Munir Pirmohamed

Pharmacogenomics is the examination of how genetic variation influences drug metabolism and response, in terms of both efficacy and safety. In cardiovascular disease, patient‐specific diplotypes determine phenotypes, thereby influencing the efficacy and safety of drug treatments, including statins, antiarrhythmics, anticoagulants and antiplatelets. Notably, polymorphisms in key genes, such as CYP2C9, CYP2C19, VKORC1 and SLCO1B1, significantly impact the outcomes of treatment with clopidogrel, warfarin and simvastatin. Furthermore, the CYP2C19 polymorphism influences the pharmacokinetics and safety of the novel hypertrophic cardiomyopathy inhibitor, mavacamten. In this review, we critically assess the clinical application of pharmacogenomics in cardiovascular disease and delineate present and future utilization of pharmacogenomics. This includes insights into identifying missing heritability, the …

ObjectivesPharmacovigilance databases play a critical role in monitoring drug safety. The duplication of reports in pharmacovigilance databases, however, undermines their data integrity. This scoping review sought to provide a comprehensive understanding of duplication in pharmacovigilance databases worldwide.DesignA scoping review.Data sourcesReviewers comprehensively searched the literature in PubMed, Web of Science, Wiley Online Library, EBSCOhost, Google Scholar and other relevant websites.Eligibility criteriaPeer-reviewed publications and grey literature, without language restriction, describing duplication and/or methods relevant to duplication in pharmacovigilance databases from inception to 1 September 2023.Data extraction and synthesisWe used the Joanna Briggs Institute guidelines for scoping reviews and conformed with the Preferred Reporting Items for Systematic Reviews and Meta …

MP has received partnership funding for the following: MRC Clinical Pharmacology Training Scheme (co-funded by MRC and Roche, UCB, Eli Lilly and Novartis). He has developed an HLA genotyping panel with MC Diagnostics, but does not benefit financially from this. He is part of the IMI Consortium ARDAT (www. ardat. org). None of the funding MP received is related to the current paper. IGA reports no conflicts of interest in this work.

Clinical drug response constitutes a complex phenotype emerging from the interplay of demographic, clinical, environmental, and genomic factors, among others. This complexity results in a marked interindividual variation in cardiovascular drug response, affecting both efficacy and toxicity, which can result in patient harm and the inefficient utilization of limited healthcare resources. Pharmacogenomics is the study and clinical application of the genetic determinants of drug response variation and aims to optimize drug efficacy and minimize adverse drug reactions through genotype-informed prescribing and monitoring recommendations. Pharmacogenomic associations have been established for several licensed cardiovascular drugs, including clopidogrel (CYP2C19), warfarin (VKORC1, CYP2C9, CYP4F2), and simvastatin (SLCO1B1). However, no cardiovascular pharmacogenomic association has yet been …

Anticoagulants are potent therapeutics widely used in medical and surgical settings, and the amount spent on anticoagulation is rising. Although warfarin remains a widely prescribed oral anticoagulant, prescriptions of direct oral anticoagulants (DOACs) have increased rapidly. Heparin-based parenteral anticoagulants include both unfractionated and low molecular weight heparins (LMWHs). In clinical practice, anticoagulants are generally well tolerated, although interindividual variability in response is apparent. This variability in anticoagulant response can lead to serious incident thrombosis, haemorrhage and off-target adverse reactions such as heparin-induced thrombocytopaenia (HIT). This review seeks to highlight the genetic, environmental and clinical factors associated with variability in anticoagulant response, and review the current evidence base for tailoring the drug, dose, and/or monitoring decisions to …

About 1 in 2 to 1 in 3 people will develop cancer during their lifetime. Cancer is a genetic disease, and any patient who develops cancer has two genomes, the germline genome and the cancer genome. The cancer genome accumulates mutations, some of which may drive the progression of the disease (driver mutations). Our ability to sequence genomes has allowed (1) the development of targeted therapies (which target particular aberrant tumour proteins);(2) the identification of common genetic abnormalities across different tumour types leading to the development of tumour agnostic drugs;(3) the understanding of the role of the immune system in the cancer growth and spread; and (4) the development of liquid biopsy approaches for diagnosis, recurrence and prognosis. More recently, following the COVID-19 pandemic, there has been increasing interest in using mRNA technologies to develop highly …

