The variant allele HLA‐B*15:02 is strongly associated with greater risk of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients treated with carbamazepine or oxcarbazepine. ...The variant allele HLA‐A*31:01 is associated with greater risk of maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms, and SJS/TEN in patients treated with carbamazepine. We summarize evidence from the published literature supporting these associations and provide recommendations for carbamazepine and oxcarbazepine use based on HLA genotypes.
Summary
Objective
To systematically review evidence on genetic risk factors for carbamazepine (CBZ)–induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key ...questions: (1) Should genetic testing for HLA‐B*15:02 and HLA‐A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ‐induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA‐B*15:02 or HLA‐A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results?
Methods
A systematic literature search was performed for HLA‐B*15:02 and HLA‐A*31:01 and their association with CBZ‐induced HSRs. Evidence was critically appraised and clinical practice recommendations were developed based on expert group consensus.
Results
Patients carrying HLA‐B*15:02 are at strongly increased risk for CBZ‐induced Stevens‐Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in populations where HLA‐B*15:02 is common, but not CBZ‐induced hypersensitivity syndrome (HSS) or maculopapular exanthema (MPE). HLA‐B*15:02–positive patients with CBZ‐SJS/TEN have been reported from Asian countries only, including China, Thailand, Malaysia, and India. HLA‐B*15:02 is rare among Caucasians or Japanese; no HLA‐B*15:02‐positive patients with CBZ‐SJS/TEN have been reported so far in these groups. HLA‐A*31:01–positive patients are at increased risk for CBZ‐induced HSS and MPE, and possibly SJS/TEN and acute generalized exanthematous pustulosis (AGEP). This association has been shown in Caucasian, Japanese, Korean, Chinese, and patients of mixed origin; however, HLA‐A*31:01 is common in most ethnic groups. Not all patients carrying either risk variant develop an HSR, resulting in a relatively low positive predictive value of the genetic tests.
Significance
This review provides the latest update on genetic markers for CBZ HSRs, clinical practice recommendations as a basis for informed decision making regarding the use of HLA‐B*15:02 and HLA‐A*31:01 genetic testing in patients with an indication for CBZ therapy, and identifies knowledge gaps to guide future research.
A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Aims
Anthracycline‐induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline‐based chemotherapy. In various genetic association studies, ...potential genetic risk markers for ACT have been identified. Therefore, we developed evidence‐based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk.
Methods
We followed a standard guideline development process, including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group.
Results
RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B – moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow‐up, as well as therapeutic options within the current standard of clinical practice.
Conclusions
Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT.
The effectiveness of anthracycline chemotherapeutics (e.g., doxorubicin) is limited by anthracycline-induced cardiotoxicity (ACT). A nonsynonymous variant (S427L) in the retinoic acid receptor-γ ...(RARG) gene has been associated with ACT. This variant causes reduced RARG activity, which is hypothesized to lead to increased susceptibility to ACT through reduced activation of the retinoic acid pathway. This study explored the effects of activating the retinoic acid pathway using a RAR-agonist, all-trans retinoic acid (ATRA), in human cardiomyocytes and mice treated with doxorubicin. In human cardiomyocytes, ATRA induced the gene expression of RARs (RARG, RARB) and repressed the expression of topoisomerase II enzyme genes (TOP2A, TOP2B), which encode for the molecular targets of anthracyclines and repressed downstream ACT response genes. Importantly, ATRA enhanced cell survival of human cardiomyocytes exposed to doxorubicin. The protective effect of ATRA was also observed in a mouse model (B6C3F1/J) of ACT, in which ATRA treatment improved heart function compared to doxorubicin-only treated mice. Histological analyses of the heart also indicated that ATRA treatment reduced the pathology associated with ACT. These findings provide additional evidence for the retinoic acid pathway's role in ACT and suggest that the RAR activator ATRA can modulate this pathway to reduce ACT.
Medication use in children represents 15–20% of total drug sales. More than 50% of children receive at least one prescription medication a year. Despite this, few drugs have a paediatric formulation ...available. Furthermore, 80% of paediatric prescriptions are considered off‐label. Off‐label use is defined as the use of products that differ in dose, indication or route of administration from the one established in the summary of product characteristics. Off‐label use is associated with an increased risk of adverse drug reactions, including therapeutic failure. The US Food and Drug Administration and the European Medicines Agency have made changes to regulations to incentivize the development of paediatric formulations.
