Pharmacogenomics In Pharmacy Practice: Current Perspectives.

Pharmacogenomics (i.e., the application of genetic information in predicting an individual's response to drug therapy) plays an increasingly important role in drug development and decision-making regarding precision medicine. This has been shown to reduce the risk of adverse events and improve patient health-care outcomes through targeted therapies and dosing. As the field of pharmacogenomics rapidly evolves, the role of pharmacists in the education, implementation, and research applications of pharmacogenomics is becoming increasingly recognized. This paper aims to provide an overview and current perspectives of pharmacogenomics in contemporary clinical pharmacy practice and to discuss the future directions on advancing pharmacogenomics education, application, and research in pharmacy practice

Rifampin-warfarin interaction in a mitral valve replacement patient receiving rifampin for infective endocarditis: a case report

Warfarin therapy is associated with many drug interactions that may cause a significant alteration in its anticoagulant effect. Rifampin is a widely used antimicrobial that has major interactions with several medications including warfarin due to its strong P-glycoprotein and liver enzyme inducer activity especially on CYP2C9, CYP3A4, CYP1A2 and CYP2C19. We report a case of a 34-year-old Sri Lankan female chronically treated with warfarin for her mitral valve replacement. The patient developed infective endocarditis and was started on a 6-week treatment with rifampin along with other antibiotics. Warfarin dose was increased from 52.5 to 210 mg/week over the course of the rifampin therapy, however, the INR remained subtherapeutic throughout the whole period and reached 2.4 by the end of rifampin therapy. Anticoagulation management was challenging in the period following the end of rifampin therapy as well, and multiple dose adjustments starting with an increase and followed by reduction were required till she was stable on an 80 mg/week warfarin dose 5 weeks post-rifampin therapy. Our findings suggest the importance of close monitoring of warfarin therapy during and after the use of rifampin to minimize the risks of under and over-anticoagulation and improve the safety and efficacy of warfarin therapy.Scopu

Preemptive Dose Adjustment Effect on the Quality of Anticoagulation Management in Warfarin Patients With Drug Interactions: A Retrospective Cohort Study

One strategy to manage patients on warfarin starting an interacting drug is to increase the frequency of monitoring. Another strategy is to adjust warfarin dose around the time patient is started on an interacting medication, which is known as preemptive warfarin dose adjustment. The main objective of this study is to compare preemptive to nonpreemptive strategy and their impact on the quality of anticoagulation management. This is a retrospective cohort study performed at the pharmacist-managed anticoagulation clinic in a tertiary hospital in the State of Qatar. Over a 4-year period, 340 patients were evaluated, and 58 warfarin drug interaction encounters were identified. Mean age of the patients was (57.7 n 13.7), and 50% of them were females. Preemptive dose adjustment was used in 17 (29.3%) cases. Incidence of out-of-target international normalized ratio (INR) was statistically lower in the preemptive arm compared to the control group (41.2% [7/17] vs 69.2% [27/39], P =.048). Incidence of extreme out-of-target INR was numerically lower in the preemptive arm compared to the control but did not reach statistical significance (11.8% [2/17] vs 29.3% [12/41], P =.139). Change in frequency of INR monitoring was not different between the 2 groups. However, overall frequency of INR monitoring after onset/discontinuation of interacting medication increased compared to baseline (7 [9] vs 21 [16] days, P <.001). Preemptive strategy was shown in our study to decrease incidence of the out-of-target INR visits, although patients remained in need for close monitoring.This work is supported by Medical Research Center, Hamad Medical Corporation. RP#17226/17. ORCID iD Hazem Elewa https://orcid.org/0000-0003-1594-1199Scopu

Effect of Pharmacogenetic-Based Decision Support Tools in Improving Depression Outcomes: A Systematic Review

Introduction: Evidence supporting pharmacogenetic (PGX) tests utility in depression is scarce. The main objectives of this study were to summarize, update, and assess the quality of the available evidence regarding PGX testing in depression as well as estimating the impact of using PGX testing tools in depression outcomes in the MENA region. Methodology: Scientific databases were systematically searched from inception to June 30, 2020 for systematic reviews (SRs) and randomized controlled trials (RCTs) assessing clinical utility of PGX tests in treatment of depression. Meta-analysis only and RCTs that that were included in eligible SRs were excluded. Quality of the eligible studies were assessed using Crowe Critical Appraisal Tool (CCAT). Results: Six SRs and three RCTs met the inclusion criteria and were included in this study. Results of the SRs have provided weak evidence on the efficacy of PGX testing especially in patients with moderate-severe depression at eight weeks. In addition, there was a lack of evidence regarding safety outcomes. Newer RCTs with better qualities showed clinical promise regarding efficacy outcomes especially in patients with gene-drug interactions. No evidence was found regarding PGX testing impact in the MENA region. Conclusion: This SR summarizes findings, provides an update, and assesses the quality of available SRs on this topic. Findings of this study have demonstrated that PGX testing prior to treatment initiation might improve efficacy outcomes. Further studies are warranted to assess PGX testing impact on safety outcomes

