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CMAJ : Canadian Medical Association... Nov 2023Pharmacogenomic testing to identify variations in genes that influence metabolism of antidepressant medications can enhance efficacy and reduce adverse effects of...
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.
Topics: Adult; Humans; Depressive Disorder, Major; Pharmacogenetics; Depression; Cost-Benefit Analysis; Antidepressive Agents; Quality-Adjusted Life Years; British Columbia
PubMed: 37963621
DOI: 10.1503/cmaj.221785 -
The Pharmacogenomics Journal Nov 2023Compound-analgesics containing codeine (CACC) have been a common source of codeine for people seeking opioid replacement therapy (ORT) for codeine use disorder (CUD)....
Compound-analgesics containing codeine (CACC) have been a common source of codeine for people seeking opioid replacement therapy (ORT) for codeine use disorder (CUD). Our previous work demonstrated no relationship between pre-treatment CACC and ORT buprenorphine doses; we hypothesised that CYP2D6 activity would partially account for this disconnection. One hundred six participants with CUD were compared to a published population sample of 5408 Australian patients. Mean age of participants with CUD at treatment entry was 35 years, with mean 6.1 years duration of CUD. Mean codeine dose was 660 mg/day (range 40-2700 mg). Mean calculated CYP2D6 activity scores were significantly higher in the codeine group (CUD 1.65 + 0.63 vs. Gen pop 1.39 + 0.65, Wilcoxon W = 347,001, p < 0.001). Pre-treatment CACC dose weakly predicted sublingual buprenorphine doses overall; there was a stronger relationship within ultrarapid metabolisers. While normal and ultrarapid metabolisers of codeine were more likely to have a diagnosis of CUD, poor or intermediate CYP2D6 metaboliser status may protect against CUD.
Topics: Humans; Adult; Analgesics, Opioid; Cytochrome P-450 CYP2D6; Australia; Codeine; Buprenorphine; Chloride Channels
PubMed: 37940651
DOI: 10.1038/s41397-023-00319-6 -
Genes Oct 2023Pharmacogenomic (PGx) testing to inform antidepressant medication selection and dosing is gaining attention from healthcare professionals, patients, and payors in...
Pharmacogenomic (PGx) testing to inform antidepressant medication selection and dosing is gaining attention from healthcare professionals, patients, and payors in Australia. However, there is often uncertainty regarding which test is most suitable for a particular patient. Here, we identified and evaluated the coverage of and variants in commercial antidepressant PGx testing panels in Victoria, a large and ethnically diverse state of Australia. Test characteristics and star alleles tested for both genes were obtained directly from pathology laboratories offering PGx testing and compared against the Association of Molecular Pathology's recommended minimum (Tier 1) and extended (Tier 2) allele sets. Although all tests covered the minimum recommended alleles for , this was not the case for . This study emphasizes that PGx tests might not be suitable for all individuals in Australia due to the limited range of star alleles assessed. Inadequate haplotype coverage may risk misclassification of an individual's predicted metabolizer phenotype, which has ramifications for depression medication selection and dosage. This study underscores the urgent need for greater standardization in PGx testing and emphasizes the importance of considering genetic ancestry when choosing a PGx testing panel to ensure optimal clinical applicability.
Topics: Humans; Pharmacogenomic Testing; Cytochrome P-450 CYP2D6; Victoria; Cytochrome P-450 CYP2C19; Antidepressive Agents
PubMed: 37895294
DOI: 10.3390/genes14101945 -
Clinical and Translational Science Dec 2023This study explored the acceptability of a novel pharmacist-led pharmacogenetics (PGx) screening program among patients with cancer and healthcare professionals (HCPs)...
