Murray L Barclay

Canterbury District Health Board | CDHB · Department of Clinical Pharmacology

Background: New Zealand went into 'lockdown' March 2020 successfully eliminating circulating COVID19 virus. During 'lockdown' there were reduced rates of respiratory infections and hospital admissions numbers were low. At the time rumors of benefit and harm of medicines for COVID were widespread in the lay and medical media. Aim: To describe cha...

Background and Aims For infants exposed in utero to anti-tumour necrosis factor-a (TNF) medications, it is advised that live-attenuated vaccinations be postponed until drug is cleared, but little is known about time to clearance. To minimize delays before live-attenuated vaccination can be given, we aimed to develop a pharmacokinetic model to predi...

Omeprazole is extensively used to manage gastroesophageal reflux disease (GERD). It is primarily metabolized by CYP2C19. The CYP2C19*17 (rs12248560) allele and the recently described CYP2C:TG haplotype (rs11188059 and rs2860840) are associated with increased enzymatic activity, and may reduce omeprazole exposure. This observational study aimed to i...

Background: Azathioprine and mercaptopurine are considered safe during pregnancy. However, the pharmacokinetic effects of pregnancy on thiopurine metabolism are undefined. Aims: To characterise thiopurine metabolism in pregnancy and measure infant metabolite levels and outcomes. Methods: Women with IBD who were taking a thiopurine and pregnant...

Background The utility of risk scoring systems has not been validated in hospitalised patients that develop upper gastrointestinal bleeding (UGIB). This study’s aim is to compare the accuracy of different risk scoring systems in these patients. Methods Consecutive hospitalised patients that developed UGIB were included. Patients who had onset of U...

One hundred and ninety‐four patient episodes were audited for response to a standardised 1 g intravenous iron infusion for medical outpatients with iron deficiency anaemia. Patients received either ferric carboxymaltose or iron polymaltose. At 5–7 weeks after infusion, mean increase in Hb was 26.7 g/L and ferritin was 161 mcg/L, and only one patien...

Background: Since the start of the COVID-19 pandemic, there have been many sci- entific reports regarding gastrointestinal manifestations. Several reports indicate the possibility of viral shedding via faeces and the possibility of faecal-oral transmission. Aims: To critically assess the clinical relevance of testing stool samples and anal swabs an...

Routine therapeutic drug monitoring (TDM) during treatment with anti‐tumour necrosis factor (anti‐TNF) agents in inflammatory bowel disease (IBD) may increase treatment efficacy and cost‐effectiveness, and reduce the risk of loss of response. The aim was to assess the current use of anti‐TNF agent TDM, including trough concentration and anti‐drug a...

Background: An electronic prescribing and administration (ePA) system has been progressively rolled out to Canterbury District Health Board (CDHB, Christchurch, New Zealand) public hospitals since 2014, and is currently used for around 1300 tertiary beds. ePA data can be used to monitor user behaviour, and to evaluate and inform the local customis...

Background Providing timely follow-up care for patients with inflammatory bowel disease in remission is important but often difficult because of resource limitations. Using smartphones to communicate symptoms and biomarkers is a potential alternative. We aimed to compare outpatient management using 2 smartphone apps (IBDsmart for symptoms and IBDoc...

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of met...

The aims of this study were to determine factors that predict serum urate (SU) lowering response to allopurinol and the conversion of allopurinol to oxypurinol, and to determine a minimum therapeutic oxypurinol concentration. Data from 129 participants in a 24‐month open, randomized, controlled, parallel‐group, comparative clinical trial were analy...

Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people accordin...

The incidence of inflammatory bowel disease (IBD) in New Zealand has increased over the last several decades. The management of IBD has been transformed since the introduction of monoclonal antibody drugs. Other medications used in the treatment of IBD include amino-salicylates, steroids, thiopurines and methotrexate. Therapeutic drug monitoring (T...

Background Using smartphones to communicate symptoms and biomarkers is a potentially cost-effective and quality-of-care equivalent method for managing inflammatory bowel disease (IBD). We aim to compare the management of IBD using two smartphone apps (IBDsmart for symptom monitoring and IBDoc® for faecal calprotectin [FC] monitoring) vs. standard f...