Background: DNA methylation episignatures have been recognised to display specific patterns in individuals with congenital neurodevelopmental disorders. Investigating and establishing technologies for episignature detection has been a focus at NSW Health Pathology Genetics, Randwick resulting in recent accreditation for EpiSign and ongoing research investment in long-read sequencing technologies. Methodology and results: Episign was verified using 15 known control samples and 33 discovery samples with normal whole exome sequencing and/or microarray, or variants of unknown clinical significance sourced from the Australian ID Flagship cohort. DNA was bisulfite converted and processed using an Illumina Infinium MethylationEPIC beadchip according to manufacturer, s protocols. Episignature analysis was performed externally by London Health Services Canada using the EpiSign analysis protocol …

Objectives To use text mining approaches to identify instances of suspected adverse drug reactions recorded in first opinion veterinary free‐text clinical narratives, and to evaluate whether these were also reported to either the Veterinary Medicines Directorate or the relevant Marketing Authorisation holder in order to derive an estimate of the suspected adverse drug reaction (sADR) minimum under‐reporting rate. To characterise sADR reports and explore whether particular features are associated with report submission. Materials and Methods Two regular expressions were developed to identify mentions of “adverse drug reactions” and “side effects” in the free‐text clinical narratives of electronic health records contained within the Small Animal Veterinary Surveillance Network database. Consultations containing a match for the developed regular expressions were manually reviewed for inclusion and further …

In vitro preclinical drug-induced liver injury (DILI) risk assessment relies largely on the use of hepatocytes to measure drug-specific changes in cell function or viability. Unfortunately, this does not provide indications toward the immunogenicity of drugs and/or the likelihood of idiosyncratic reactions in the clinic. This is because the molecular initiating event in immune DILI is an interaction of the drug-derived antigen with MHC proteins and the T-cell receptor. This study utilized immune cells from drug-naïve donors, recently established immune cell coculture systems and blinded compounds with and without DILI liabilities to determine whether these new methods offer an improvement over established assessment methods for the prediction of immune-mediated DILI. Ten blinded test compounds (6 with known DILI liabilities; 4 with lower DILI liabilities) and 5 training compounds, with known T-cell-mediated …

Thiazide diuretics, widely used in hypertension, cause a variety of adverse reactions, including hyperglycemia, hyperuricemia, and electrolyte abnormalities. In this study, we aimed to identify genetic variants that interact with thiazide‐use to increase the risk of these adverse reactions. Using UK Biobank data, we first performed genomewide variance quantitative trait locus (vQTL) analysis of ~ 6.2 million SNPs on 95,493 unrelated hypertensive White British participants (24,313 on self‐reported bendroflumethiazide treatment at recruitment) for 2 blood (glucose and urate) and 2 urine (potassium and sodium) biomarkers. Second, we conducted direct gene–environment interaction (GEI) tests on the significant (P < 2.5 × 10−9) vQTLs, included a second UK Biobank cohort comprising 13,647 unrelated hypertensive White British participants (3,478 on thiazides other than bendroflumethiazide) and set significance at …

4-Chlorokynurenine (4-Cl-KYN, AV-101) is a prodrug of a NMDA receptor antagonist and is in clinical development for potential CNS indications. We sought to further understand the distribution and metabolism of 4-Cl-KYN, as this information might provide a strategy to enhance the clinical development of this drug. We used excretion studies in rats, in vitro transporter assays, and pharmacogenetic analysis of clinical trial data to determine how 4-Cl-KYN and metabolites are distributed. Our data indicated that a novel acetylated metabolite (N-acetyl-4-Cl-KYN) did not affect the uptake of 4-Cl-KYN across the blood–brain barrier via LAT1. 4-Cl-KYN and its metabolites were found to be renally excreted in rodents. In addition, we found that N-acetyl-4-Cl-KYN inhibited renal and hepatic transporters involved in excretion. Thus, this metabolite has the potential to limit the excretion of a range of compounds. Our …

Background Adverse drug reactions (ADRs) are common and a leading cause of injury. However, information on ADR risks of individual medicines is often limited. The aim of this hypothesis‐generating study was to assess the relative importance of ADR‐related and emergency hospital admission for large group of medication classes. Methods This study was a propensity‐matched case‐control study in English primary care. Data sources were Clinical Practice Research Databank and Aurum with longitudinal, anonymized, patient level electronic health records (EHRs) from English general practices linked to hospital records. Cases aged 65–100 with ADR‐related or emergency hospital admission were matched to up to six controls by age, sex, morbidity and propensity scores for hospital admission risk. Medication groups with systemic administration as listed in the British National Formulary (used by prescribers …