This study explored the acceptability of a novel pharmacist-led pharmacogenetics (PGx) screening program among patients with cancer and healthcare professionals (HCPs) taking part in a multicenter clinical trial of PGx testing (PACIFIC-PGx ANZCTR:12621000251820). Medical oncologists, oncology pharmacists, and patients with cancer from across four sites (metropolitan/regional), took part in an observational, cross-sectional survey. Participants were recruited from the multicenter trial. Two study-specific surveys were developed to inform implementation strategies for scaled and sustainable translation into routine clinical care: one consisting of 21 questions targeting HCPs and one consisting of 17 questions targeting patients. Responses were collected from 24 HCPs and 288 patients. The 5-to-7-day PGx results turnaround time was acceptable to HCP (100%) and patients (69%). Most HCPs (92%) indicated that it was appropriate for the PGx clinical pharmacist to provide results to patients. Patients reported equal preference for receiving PGx results from a doctor/pharmacist. Patients and HCPs highly rated the pharmacist-led PGx service. HCPs were overall accepting of the program, with the majority (96%) willing to offer PGx testing to their patients beyond the trial. HCPs identified that lack of financial reimbursements (62%) and lack of infrastructure (38%) were the main reasons likely to prevent/slow the implementation of PGx screening program into routine clinical care. Survey data have shown overall acceptability from patients and HCPs participating in the PGx Program. Barriers to implementation of PGx testing in routine care have been identified, providing opportunity to develop targeted implementation strategies for scaled translation into routine practice.
Topics: Humans; Cross-Sectional Studies; Health Personnel; Neoplasms; Patient Acceptance of Health Care; Pharmacogenetics; Pharmacogenomic Testing; Dihydropyrimidine Dehydrogenase Deficiency
PubMed: 37877594
DOI: 10.1111/cts.13664 -
Journal of Developmental and Behavioral...This study investigated outcomes of pharmacogenetic testing of youth with autism spectrum disorder (ASD) referred to a precision medicine clinic and explored...
OBJECTIVE
This study investigated outcomes of pharmacogenetic testing of youth with autism spectrum disorder (ASD) referred to a precision medicine clinic and explored associations between patient characteristics and pharmacogenomic testing results.
METHODS
Records for patients diagnosed with ASD and subsequently referred to a pediatric hospital's precision medicine clinic between July 1, 2010, and June 30, 2020, were reviewed. Pharmacogenetic testing results were abstracted focusing on CYP2D6 and CYP2C19. In addition, we compiled counts of patients' co-occurring diagnoses, histories of adverse drug reactions (ADRs), previously trialed ineffective medications, and previous psychiatric medication changes. Logistic regression models were fit to examine CYP2C19 and CYP2D6 metabolizer status as functions of patient demographics and prereferral medication histories.
RESULTS
Of 202 patients (mean age = 12.18 yrs), 66% were referred to precision medicine because of poor medication response. Among patients with pharmacogenomic testing results for CYP2D6, 9% were classified as poor metabolizers; among patients with results for CYP2C19, 10% were classified as rapid/ultrarapid metabolizers. Patient demographics and medication response history did not predict pharmacogenomic results. However, the number of co-occurring diagnoses positively predicted the number of nonpsychiatric ADRs and a higher probability of CYP2D6 poor metabolizer status; moreover, nonpsychiatric ADRs positively predicted CYP2C19 rapid/ultrarapid metabolizer status.
CONCLUSION
In one of the largest reported samples of youth with ASD clinically referred for pharmacogenetic testing, we observed high variability in medication response and yield for actionable results. Our findings suggest potential clinical utility for pharmacogenetic testing and introduce possible clinical profiles associated with metabolizer status.
Topics: Child; Adolescent; Humans; Cytochrome P-450 CYP2D6; Precision Medicine; Cytochrome P-450 CYP2C19; Pharmacogenomic Testing; Autism Spectrum Disorder; Genotype
PubMed: 37807195
DOI: 10.1097/DBP.0000000000001215 -
JAMA Network Open Oct 2023Limited evidence supports multigenetic pharmacogenomics-guided treatment (MPGT) in schizophrenia. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Limited evidence supports multigenetic pharmacogenomics-guided treatment (MPGT) in schizophrenia.
OBJECTIVE
To evaluate the clinical effectiveness of MPGT in schizophrenia in a randomized clinical trial (RCT).
DESIGN, SETTING, AND PARTICIPANTS
This RCT was conducted from March 2020 to March 2022. Male Chinese Han inpatients aged 18 to 60 years diagnosed with schizophrenia with a Positive and Negative Symptom Scale (PANSS) score of 60 or more from 2 selected study hospitals were included. Patients and raters were masked to MPGT or treatment as usual (TAU) randomization.
INTERVENTIONS
Participants were randomly assigned in a 1:1 ratio to receive either MPGT or TAU for 12 weeks.
MAIN OUTCOMES AND MEASURES
The primary efficacy outcome was the percentage change in PANSS total scores (range, 30 to 210) from baseline to week 6 analyzed by a modified intention-to-treat mixed model for repeated measures. The secondary outcome included response and symptomatic remission rates.
