Munir Pirmohamed

University of Liverpool | UoL · Department of Molecular and Clinical Pharmacology

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 perso...

In vitro preclinical drug-induced liver injury (DILI) risk assessment relies largely on use of hepatocytes to measure drug-specific changes in cell function or viability. Unfortunately, this does not provide indications towards the immunogenicity of drugs and/or the likelihood for idiosyncratic reactions in the clinic. This is because the molecular...

Antidepressants and antipsychotics, commonly prescribed worldwide, exhibit significant variability in patient responses. Genetic variations contribute substantially to this variability, offering the potential for predicting individual responses through pharmacogenetic testing. Clinical guidelines provided by organizations like the Clinical Pharmaco...

Introduction Anticholinergic medications block the neurotransmitter acetylcholine in the brain and peripheral nervous system. Many medications have anticholinergic properties, and the cumulative effect of these medications is termed anticholinergic burden. Increased anticholinergic burden can have short-term side effects such as dry mouth, blurred...

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 stud...

Background & Aims Population screening for non-alcoholic fatty liver disease (NAFLD) and associated comorbidities remains an unaddressed clinical need. We aimed to assess the utility of the fatty liver index (FLI) for risk stratification of NAFLD and related comorbidities using the UK Biobank. Methods Electronic health records and liver MRI-proton...

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. Howev...

Background: The quality of warfarin anticoagulation among Sub-Saharan African patients is suboptimal. This is due to several factors, including a lack of standardized dosing algorithms, difficulty in providing timely international normalized ratio (INR) results, a lack of patient feedback on their experiences with treatment, a lack of education on...

4-chlorokynurenine (4-Cl-KYN) is in clinical development for potential CNS indications. We have 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 ana...

Objective. The aim of this exploratory study was to ascertain the current educational status of pharmacogenomics (PGx) within the present and future UK pharmacy profession, in addition to ascertaining future educational and infrastructure needs of pharmacists to adopt PGx into practice. Methods. A 35-question survey was sent electronically to pract...

Background: Taxane-induced peripheral neuropathy (TIPN) is an important cause of premature treatment cessation and dose-limitation in cancer therapy. It also reduces quality of life and survivorship in affected patients. Genetic polymorphisms in the CYP3A family have been investigated but the findings have been inconsistent and contradictory. Metho...

Decreased epidermal high-mobility group box 1 (HMGB1) expression is an early marker of epidermal injury in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Etanercept, an anti-tumor necrosis factor therapeutic, is effective in the treatment of SJS/TEN. The objective was to characterize antitumor necrosis factor-alpha (TNF-α)-mediated...

Introduction: Adverse drug reactions (ADRs) are an important public health challenge worldwide; however, pharmacovigilance systems are plagued by under-reporting. Mobile technologies, including mobile applications such as Med Safety, could strengthen ADR reporting. We explored the acceptability, and factors that could influence uptake of, Med Safe...

Carbamazepine (CBZ) is an aromatic anticonvulsant known to cause drug hypersensitivity reactions, which range in severity from relatively mild maculopapular exanthema to potentially fatal Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN). These reactions are known to be associated with human leukocyte antigen (HLA) class I alleles,...

Purpose: To evaluate the impact of multiple design criteria for reference sets that are used to quantitatively assess the performance of pharmacovigilance signal detection algorithms (SDAs) for drug-drug interactions (DDIs). Methods: Starting from a large and diversified reference set for two-way DDIs, we generated custom-made reference sets of...

Previous studies have shown that cysteine-reactive drug metabolites bind covalently with protein to activate patient T cells. However, the nature of the antigenic determinants that interact with HLA and whether T cell stimulatory peptides contain the bound drug metabolite has not been defined. Because susceptibility to dapsone hypersensitivity is a...

The advent of immune checkpoint inhibitor therapy was a significant step in the development of treatments for cancer. It is, however, a double-edged sword. Immune related adverse events are the result of unleashing brakes on the immune system and affect many patients undergoing checkpoint inhibitor therapy, often being debilitating and occasionally...

BACKGROUND The quality of warfarin anticoagulation among sub-Saharan African patients is sub-optimal. This is due to several factors including lack of standardized dosing algorithms; difficulty in providing timely INR results; lack of patient feedback on their experiences on treatment; lack of education on adherence and inadequate knowledge and tra...