Cost-Benefit Analysis of Genotype-Guided Interruption Days in Warfarin Pre-Procedural Management

Warfarin is commonly used in thromboembolic conditions. Warfarin interruption represents a significant challenge in pre-operative warfarin management as it is associated with major consequences. Genetics polymorphism demonstrated to be a significant predictor of the required days of warfarin interruption. This study sought to assess the economic benefit of implementing a pharmacogenetic-guided approach in the preprocedural warfarin management. From the hospital's perspective, a cost-benefit analysis was conducted based on a 1-year decision-analytic follow-up model of the economic implications of using a pharmacogenetic algorithm vs standard of care in pre-operative warfarin management in the Hamad Medical Corporation, Qatar. The benefit of the interventional algorithm was based on estimated reduction in the probabilities of clinical events and their cost, added to the avoided cost because of canceled procedures. The cost of the algorithm was the cost of the genotyping assay. The model event probability inputs were extracted from major literature clinical trials, and the setting-specifc and cost inputs were locally obtained. The model was based on a multivariate analysis at its base case. As per 10.3% prevalence of genetic variants, 82% bridging, and a calculated 20% optimization in the preparative period of warfarin management, the benefit to cost ratio was 4.0 in favor genotype-guided approach. This positive benefit to cost ratio was maintained in 100% of the simulated study cases. Sensitivity analyses confirmed the robustness and generalizability of the study conclusion. A pharmacogenetic- guided pre-operative warfarin interruption management is a cost-beneficial approach in the Qatari practice.This work was supported by Hamad Medical Corporation MRC [grant number 1698/2017 ]

Effect of SAMe-TT2R2 score and genetic polymorphism on the quality of anticoagulation control in Qatari patients treated with warfarin.

There is no strong evidence on pharmacogenetics role on the quality of INR control after the initiation phase and on the maintenance of stable INR on the long term as measured by the time in therapeutic range (TTR). The benefit of a score such as SAMe-TT2R2 is that it can preemptively guide clinicians on whether to start the patient on warfarin or direct oral anticoagulant. To determine the association between genetic variants in CYP2C9, VKORC1, and CYP4F2 and TTR. To validate SAMe-TT2R2 score predictive ability on the quality of anticoagulation in Qatari patients. This is an observational nested case-control study that was conducted on a cohort of Qatari patients treated with warfarin with previously identified genotype for the CYP2C9, VKORC1, and CYP2F4. The sample size of this cohort was 148 patients. Mean TTR was 62.7 ± 21%. TTR was not significantly different among carriers of the CYP2C9*2 &*3, VKORC1(-1639G>A) or CYP4F2*3 compared to their non-carriers alleles. None of the factors in the SAMe-TT2R2 score had a significant effect on the TTR except for the female gender where TTR was significantly lower in females (n = 89) compared to males (n = 59) (59.6 ± 21% vs. 67.2 ± 20%, p = 0.03). Furthermore, patients with SAMe-TT2R2 score of zero had significantly better TTR compared to those with higher scores (76.5 ± 17% vs. 61.8 ± 21%, p = 0.04). Logistic regression analysis showed that high SAMe-TT2R2 score was the only statistically significant predicting factor of poor INR control (odds ratio (OR) 5.7, 95% confidence interval (CI) 1.1-28.3, p = 0.034). Genetic variants have no contribution to the quality of INR control. SAMe-TT2R2 score was predictive for the poor quality of anticoagulation in a cohort of Qatari patients.This work was funded by UREP Grant # (UREP23-046-3-012) from the Qatar National Research Fund (a member of Qatar Foundation). The statements made herein are solely the responsibility of the authors