RESULTS
A total of 210 participants (mean [SD] age, 29.2 [8.8] years) were enrolled and analyzed, with 113 assigned to MPGT and 97 to TAU. Compared with those randomized to TAU, participants randomized to MPGT demonstrated a significantly higher percentage change in PANSS score (74.2% vs 64.9%; adjusted mean difference, 9.2 percentage points; 95% CI, 4.4-14.1 percentage points; P < .001) and a higher response rate (93 of 113 [82.3%] vs 63 of 97 [64.9%]; adjusted odds ratio, 2.48; 95% CI, 1.28-4.80; P = .01) at the end of week 6.
CONCLUSIONS AND RELEVANCE
In this RCT of MPGT, MPGT was more effective than TAU in treating patients with schizophrenia. These findings suggest that multigenetic pharmacogenomic testing could serve as an effective tool to guide the treatment of schizophrenia.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR2000029671.
Topics: Male; Humans; Adult; Pharmacogenetics; Schizophrenia; Treatment Outcome
PubMed: 37801319
DOI: 10.1001/jamanetworkopen.2023.35518 -
Frontiers in Neuroscience 2023The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field...
BACKGROUND
The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug.
METHODS
Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals ( = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants.
RESULTS
The GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing.
CONCLUSION
We set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.
PubMed: 37790589
DOI: 10.3389/fnins.2023.1156362 -
Acta Medica Portuguesa Oct 2023
Topics: Humans; Pharmacogenetics; Drug-Related Side Effects and Adverse Reactions
PubMed: 37788651
DOI: 10.20344/amp.20170 -
PloS One 2023Pharmacogenomic testing may be used to improve treatment outcomes and reduce the frequency of adverse drug reactions (ADRs). Population specific, targeted...
Pharmacogenomic testing may be used to improve treatment outcomes and reduce the frequency of adverse drug reactions (ADRs). Population specific, targeted pharmacogenetics (PGx) panel-based testing methods enable sensitive, accurate and economical implementation of precision medicine. We evaluated the analytical performance of the GenoPharm® custom open array platform which evaluates 120 SNPs across 46 pharmacogenes. Using commercially available reference samples (Coriell Biorepository) and in-house extracted DNA, we assessed accuracy, precision, and linearity of GenoPharm®. We then used GenoPharm® on 218 samples from two Southern African black populations and determined allele and genotype frequencies for selected actionable variants. Across all assays, the GenoPharm® panel demonstrated 99.5% concordance with the Coriell reference samples, with 98.9% reproducibility. We observed high frequencies of key genetic variants in people of African ancestry: CYP2B6*6 (0.35), CYP2C9*8, *11 (0.13, 0.03), CYP2D6*17 (0.21) and *29 (0.11). GenoPharm® open array is therefore an accurate, reproducible and sensitive test that can be used for clinical pharmacogenetic testing and is inclusive of variants specific to the people of African ancestry.
Topics: Humans; Genotype; Reproducibility of Results; Precision Medicine; Pharmacogenetics; Cytochrome P-450 CYP2D6
PubMed: 37788265
DOI: 10.1371/journal.pone.0292131 -
Journal of Pharmacological Sciences Nov 2023The usefulness of NUDT15 genotyping as a pharmacogenomic test for thiopurine has been established. The first such test developed to date, NUDT15 genotyping was approved...
The usefulness of NUDT15 genotyping as a pharmacogenomic test for thiopurine has been established. The first such test developed to date, NUDT15 genotyping was approved for reimbursement in Japan in February 2019 for all indicated patients. We retrospectively examined claims data in Japan and confirmed that the proportion of patients who undergo genotyping before initiating a new thiopurine regimen has increased; furthermore, genotyping has improved the rate of treatment continuation and reduced on-treatment hospitalization. However, the genotyping rate before thiopurine induction was >50% for patients with inflammatory bowel disease and <20% for those with other immune-related diseases, indicating significant variation by disease field. Additionally, over 10% of tests were found to have been performed inappropriately, such as multiple genotyping of the same patient or testing more than 2 weeks after starting treatment. Although NUDT15 genotyping for patients requiring thiopurine treatment has been shown to improve thiopurine treatment continuation rate, measures are required to address the systematic issues identified in our analysis.
PubMed: 37770157
DOI: 10.1016/j.jphs.2023.09.002