1S, diazepam/CYP2C19, phenytoin/CYP2C9, succinylcholine/mivacurium/BCHE, and morphine/OPRM1. Novel CDS summaries were developed for these 18 medications. AGREE II mean ± standard deviation scores were high for Scope and Purpose (95.0 ± 2.8), Rigor of Development (93.2 ± 2.8), Clarity of Presentation (87.3 ± 3.0), and Applicability (86.5 ± 3.7) (maximum score = 100). Overall mean guideline quality score was 6.7 ± 0.2 (maximum score = 7). All summaries were recommended for clinical implementation. A critical mass of pharmacogenomic evidence exists for select medications commonly used in the perioperative setting, warranting prospective examination for clinical utility.
Topics: Analgesics; Anesthetics; Clinical Decision-Making; Decision Support Techniques; Evidence-Based Medicine; Humans; Perioperative Care; Pharmacogenetics; Pharmacogenomic Testing; Pharmacogenomic Variants; Predictive Value of Tests; Risk Assessment; Risk Factors
PubMed: 34376788
DOI: 10.1038/s41397-021-00248-2 -
Farmacia Hospitalaria : Organo Oficial... Dec 2021The rise in the development of monoclonal antibodies has brought about a revolution in the pharmacotherapy of inflammatory bowel disease (Crohn's disease and...
OBJECTIVE
The rise in the development of monoclonal antibodies has brought about a revolution in the pharmacotherapy of inflammatory bowel disease (Crohn's disease and ulcerative colitis). Systematic plasma concentrations monitoring of these biological drugs in anticipation of potential clinical failures of treatment is known as proactive therapeutic drug monitoring. New pharmacogenetic analysis techniques have recently been developed that can predict response to these treatments even before they are administered. The goal of this systematic review is to analyze the potential benefits of proactive therapeutic drug monitoring and of the harmacogenetic analysis of biological drugs in inflammatory bowel disease patients in terms of clinical remission.
METHOD
A systematic search was performed in the MEDLINE/Pubmed, Embase and Cochrane Library databases using the escriptors proactive drug monitoring, biological drugs, inflammatory bowel disease and pharmacogenetics. Only randomized clinical trials published between January 2015 and May 2021 were included; all articles whose main topic was not related to the topic were excluded by hand. The quality of the articles was assessed using the Jadad scale and risk of bias was assessed using the Cochrane Collaboration tool.
RESULTS
After applying inclusion and exclusion criteria, seven of the 228 retrieved articles were selected for review. Almost all the studies measured the same clinical variables (Harvey-Bradshaw index for Crohn's disease and Mayo score for ulcerative colitis). Only in two of the included studies was proactive therapeutic drug monitoring superior to reactive monitoring- or no level-guided dose adjustments. No pharmacogenetic analyses were found that met the criteria defined. Conclusions: This review shows that the data supporting the use of proactive therapeutic drug monitoring in inflammatory bowel disease is limited and of low quality. Although pharmacogenetic analysis can be a useful tool for personalizing treatment, further and better designed randomized clinical trials are needed to determine the role of proactive drug monitoring strategies in clinical practice.
Topics: Colitis, Ulcerative; Crohn Disease; Drug Monitoring; Humans; Inflammatory Bowel Diseases; Pharmacogenomic Testing
PubMed: 35379111
DOI: No ID Found -
Value in Health : the Journal of the... Jan 2020Monoclonal antibodies against epidermal growth factor receptor (EGFR) have proved beneficial for the treatment of metastatic colorectal cancer (mCRC), particularly when...
BACKGROUND
Monoclonal antibodies against epidermal growth factor receptor (EGFR) have proved beneficial for the treatment of metastatic colorectal cancer (mCRC), particularly when combined with predictive biomarkers of response. International guidelines recommend anti-EGFR therapy only for RAS (NRAS,KRAS) wild-type tumors because tumors with RAS mutations are unlikely to benefit.