Background Stricturing Crohn’s disease (CD) is associated with significant morbidity and high rates of surgery with anastomotic strictures commonly occurring after surgery. Endoscopic balloon dilatation (EBD) may avoid or delay operative management of strictures. Methods A retrospective audit of CD patients undergoing EBD was conducted at 11 hospi...

Objective: Allopurinol dosing has frequently been limited based on creatinine clearance (CrCL), resulting in failure to achieve target serum urate (SU). The aim of this analysis was to determine how many milligrams of allopurinol above the recommended CrCL-based dose (R+) are required to achieve target SU and to investigate the factors that influe...

Objective: We developed a 30-state QSP model for azathioprine metabolism, including metabolites associated with clinical response and adverse effects. The model was developed using published metabolite and enzyme kinetic data, knowledge of purine biochemistry and expert opinion. An evaluation of the model structure indicated that it was not capable...

Objectives: To determine factors that predict inadequate serum urate (SU) lowering response in a randomized controlled trial of allopurinol dose escalation (DE) in gout. Methods: Participants undergoing allopurinol DE were classified as: complete response (CR)-reached target SU at month 9 and 12 of the DE phase or if still dose escalating at mon...

Background and Aim We aimed to correlate IBD disease activity in New Zealand patients with trough concentrations of infliximab and adalimumab using a locally developed enzyme‐linked immunosorbent assay (ELISA), and anti‐drug antibodies (ADA) using competitive‐binding ELISA and homogeneous mobility shift assay (HMSA), to establish threshold concentr...

Background/objective: The aim of this study was to determine whether reducing the dose of supplemental folic acid used in conjunction with methotrexate (MTX) therapy in people with active rheumatoid arthritis (RA) improved disease control and/or increased MTX-related adverse effects. Methods: A randomized double-blind randomized controlled trial...

Background Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine mon...

To estimate prevalence of and factors contributing to bullying among senior doctors and dentists in New Zealand's public health system, to ascertain rates of reporting bullying behaviour, perceived barriers to reporting and the effects of bullying professionally and personally. Cross-sectional, mixed methods study. New Zealand. Members of the Assoc...

Background The thiopurines azathioprine and mercaptopurine remain pivotal maintenance treatments in inflammatory bowel disease (IBD); however, up to 15%–20% of patients preferentially produce the hepatotoxic metabolite 6-methylmercaptopurine (6MMP) at the expense of the therapeutic 6-thioguanine nucleotides (6TGN). This metabolic shunting usually b...

Objectives To estimate prevalence of and factors contributing to bullying among senior doctors and dentists in New Zealand’s public health system, to ascertain rates of reporting bullying behaviour, perceived barriers to reporting and the effects of bullying professionally and personally. Design Cross-sectional, mixed methods study. Setting New Z...

Background: Thiopurine hypermethylation towards 6-methylmercaptopurine (6MMP) instead of 6-thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation. Aims: To prospectively determine efficacy of allopurinol-thiopurine combination and to compare 2 doses of allopurinol. Design:...

Whether to use biologic treatment for inflammatory bowel disease as monotherapy or in combination with immunosuppressives has been a matter of debate in the last 2 decades. Combination therapy was not superior in any of the registration trials for Crohn’s disease and ulcerative colitis for TNF antagonists, vedolizumab, or ustekinumab. It needs to b...

en Linked Content This article is linked to Tadbiri et al. To view this article visit https://doi.org/10.1111/apt.14419.

Aim: This research aims to evaluate the predictive performance of a published allopurinol dosing tool. Methods: Allopurinol dose predictions were compared to the actual dose required to achieve serum urate (SU) <0.36 mmol l-1using mean prediction error. The influence of patient factors on dose predictions was explored using multilinear regressio...

Allopurinol hypersensitivity syndrome (AHS) is a severe and sometimes life-threatening adverse drug reaction. Although AHS is rare, the number of patients with gout requiring allopurinol is high, and there are sufficient overall cases of AHS to warrant consideration of preventive measures. Most cases occur within 8-9 weeks of commencing allopurinol...

