Kaitlyn Shaw

The emerging era of pharmacogenomics: current successes, future potential, and challenges

The vast range of genetic diversity contributes to a wonderful array of human traits and characteristics. Unfortunately, a consequence of this genetic diversity is large variability in drug response between people, meaning that no single medication is safe and effective in everyone. The debilitating and sometimes deadly consequences of adverse drug reactions (ADRs) are a major and unmet problem of modern medicine. Pharmacogenomics can uncover associations between genetic variation and drug safety and has the potential to predict ADRs in individual patients. Here we review pharmacogenomic successes leading to changes in clinical practice, as well as clinical areas probably to be impacted by pharmacogenomics in the near future. We also discuss some of the challenges, and potential solutions, that remain for the implementation of pharmacogenomic testing into clinical practice for the significant improvement of drug safety.

VKORC1 and CYP2C9 genotypes are predictors of warfarin‐related outcomes in children

Despite substantial evidence supporting a pharmacogenetic approach to warfarin therapy in adults, evidence on the importance of genetics in warfarin therapy in children is limited, particularly for clinical outcomes. We assessed the contribution of CYP2C9/VKORC1/CYP4F2 genotypes and variation in other genes involved in vitamin K and coagulation pathways to warfarin dose and related clinical outcomes in children.

Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy.

Objective: To systematically review evidence on genetic variants influencing outcomes during warfarin therapy and provide practice recommendations addressing the key questions: (1) Should genetic testing be performed in patients with an indication for warfarin therapy to improve achievement of stable anticoagulation and reduce adverse effects? (2) Are there subgroups of patients who may benefit more from genetic testing compared with others? (3) How should patients with an indication for warfarin therapy be managed based on their genetic test results? Methods: A systematic literature search was performed for VKORC1 and CYP2C9 and their association with warfarin therapy. Evidence was critically appraised, and clinical practice recommendations were developed based on expert group consensus. Results: Testing of VKORC1 (−1639G>A), CYP2C9*2, and CYP2C9*3 should be considered for all patients, including pediatric patients, within the first 2 weeks of therapy or after a bleeding event. Testing for CYP2C9*5, *6, *8, or *11 and CYP4F2 (V433M) is currently not recommended. Testing should also be considered for all patients who are at increased risk of bleeding complications, who consistently show out-of-range international normalized ratios, or suffer adverse events while receiving warfarin. Genotyping results should be interpreted using a pharmacogenetic dosing algorithm to estimate the required dose. Significance: This review provides the latest update on genetic markers for warfarin therapy, clinical practice recommendations as a basis for informed decision making regarding the use of genotype-guided dosing in patients with an indication for warfarin therapy, and identifies knowledge gaps to guide future research.

Hair cortisol as a novel biomarker of HPA suppression by inhaled corticosteroids in children

Background:Asthma is the most common chronic condition in childhood, and the recommended pharmacotherapy for long-term control includes the use of inhaled corticosteroids (ICS). ICS were designed to act at the site of inflammation in the lung, thus decreasing systemic absorption and reducing the risk of adverse effects associated with corticosteroid use (e.g., HPA suppression and its consequent effects). Available data show that measurement of hair cortisol successfully reflects endogenous cortisol levels. We sought to examine whether hair cortisol measurements can be used to identify HPA suppression surrounding ICS therapy in children with asthma.Methods:Hair samples were collected from the vertex posterior region of the head of 18 asthmatic children. We compared their hair cortisol concentration during ICS use with the concentration prior to ICS use.Results:During ICS therapy, median hair cortisol levels were twofold lower compared with the period of no ICS use (median 89.8 ng/g vs. 198.2 ng/g, P = 0.0015).Conclusion:Hair cortisol is an effective biomarker of the HPA suppression associated with ICS therapy and can be a sensitive tool for determining systemic effects of ICS use and monitoring adherence. Future research is needed to characterize the effect of untreated asthma on hair cortisol concentrations, if any.

Suspected opioid overdose case resolved by CYP2D6 genotyping.