OBJECTIVES
We aimed to review the cost-effectiveness of RAS testing in mCRC patients before anti-EGFR therapy and to assess how well economic evaluations adhere to guidelines.
METHODS
A systematic review of full economic evaluations comparing RAS testing with no testing was performed for articles published in English between 2000 and 2018. Study quality was assessed using the Quality of Health Economic Studies scale, and the British Medical Journal and the Philips checklists.
RESULTS
Six economic evaluations (2 cost-effectiveness analyses, 2 cost-utility analyses, and 2 combined cost-effectiveness and cost-utility analyses) were included. All studies were of good quality and adopted the perspective of the healthcare system/payer; accordingly, only direct medical costs were considered. Four studies presented testing strategies with a favorable incremental cost-effectiveness ratio under the National Institute for Clinical Excellence (£20 000-£30 000/QALY) and the US ($50 000-$100 000/QALY) thresholds.
CONCLUSIONS
Testing mCRC patients for RAS status and administering EGFR inhibitors only to patients with RAS wild-type tumors is a more cost-effective strategy than treating all patients without testing. The treatment of mCRC is becoming more personalized, which is essential to avoid inappropriate therapy and unnecessarily high healthcare costs. Future economic assessments should take into account other parameters that reflect the real world (eg, NRAS mutation analysis, toxicity of biological agents, genetic test sensitivity and specificity).
Topics: Antineoplastic Agents, Immunological; Clinical Decision-Making; Colorectal Neoplasms; Cost-Benefit Analysis; DNA Mutational Analysis; Drug Costs; ErbB Receptors; Genes, ras; Genetic Predisposition to Disease; Health Care Costs; Humans; Mutation; Neoplasm Metastasis; Patient Selection; Pharmacogenomic Testing; Pharmacogenomic Variants; Phenotype; Precision Medicine; Predictive Value of Tests; Quality-Adjusted Life Years
PubMed: 31952666
DOI: 10.1016/j.jval.2019.07.009 -
Pediatric Diabetes Sep 2020A precision medicine approach is used to improve treatment of patients with monogenic diabetes. Herein, we searched SU efficiency according to the genotype-phenotype...
OBJECTIVE
A precision medicine approach is used to improve treatment of patients with monogenic diabetes. Herein, we searched SU efficiency according to the genotype-phenotype correlation, dosage used, and side effects.
RESEARCH DESIGN AND METHODS
Systematic review conducted according the PRISMA control criteria identifying relevant studies evaluating the in vivo and in vitro sensitivity of ATP-dependent potassium channels according to the characteristics of genetic mutation.
RESULTS
Hundred and three selected articles with complete data in 502 cases in whom 413 (82.3%) had mutations in KCNJ11 (#64) and 89 in ABCC8 (# 56). Successful transfer from insulin to SU was achieved in 91% and 86.5% patients, respectively, at a mean age of 36.5 months (0-63 years). Among patients with KCNJ11 and ABCC8 mutations 64 and 46 were associated with constant success, 5 and 5 to constant failure, and 10 and 4 to variable degrees of reported success rate, respectively. The glibenclamide dosage required for each genotype ranged from 0.017 to 2.8 mg/kg/day. Comparing both the in vivo and in vitro susceptibility results, some mutations appear more sensitive than others to sulfonylurea treatment. Side effects were reported in 17/103 of the included articles: mild gastrointestinal symptoms and hypoglycaemia were the most common. One premature patient had an ulcerative necrotizing enterocolitis which association with SU is difficult to ascertain.
CONCLUSIONS
Sulfonylureas are an effective treatment for monogenic diabetes due to KCNJ11 and ABCC8 genes mutations. The success of the treatment is conditioned by differences in pharmacogenetics, younger age, pharmacokinetics, compliance, and maximal dose used.