Thiopurines, available as azathioprine, mercaptopurine, and thioguanine, are immunomodulating agents primarily used to maintain corticosteroid-free remission in patients with inflammatory bowel disease. To provide a state-of-the-art overview of thiopurine treatment in inflammatory bowel disease, this clinical review critically summarises the availa...

Background The use of allopurinol in people with chronic kidney disease (CKD) remains one of the most controversial areas in gout management. The aim of this study was to determine the effect of baseline kidney function on safety and efficacy of allopurinol dose escalation to achieve serum urate (SU) <6 mg/dl. Methods We undertook a post hoc analys...

A QSP model for azathioprine metabolism was developed based on a full meta-analysis of mechanistic pathways from the literature and expert opinion • The model predicted normal reference concentrations of 6-TGN and 6-MMP • However the model was not able to describe atypical clinical scenarios (i.e. excessive 6-TGN or 6-MMP) • In this work we used a...

Background: Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti-tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements based on current evidence will help the development of treatment guidelines. Aim: To develop evidence-based consensus statements for TDM-guided anti-TNF the...

Objectives: To determine the long-term safety and efficacy of allopurinol dose escalation (DE) to achieve target serum urate (SU) in gout. Methods: People, including those with chronic kidney disease, who completed the first 12 months of a randomised controlled trial continued into a 12-month extension study. Participants randomised to continue...

We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the ext...

Background Minimum biodrug concentrations of ∼7mg/l are predictive of disease remission¹. Very low/absent biodrug concentrations associate with loss of benefit which may be due to ADA² however the clinical utility of ADA is assay dependant. In rheumatoid arthritis the combination of low/absent drug concentration and the presence of ADA appears to h...

Aims: The aims of the study were to 1) determine if a plasma oxypurinol concentration-response relationship or an allopurinol dose-response relationship best predicts the dose requirements of allopurinol in the treatment of gout; and, 2) to construct a nomogram for calculating the optimum maintenance dose of allopurinol to achieve target serum ura...

Objectives To determine the efficacy and safety of allopurinol dose escalation using a treat-to-target serum urate (SU) approach. Methods A randomised, controlled, parallel-group, comparative clinical trial was undertaken. People with gout receiving at least creatinine clearance (CrCL)-based allopurinol dose for ≥1 month and SU ≥6 mg/dL were recru...

Aim: To estimate rates of presenteeism in the New Zealand senior medical workforce and identify reasons why this workforce feels pressured to work through illness. Methods: A cross-sectional survey was returned by 1,806/3,740 publically employed senior doctors and dentists (48%). Relationships between rates of presenteeism, sick leave and demogr...

Purpose: The aims of this study were to characterise the population pharmacokinetics of oxypurinol in patients receiving haemodialysis and to compare oxypurinol exposure in dialysis and non-dialysis patients. Methods: Oxypurinol plasma concentrations from 6 gout people receiving haemodialysis and 19 people with gout not receiving dialysis were u...

BACKGROUND: Clinical examination of the liver requires experience to achieve accuracy. The scratch test is a simple technique to identify the lower liver edge and enhance liver palpation, and may be easier for trainees. AIM: We aimed to evaluate the accuracy of the scratch test compared to percussion at different levels of medical training. METHOD:...

Objectives To explore the prevalence of, and associated factors contributing to burnout among senior doctors and dentists working in the New Zealand's public health system. Design Cross-sectional, mixed methods study. Setting New Zealand's 20 district health boards (DHBs). Participants A total of 1487 of 3740 senior doctors and dentists who are...

BACKGROUND: Idiopathic achalasia is a non-curable, primary motility disorder of the oesophagus. Most established long-term palliative treatment options are laparoscopic Heller myotomy (LHM) and endoscopic balloon dilatation (BD). Aim We aimed to compare the outcome of both therapies and the risk of serious complications, defined as perforation or...

Aims: The primary aim of this research was to predict the allopurinol maintenance doses required to achieve the target plasma urate of ≤0.36 mmol/L. Methods: A population analysis was conducted in NONMEM using oxypurinol and urate plasma concentrations from 133 gout patients. Maintenance dose predictions to achieve the recommended plasma urate t...