Background: Polypharmacy can be a consequence of overprescribing that is prevalent in older adults with multimorbidity. Polypharmacy can cause adverse reactions and result in hospital admission. This study predicted risks of adverse drug reaction (ADR)-related and emergency hospital admissions by medicine classes. Methods: We used electronic hea...

Background: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. Methods: We conducted an open-label, multicentre, controlled, cluste...

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS) cause significant morbidity and mortality and impede new drug development. HLA class I associations with SJS/TEN and drug r...

Inter-individual variability in drug response, be it efficacy or safety, is common and likely to become an increasing problem globally given the growing elderly population requiring treatment. Reasons for this inter-individual variability include genomic factors, an area of study called pharmacogenomics. With genotyping technologies now widely avai...

Aim: Serum microRNA-122 (miR-122) is a novel biomarker for drug-induced liver injury, with good sensitivity in early diagnosis of paracetamol-induced liver injury. We describe miR-122 concentrations in participants with anti-tuberculosis drug-induced liver injury (AT-DILI). We explored the relationship between miR-122 and alanine aminotransferase...

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United...

Clinical implementation of pharmacogenomics will help in personalizing drug prescriptions and alleviate the personal and financial burden due to inefficacy and adverse reactions to drugs. However, such implementation is lagging in many parts of the world, including the Middle East, mainly due to the lack of data on the distribution of actionable ph...

Stevens Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse drug reactions (ADRs) characterised by widespread keratinocyte cell-death and epidermal detachment. At present, there is little understanding of how the detachment occurs or how it is abrogated by the TNF-α inhibitor etanercept, an effective SJS/TEN treat...

Since the first polygenic risk score (PRS) in 2007, research in this area has progressed significantly. The increasing number of SNPs that have been identified by large scale GWAS analyses has fuelled the development of a myriad of PRSs for a wide variety of diseases and, more recently, to PRSs that potentially identify differential response to spe...

Background: High alcohol intake is associated with increased mortality. We aimed to identify factors affecting mortality in people drinking extreme amounts. Methods: Information was obtained from the UK Biobank on approximately 500,000 participants aged 40-70 years at baseline assessment in 2006-2010. Habitual alcohol intake, lifestyle and physiol...

Cardiovascular disease remains a leading cause of both morbidity and mortality worldwide. It is widely accepted that both concomitant medications (drug-drug interactions, DDIs) and genomic factors (drug-gene interactions, DGIs) can influence cardiovascular drug-related efficacy and safety outcomes. Although thousands of DDI and DGI (aka pharmacogen...

β-Lactamase inhibitors such as clavulanic acid and tazobactam were developed to overcome β-lactam antibiotic resistance. Hypersensitivity reactions to these drugs have not been studied in detail, and the antigenic determinants that activate T-cells have not been defined. The objectives of this study were to (i) characterize clavulanate- and tazobac...

Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is associated with development of acute hemolytic anemia in the setting of oxidative stress, which can be caused by medication exposure. Regulatory agencies worldwide warn against the use of certain medications in G6PD deficient persons, but in many cases, this information is conflicting, and the...

Diversity in pharmacogenomic studies is poor, especially in relation to the inclusion of black African patients. Lack of funding and difficulties in recruitment, together with the requirement for large sample sizes because of the extensive genetic diversity in Africa, are amongst the factors which have hampered pharmacogenomic studies in Africa. Wa...

Objective To ascertain the burden and associated cost of adverse drug reactions (ADRs), polypharmacy and multimorbidity through a prospective analysis of all medical admissions to a large university teaching hospital over a 1-month period. Design Prospective observational study. Setting Liverpool University Hospital Foundation National Health Ser...

Introduction Combination antiretroviral therapy (cART) has massively reduced HIV mortality. However, longterm cART increases the risk of adverse drug reactions (ADRs), which can lead to higher morbidity, mortality and healthcare costs for people living with HIV (PLHIV). Pharmacovigilance—monitoring the effects of medicines—is essential for unders...

Background: The clinical implementation of pharmacogenomics (PGx) could be one of the first milestones towards realizing personalized medicine in routine care. However, its widespread adoption requires the availability of suitable clinical decision support (CDS) systems, which is often impeded by the fragmentation or absence of adequate health IT...

Background: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of geno...