Topics: Adolescent; Adult; Child; Child, Preschool; Diabetes Mellitus; Female; Genetic Association Studies; Genotype; Humans; Hypoglycemic Agents; Infant; Infant, Newborn; Infant, Newborn, Diseases; Male; Middle Aged; Mutation; Pharmacogenomic Testing; Potassium Channels, Inwardly Rectifying; Sulfonylurea Compounds; Sulfonylurea Receptors; Young Adult
PubMed: 32418263
DOI: 10.1111/pedi.13041 -
Journal of Gastrointestinal and Liver... Jun 2020The coexistence of RAS and BRAF mutations is extremely rare, occurring in approximately 0.05% of patients with metastatic colorectal cancer (mCRC). Starting from a case...
BACKGROUND AND AIMS
The coexistence of RAS and BRAF mutations is extremely rare, occurring in approximately 0.05% of patients with metastatic colorectal cancer (mCRC). Starting from a case presentation, this review aims to examine the prevalence, clinical, histopathological and molecular features of tumors with concomitant mutations.
METHODS
Case report and systematic review. We performed a systematic literature search in PubMed and EMBASE using the following MeSH terms: "coexistence" OR "concomitant" AND "RAS" AND "BRAF" AND "colorectal cancer" from the inception of the databases onwards.
RESULTS
We present the case of a 53-year-old man diagnosed with metastatic rectal adenocarcinoma with both a KRAS and a BRAF mutation. The review included eleven papers reporting on a total of 30 mCRC cases with concomitant RAS and BRAF mutations. The male/female ratio was 11/5. The average age was 58.5 years. The tumor was located in nine cases on the right colon and in two cases in the left colon. 43.3% of subjects had liver metastases, and 6.6% had lung metastases. Next-generation sequencing (NGS) was used in 36.6% of cases and polymerase chain reaction (PCR) in 16.6% of cases. KRAS mutations were present in 83.3% of patients and NRAS mutations in 16.6% of patients. Survival could be assessed in 10 patients and the median was 21.1 months (about 30% lower than the survival in the general mCRC population).
CONCLUSION
The results of this systematic review suggest the need to design a cohort study (either prospective or retrospective) to better characterize the patients with concomitant RAS and BRAF mutations and to establish the optimal treatment for this rare situation.
Topics: Adenocarcinoma; Antineoplastic Protocols; Colorectal Neoplasms; Female; GTP Phosphohydrolases; High-Throughput Nucleotide Sequencing; Humans; Liver Neoplasms; Lung Neoplasms; Male; Membrane Proteins; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Pharmacogenomic Testing; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Rectal Neoplasms; Rectum; Response Evaluation Criteria in Solid Tumors; Survival Analysis
PubMed: 32530992
DOI: 10.15403/jgld-1003 -
Clinical Pharmacology and Therapeutics Feb 2022Aminoglycosides are widely used antibiotics with notable side effects, such as nephrotoxicity, vestibulotoxicity, and sensorineural hearing loss (cochleotoxicity)....
Aminoglycosides are widely used antibiotics with notable side effects, such as nephrotoxicity, vestibulotoxicity, and sensorineural hearing loss (cochleotoxicity). MT-RNR1 is a gene that encodes the 12s rRNA subunit and is the mitochondrial homologue of the prokaryotic 16s rRNA. Some MT-RNR1 variants (i.e., m.1095T>C; m.1494C>T; m.1555A>G) more closely resemble the bacterial 16s rRNA subunit and result in increased risk of aminoglycoside-induced hearing loss. Use of aminoglycosides should be avoided in individuals with an MT-RNR1 variant associated with an increased risk of aminoglycoside-induced hearing loss unless the high risk of permanent hearing loss is outweighed by the severity of infection and safe or effective alternative therapies are not available. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of aminoglycosides based on MT-RNR1 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).
Topics: Aminoglycosides; Anti-Bacterial Agents; Clinical Decision-Making; Genotype; Hearing Loss, Sensorineural; Humans; Ototoxicity; Patient Safety; Pharmacogenetics; Pharmacogenomic Testing; Pharmacogenomic Variants; Predictive Value of Tests; RNA, Ribosomal; Risk Assessment; Risk Factors
PubMed: 34032273
DOI: 10.1002/cpt.2309