Novel paediatric formulations can ease drug administration, reducing medication errors, increasing dosing acceptability, medication adherence and improve safety. Two routes for paediatric drug approval are available, the traditional, requiring clinical trials and the formulation bridging path, where these formulations need to demonstrate equivalence with the existing adult formulations.
New formulations seeking regulatory approval require bioequivalence studies, but the regulatory framework, which states that bioequivalence data are obtained from adults and then extrapolated to children, may be disregarding important physiological differences between these two populations of patients.
It is important to ensure that drugs for children have been appropriately studied and are properly manufactured for them. Adequately designed studies will provide data that will improve our understanding of how drug disposition differs between adults and children and will pave the way for children to get the best possible treatment.
Multiple pharmacogenomic studies have identified the synonymous genomic variant rs7853758 (G > A, L461L) and the intronic variant rs885004 in
(solute carrier family 28 member 3) as statistically ...associated with a lower incidence of anthracycline-induced cardiotoxicity. However, the true causal variant(s), the cardioprotective mechanism of this locus, the role of
and other solute carrier (SLC) transporters in anthracycline-induced cardiotoxicity, and the suitability of SLC transporters as targets for cardioprotective drugs has not been investigated.
Six well-phenotyped, doxorubicin-treated pediatric patients from the original association study cohort were recruited again, and human induced pluripotent stem cell-derived cardiomyocytes were generated. Patient-specific doxorubicin-induced cardiotoxicity (DIC) was then characterized using assays of cell viability, activated caspase 3/7, and doxorubicin uptake. The role of
in DIC was then queried using overexpression and knockout of
in isogenic human-induced pluripotent stem cell-derived cardiomyocytes using a CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9). Fine-mapping of the
locus was then completed after
resequencing and an extended in silico haplotype and functional analysis. Genome editing of the potential causal variant was done using cytosine base editor.
overexpression was done using a lentiviral plasmid-based transduction and was validated using stranded RNA-sequencing after ribosomal RNA depletion. Drug screening was done using the Prestwick Chemical Library (n = 1200), followed by in vivo validation in mice. The effect of desipramine on doxorubicin cytotoxicity was also investigated in 8 cancer cell lines.
Here, using the most commonly used anthracycline, doxorubicin, we demonstrate that patient-derived cardiomyocytes recapitulate the cardioprotective effect of the
locus and that SLC28A3 expression influences the severity of DIC. Using Nanopore-based fine-mapping and base editing, we identify a novel cardioprotective single nucleotide polymorphism, rs11140490, in the
locus; its effect is exerted via regulation of an antisense long noncoding RNA (
) that overlaps with
Using high-throughput drug screening in patient-derived cardiomyocytes and whole organism validation in mice, we identify the SLC competitive inhibitor desipramine as protective against DIC.
This work demonstrates the power of the human induced pluripotent stem cell model to take a single nucleotide polymorphism from a statistical association through to drug discovery, providing human cell-tested data for clinical trials to attenuate DIC.
In a study by Perez-Vilar et al in this issue of The Journal of Infectious Diseases, the Vaccine Safety Datalink (VSD) identified a statistical signal for an increased risk of GBS in days 1–42 ...following 2018–2019 high-dose influenza vaccine, and this signal was explored among Medicare beneficiaries aged ≥65 years and VSD chart-confirmed analyses. The study found a small, nonsignificant risk (point estimates ranging from 1.12 to 1.85 depending on the analysis) among Medicare beneficiaries and a relative risk of 1.0 among chart-confirmed cases in the VSD. The authors appropriately conclude from these data that they could not exclude an association between high-dose influenza vaccine and GBS, but if such a risk existed, it was similar to previous seasons.The benefits of influenza vaccine vastly outweigh the very small risks associated with vaccination, as exemplified in this study. Had a risk of GBS at the level seen in 1976 occurred, ongoing federal vaccine safety activities would have identified it quickly. However, studying extremely small risks on order of 1–3 per million is exceedingly difficult. Large linked administrative databases such as the VSD and Medicare greatly facilitate the efficiency and validity of such studies. Examining multiple years of data and combining databases globally affords the opportunity to increase power sufficiently to answer such questions 29.
Anthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants ...associated with ACT in patients treated for childhood cancer.
We carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands.
We identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 × 10(-5) for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate-binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT.
We have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.
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