Introduction Non-alcoholic fatty liver disease (NAFLD) is a complex trait disorder. Genome-wide association studies (GWAS) of MRI hepatic image phenotypes and health records may allow identification of single nucleotide polymorphisms (SNPs) associated with NAFLD. In this study, we have used the UK Biobank to identify potential genetic risk factors...

Objectives To examine the socioeconomic and demographic drivers associated with polypharmacy (5–9 medicines), extreme polypharmacy (9–20 medicines) and increased medication count. Design, setting and participants A total of 5509 participants, from two waves of the English North West Coast, Household Health Survey were analysed Outcome measures Lo...

Warfarin has remained the most commonly prescribed vitamin K oral anticoagulant worldwide since its approval in 1954. Dosing challenges including having a narrow therapeutic window and a wide interpatient variability in dosing requirements have contributed to making it the most studied drug in terms of genotype-phenotype relationships. However, mos...

Aim: To explore the level of agreement on drug-drug interaction (DDI) information listed in three major online drug information resources (DIRs) in terms of: (1) interacting drug pairs; (2) severity rating; (3) evidence rating and (4) clinical management recommendations. Methods: We extracted information from the British National Formulary (BNF)...

Purpose: Bisoprolol is a widely used beta-blocker in patients with cardiovascular diseases. As with other beta-blockers, there is variability in response to bisoprolol, but the underlying reasons for this have not been clearly elucidated. Our aim was to investigate genetic factors that affect bisoprolol pharmacokinetics (PK) and pharmacodynamics (...

BACKGROUND & AIMS Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. METHODS Three cohorts (GenomALC-1: n=1690, GenomALC-2: n=3037, UK Biobank: relevant n=6898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10...

Aims: To update our previously reported systematic review and meta-analysis of observational studies on cardiovascular drug exposure and COVID-19 clinical outcomes by focusing on newly published randomized controlled trials (RCTs). Methods: More than 500 databases were searched between 1-Nov-2020 and 2-Oct-2021 to identify RCTs that were publish...

Hypersensitivity reactions are caused by many structurally unrelated drugs used for many different diseases. These reactions vary in severity and can be fatal. Only a minority of patients are affected by drug hypersensitivity reactions. Predisposition seems to be mediated by genetic factors, particularly within the HLA system. Apart from HLA-B∗57:0...

Aims: To update our previously reported systematic review and meta-analysis of observational studies on cardiovascular drug exposure and COVID-19 clinical outcomes by focusing on newly published randomized controlled trials (RCTs). Methods: More than 500 databases were searched between 1-Nov-2020 and 2-Oct-2021 to identify RCTs that were published...

Teicoplanin is a glycopeptide antibiotic deployed to combat Gram-positive bacterial infection and has recently been associated with development of adverse drug reactions, particularly following previous exposure to vancomycin. In this study, we generated teicoplanin-specific monoclonal T-cell populations from healthy volunteers expressing HLA-A*32:...

Vitamin D and mortality from Covid-19

Background: Vitamin D deficiency has been associated with worse coronavirus disease 2019 (COVID-19) outcomes but circulating 25-hydroxyvitamin D (25(OH)D) is largely bound to vitamin D binding protein (DBP) or albumin both of which tend to fall in illness making 25(OH)D status hard to interpret. Because of this, measurement of unbound "free" and a...

Human leukocyte antigen (HLA) is a hallmark genetic marker for the prediction of certain immune-mediated adverse drug reactions (ADRs). Numerous basic and clinical research studies have provided the evidence base to push forward the clinical implementation of HLA testing for the prevention of such ADRs in susceptible patients. This review explores...

Warfarin remains the most widely prescribed oral anticoagulant in sub‐Saharan Africa. However, because of its narrow therapeutic index, dosing can be challenging. We have therefore (a) evaluated and compared the performance of 21 machine‐learning techniques in predicting stable warfarin dose in sub‐Saharan Black‐African patients and (b) externally...

Background Low-dose aspirin can cause gastric and duodenal ulceration, hereafter called peptic ulcer disease (PUD). Predisposition is thought to be related to clinical and genetic factors; our aim was to identify genetic risk factors associated with aspirin-induced PUD. Methods Patients (n=1478) were recruited from 15 UK hospitals. Cases (n=505) w...

Sequential rule mining is a well-established data mining technique for binary valued data. Many variations have been proposed, most approaches use the support-confidence-lift framework. Existing approaches make assumptions concerning the definition of what a sequence is. However, this definition is application dependent. In this paper we look at se...