Older adults are persistently underrepresented in clinical drug trials worldwide, despite increasing multiple long‐term conditions and significant prescribing in this demographic. We discuss systemic challenges such as the exclusion of people with comorbid conditions and the lack of assessment for comorbidities as modifiers of treatment effects and highlight the rising trend of polypharmacy, especially among the oldest age groups, which is linked to a significant percentage of unplanned hospitalizations and medication errors. The consequences of these trends prompted the United Kingdom National Overprescribing review, culminating in a set of recommendations for drug development tailored to older adults. Building on this, two critical reports released in April 2023 by the International Longevity Centre (ILC) and the Nuffield Council on Bioethics (NCOB) are discussed. These reports emphasize the importance of …

There are numerous clinical risk factors associated with stroke, including atrial fibrillation, hypertension, and hypercholesterolemia. Such risks can be ameliorated with appropriate pharmacotherapy. However, there is variability in response to drugs used for these conditions, which may, at least in part, be genetically determined. For instance, genetic determinants of response to warfarin, statins, antiplatelet agents, and some antihypertensives have been described.

Background Vancomycin, a glycopeptide antibiotic used for Gram‐positive bacterial infections, has been linked with drug reaction with eosinophilia and systemic symptoms (DRESS) in HLA‐A*32:01‐expressing individuals. This is associated with activation of T lymphocytes, for which glycolysis has been isolated as a fuel pathway following antigenic stimulation. However, the metabolic processes that underpin drug‐reactive T‐cell activation are currently undefined and may shed light on the energetic conditions needed for the elicitation of drug hypersensitivity or tolerogenic pathways. Here, we sought to characterise the immunological and metabolic pathways involved in drug‐specific T‐cell activation within the context of DRESS pathogenesis using vancomycin as model compound and drug‐reactive T‐cell clones (TCCs) generated from healthy donors and vancomycin‐hypersensitive patients. Methods CD4 …

Background Exposure to nonsteroidal anti‐inflammatory drugs (NSAIDs) such as ibuprofen (IBU) and naproxen (NAP) is associated with idiosyncratic drug‐induced liver injury (DILI). Carboxylate bioactivation into reactive metabolites (e.g., acyl glucuronides, AG) and resulting T‐cell activation is hypothesized as causal for this adverse event. However, conclusive evidence supporting this is lacking. Methods In this work, we identify CD4+ and CD8+ T‐cell hepatic infiltration in a biopsy from an IBU DILI patient. Lymphocyte transformation test and IFN‐γ ELIspot, conducted on peripheral blood mononuclear cells (PBMCs) of patients with NAP‐DILI, were used to explore drug‐specific T‐cell activation. T‐cell clones (TCC) were generated and tested for drug specificity, phenotype/function, and pathways of T‐cell activation. Cells were exposed to NAP, its oxidative metabolite 6‐O‐desmethyl NAP (DM‐NAP), its AG or …

There is considerable inter-individual variability in the effectiveness and safety of pharmaceutical interventions. This phenomenon can be attributed to a multitude of factors; however, it is widely acknowledged that common genetic variation affecting drug absorption or metabolism play a substantial contributory role. This is a concept known as pharmacogenetics. Understanding how common genetic variants influence responses to medications, and using this knowledge to inform prescribing practice, could yield significant advantages for both patients and healthcare systems. Some health services around the world have introduced pharmacogenetics into routine practice, whereas others are less advanced along the implementation pathway. This chapter introduces the field of pharmacogenetics, the existing body of evidence, and discusses barriers to implementation. The chapter will specifically focus on efforts to …

Background Warfarin dosing is highly variable, due to clinical, environmental, and genetic factors. To facilitate dose optimization, several genome-wide association studies have been conducted, but none in sub-Saharan Africa.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15–20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1–5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28–29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to …

This study evaluated drug–drug interactions (DDIs) between antibiotic and nonantibiotic drugs listed with warnings of severe outcomes in the British National Formulary based on adverse drug reaction (ADR) detectable with routine International Classification of Diseases, Tenth Revision coding. Data sources were Clinical Practice Research Databank GOLD and Aurum anonymized electronic health records from English general practices linked to hospital admission records. In propensity‐matched case‐control study, outcomes were ADR or emergency admissions. Analyzed were 121,546 ADR‐related admission cases matched to 638,238 controls. For most antibiotics, adjusted odds ratios (aORs) for ADR‐related hospital admission were large (aOR for trimethoprim 4.13; 95% confidence interval (CI), 3.97–4.30). Of the 51 DDIs evaluated for ADR‐related admissions, 38 DDIs (74.5%) had statistically increased …