There is increasing interest in measuring both drug and anti-drug antibody (ADA) levels in patients receiving anti-TNF treatment as part of algorithms for guiding therapeutic strategies. Many of the current assays for ADA detection have limitations with respect to specificity, sensitivity and/or laboratory requirements. Specific identification of A...

Azathioprine and 6-mercaptopurine remain pivotal therapies for the maintenance of disease remission in patients with Crohn's disease and ulcerative colitis. While thiopurine S-methyltransferase deficiency was the first pharmacogenetic phenomenon to be recognized to influence thiopurine toxicity and reliably predict leukopenia, it does not predict o...

Preferential conversion of azathioprine or 6-mercaptopurine into methylated metabolites is a major cause of thiopurine resistance. To seek potentially Mendelian causes of thiopurine hypermethylation, we recruited 12 individuals who exhibited extreme therapeutic resistance while taking azathioprine or 6-mercaptopurine and performed whole-exome seque...

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte a...

Background and objectives: Therapeutic drug monitoring in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX, MTXGlu1) has not been established. In this study, we aim to explore the relationship between red blood cell (RBC) concentrations of MTX and its polyglutamate metabolites (MTXGlu(n); n = 2, 3, 4, 5) and clinical response in...

Background and AimThe aetiology of Crohn's disease (CD) implicates both genetic and environmental factors. Smoking behaviour is one environmental risk factor to play a role in the development of CD. The study aimed to assess the contribution of the interleukin 23 receptor (IL23R) in determining disease susceptibility in two independent cohorts of C...

The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) provides practical and professional support for clinicians dealing with the gastr...

Dabigatran is largely cleared by renal excretion. Renal function is thus a major determinant of trough dabigatran concentrations, which correlate with the risk of thromboembolic and haemorrhagic outcomes. Current dabigatran dosing guidelines use the Cockcroft-Gault (CG) equation to gauge renal function, instead of contemporary equations including t...

Structured summary AimsIn patients with atrial fibrillation (AF) prescribed dabigatran: to examine the correlation between plasma dabigatran concentrations and 1) the three screening coagulation assays (International Normalised Ratio, INR, activated partial thromboplastin time, aPTT, thrombin time, TT), and 2) the dilute thrombin time (dTT); and to...

A busulfan concentration monitoring and dosing service has been provided by Christchurch Hospital since 1998. This study aimed to see (1) the percentage of patients with an area under the concentration time curve (AUC) outside the target range and had dose adjustment, (2) how busulfan clearance (CL) relates to body weight, and (3) if fewer samples...

Rapid and effective suppression of inflammation is a primary goal in the treatment of rheumatic diseases. However, the therapeutic effect of most medications may be slow to manifest, in the order of weeks or months in the case of DMARDs. Monitoring of drug concentrations allows the possibility of appropriate dose adjustment or changes in medication...

To investigate the association of macrophage migration inhibitory factor (MIF) promoter polymorphisms with inflammatory bowel disease (IBD) risk. One thousand and six New Zealand Caucasian cases and 540 Caucasian controls were genotyped for the MIF SNP -173G > C (rs755622) and the repeat polymorphism CATT5-8 (rs5844572) using a pre-designed TaqMan...

To assess the similarities in intracellular pharmacokinetics (PK) of methotrexate (MTX) in red blood cells (RBCs) and other cell lines. Three previously published PK models for intracellular MTX and MTX polyglutamates (MTXGlu2-5 ) concentrations were used: 1) a model for the kinetics in RBCs, 2) a model for the kinetics in human breast cancer cells...

Crohn's disease (CD) is an inflammatory bowel disease (IBD) caused by a combination of genetic, clinical, and environmental factors. Identification of CD patients at high risk of requiring surgery may assist clinicians to decide on a top-down or step-up treatment approach. We conducted a retrospective case-control analysis of a population-based coh...

Measurement of red blood cell thiopurine S-methyl transferase (TPMT) enzyme activity before commencing thiopurine therapy is recommended to avoid severe bone marrow suppression in TPMT-deficient patients. Patient's samples go through preanalytical transportation and storage steps before measurement. We studied patient's TPMT activity sample data to...