An emerging clinical issue associated with immune-oncology agents is the collateral effects on the tolerability of concomitant medications. One report of this phenomenon was the increased incidence of hypersensitivity reactions observed in patients receiving concurrent immune checkpoint inhibitors and sulfasalazine. Thus, the aim of this study was...

There is an evolution and increasing need for the utilization of emerging cellular, molecular and in silico technologies and novel approaches for safety assessment of food, drugs, and personal care products. Convergence of these emerging technologies is also enabling rapid advances and approaches that may impact regulatory decisions and approvals....

Currently no sensitive and specific biomarkers exist to predict drug‐resistant epilepsy. We determined whether blood levels of high‐mobility group box 1 (HMGB1), a mediator of neuroinflammation implicated in drug‐resistant epilepsies, identifies patients with drug‐resistant seizures. Patients with drug‐resistant epilepsy express significantly highe...

Background & Aims Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. Methods Three cohorts (GenomALC-1: n=1690, GenomALC-2: n=3037, UK Biobank: relevant n=6898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10...

BACKGROUND Adult chronic heart failure mainly affects an elderly population with multiple co-morbidities that often require frequent medical visits to prevent poor health outcomes. However the heart failure disease process reduces their independence by reducing mobility, exercise tolerance and cognitive decline. Remote care technologies can bridge...

Background: Adult chronic heart failure mainly affects an elderly population with multiple comorbidities that often require frequent medical visits to prevent poor health outcomes. However, the heart failure disease process reduces their independence by reducing mobility, exercise tolerance, and cognitive decline. Remote care technologies can brid...

Pharmacogenomics promises to advance cardiovascular therapy, but there remain pragmatic barriers to implementation. These are particularly important to explore within Europe, as there are differences in the populations, availability of resources and expertise, as well as in ethico-legal frameworks. Differences in healthcare delivery across Europe p...

Inhaled corticosteroids (ICS) are the most common asthma controller medication. An important contribution of genetic factors in ICS response has been evidenced. Here, we aimed to identify novel genetic markers involved in ICS response in asthma. A genome-wide association study (GWAS) of the change in lung function after 6 weeks of ICS treatment was...

Background There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pr...

Drug rash with eosinophilia with systemic symptoms (DRESS) is a serious adverse event associated with use of the glycopeptide antibiotic vancomycin. Vancomycin-induced DRESS is associated with the expression of HLA-A*32:01, suggesting that the drug interacts with this HLA to activate CD8+ T-cells. The purpose of this study was to utilize PBMC from...

The relationship between the genetic loci that influence mean corpuscular volume (MCV) and those associated with excess alcohol drinking are unknown. We used white British participants from the UK Biobank (n = 362 595) to assess the association between alcohol consumption and MCV, and whether this was modulated by genetic factors. Multivariable reg...

Aims: To continually evaluate the association between cardiovascular drug exposure and COVID-19 clinical outcomes (susceptibility to infection, disease severity, hospitalization, hospitalization length, and all-cause mortality) in patients at risk of/with confirmed COVID-19. Methods: Eligible publications were identified from >500 databases on 1...

Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of drugs which are widely used globally for the treatment of pain and inflammation, and in the case of aspirin, for secondary prevention of cardiovascular disease. Chronic non-steroidal anti-inflammatory drug use is associated with potentially serious upper gastrointestinal adverse drug rea...

HLA-B*13:01 allele has been identified as the genetic determinant of dapsone hypersensitivity syndrome (DHS) among leprosy and non-leprosy patients in several studies. Dapsone hydroxylamine (DDS-NHOH), an active metabolite of dapsone, has been believed to be responsible for DHS. However, studies have not highlighted the importance of other genetic...

Many adverse reactions associated with immune checkpoint inhibitor (ICI) treatments are immunologically driven and may necessitate discontinuation of the ICI. Herein, we present a patient who had been administered the radio contrast media amidotrizoate multiple times without issue but who then developed a Stevens-Johnson syndrome reaction after coa...

HLA-B*13:01 -positive patients in Thailand can develop frequent co-trimoxazole hypersensitivity reactions. This study aimed to characterize drug-specific T cells from three co-trimoxazole hypersensitive patients presenting with either Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms. Two of the patients carried the...

Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation resp...