A 14-year-old female with suspected narcotic overdose had CYP2D6 genotyping performed to verify opiate intoxication. The role of pharmacogenetics in pain management and individualization of opiate pharmacotherapy is discussed.

Physician and parent barriers to the use of oral corticosteroids for the prevention of paediatric URTI-induced acute asthma exacerbations at home

Objectives Administration of oral corticosteroids at the onset of an upper respiratory tract infection (URTI) can be effective in the management of acute asthma exacerbations in children. This study was designed to identify barriers to parent-initiated implementation of clinical practice guideline-recommended use of oral corticosteroids for prophylaxis against severe asthma exacerbations in children. Methods Twenty-seven children who presented to BC Childrens Hospital with URTI-induced asthma exacerbations were recruited. Parents received a filled prescription for a course of oral corticosteroids to be used at the earliest onset of their childs next URTI. Each family was contacted monthly over a 1-year period to inquire about URTI events, asthma symptoms, medication use and health care utilization. Focus groups were held with family physicians, paediatricians and parents; transcripts were analyzed qualitatively to identify key themes. Results Incidence of URTI events among participants was high (85%). Uptake of study medication was low; 44% used the medication as directed at their first URTI event. Eleven per cent of the patients who used the study medication also visited the emergency department for an exacerbation. Focus groups identified four main barriers to the effective use of parent-initiated oral corticosteroids: physician resistance and conflicting messages from providers; parent uncertainty about oral corticosteroids; multiple caregivers and relative ease of access to an emergency department. Conclusion We have identified key barriers to the effective use of parent-administered oral corticosteroids as an asthma management strategy and gained important insights regarding the research that is required to enhance the applicability of the strategy.

Response to The routine use of oral steroids in paediatric asthma is not routine

1Centre for Clinical Epidemiology and Evaluation, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia; 2Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia; 3Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia; 4Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia; 5Pharmaceutical Outcomes Programme, BC Children’s Hospital, Vancouver, British Columbia; 6Pediatric Research in Emergency Therapeutics (PRETx.org), Division of Pediatric Emergency Medicine, BC Children’s Hospital, Vancouver, British Columbia

Assessment of hair cortisol as a potential biomarker for possible adrenal suppression due to inhaled corticosteroid use in children with asthma: A retrospective observational study

BACKGROUND Inhaled corticosteroids (ICS) are the recommended long-term control therapy for asthma in children. However, concern exists regarding potential adrenal suppression with chronic ICS use. Our pilot study reported that hair cortisol in children was 50% lower during ICS therapy than prior to therapy, suggestive of adrenal suppression. OBJECTIVE To evaluate hair cortisol concentration (HCC) as a potential biomarker for possible adrenal suppression from ICS use in children with asthma. METHODS A retrospective observational study was performed at asthma clinics in Vancouver, Winnipeg, and Toronto, Canada. Children (n = 586) were recruited from July 2012 to December 2014 inclusive of those without asthma, with asthma not using ICS, and with asthma using ICS. The most recent three-month HCC was measured by enzyme immunoassay and compared among the groups. Quantile regression analysis was performed to identify factors potentially affecting HCC. RESULTS The median HCC was not significantly different among the children: No ICS (n = 47, 6.7 ng/g, interquartile range (IQR) 3.7-9.8 ng/g), ICS Treated (n = 360, 6.5 ng/g, IQR 3.8-14.3 ng/g), and Controls (n = 53, 5.8 ng/g, IQR 4.6-16.7 ng/g). 5.6% of the children using ICS had hair cortisol <2.0 ng/g compared to none in the control groups (P < .05, comparing ICS Treated (20/360) to all Controls combined (0/100)) and only half had been exposed to systemic corticosteroids. Age, sex, BMI, and intranasal corticosteroid use were significantly associated with HCC. CONCLUSIONS Results suggest HCC may be a potential biomarker for adrenal suppression as a population of children using ICS with HCC < 2.0 ng/g was identified compared to none in the control groups. Further research is needed to determine if those children have or are at risk of adrenal suppression or insufficiency.