Trends in New 75% Oral Anticgulant Use in Qatar: A 5-Year Experience

Introduction: Warfarin has been the cornerstone oral anticoagulant for more than 60 years. Direct oral anticoagulants (DOACs) have been introduced to the market since 2008. In Qatar, dabigatran was introduced in 2011 followed by rivaroxaban in 2014 and both DOACs are currently used along with warfarin for the treatment and prophylaxis of different thromboembolic diseases. Despite the perceived advantages of the DOACs and their proven efficacy and safety in randomized controlled studies, their use is not as well-established as it has been expected likely due to the lack of antidote and their high cost. Little is known about the prescription pattern of oral anticoagulants and the extent to which DOACs replaced warfarin in Qatar. Aim: In this study, we aim to explore the trends in oral anticoagulant use in Qatar over the past 5 years and to what extent did DOACs replace warfarin. We also aimed to determine the appropriateness of DOACs use based on the dose and the indication. Methods: From electronic medical records, we collected all anticoagulant prescriptions dispensed as in- or out-patient from 2011 to 2015 in all Hamad Medical Corporation (HMC) hospitals. Prescriptions were stratified by the year, the medication prescribed and the dose. For every calendar year, we calculated the number and percentage of patients using each one of the anticoagulants prescribed. We also compared the clinical and demographics characteristics of patients prescribed warfarin versus those prescribed DOACs. Descriptive and inferential statistics were performed using SPSS. Results: The attached table shows the change over the years in the number of patients prescribed warfarin versus those receiving DOACs. Overall, the percentage of patients receiving DOACs increased gradually from approximately 0.5% in 2011 to 20% in 2015. About 40% of patients receiving DOACs were previous warfarin users. DOACs were appropriately used in more 80% of the patients. Year/ Drug Warfarin Number (%) Dabigatran Number (%) Rivaroxaban Number (%) 2011 2078 (99.47%) 11 (0.53%) 2012 2364 (97.52%) 60 (2.48%) 2013 2567 (90.04%) 285 (9.06%) 2014 2823 (83.3%) 320 (9.44%) 246 (7.26%) 2015 2065 (80.54%) 196 (7.64%) 303 (11.82%). Conclusion: DOACs have been gradually replacing warfarin in Qatar in a trend that is similar to other countries as well. However, warfarin use remains essential in more than 75% of patients requiring oral anticoagulant. It is important to continue educating healthcare providers to ensure appropriate use of these novel agents.qscienc

Impact of Genetic Polymorphisms on Phenytoin Pharmacokinetics and Clinical Outcomes in the Middle East and North Africa Region

Background Genetic polymorphisms are known to influence outcomes with phenytoin yet effects in the Middle East and North Africa region are poorly understood. Objectives The objective of this systematic review was to evaluate the impact of genetic polymorphisms on phenytoin pharmacokinetics and clinical outcomes in populations originating from the Middle East and North Africa region, and to characterize genotypic and allelic frequencies within the region for genetic polymorphisms assessed. Methods MEDLINE (1946–3 May, 2017), EMBASE (1974–3 May, 2017), Pharmacogenomics Knowledge Base, and Public Health Genomics Knowledge Base online databases were searched. Studies were included if genotyping and analyses of phenytoin pharmacokinetics were performed in patients of the Middle East and North Africa region. Study quality was assessed using a National Institutes of Health assessment tool. A secondary search identified studies reporting genotypic and allelic frequencies of assessed genetic polymorphisms within the Middle East and North Africa region. Results Five studies met the inclusion criteria. CYP2C9, CYP2C19, and multidrug resistance protein 1 C3435T variants were evaluated. While CYP2C9*2 and *3 variants significantly reduced phenytoin metabolism, the impacts of CYP2C19*2 and *3 variants were unclear. The multidrug resistance protein 1 CC genotype was associated with drug-resistant epilepsy, but reported impacts on phenytoin pharmacokinetics were conflicting. Appreciable variability in minor allele frequencies existed both between and within countries of the Middle East and North Africa region. Conclusions CYP2C9 decrease-of-function alleles altered phenytoin pharmacokinetics in patients originating from the Middle East and North Africa region. The impacts of CYP2C19 and multidrug resistance protein 1 C3435T variants on phenytoin pharmacokinetic and clinical outcomes are unclear and require further investigation. Future research should focus on the clinical outcomes associated with phenytoin therapy.The quality of each study included in the primary review was assessed by two reviewers (RD, KW) using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, from the National Institutes of Health, National Heart, Lung, and Blood Institute [16].Scopu

The Flip of the Coin of Personalized Cancer Immunotherapy: A Focused Review on Rare Immune Checkpoint Related Adverse Effects

Immune checkpoint inhibitors (ICIs) are a type of cancer immunotherapy that has provided a tremendous breakthrough in the field of oncology. Currently approved checkpoint inhibitors target the cytotoxic T-lymphocyte-associated protein 4 (CTLA4), programmed death receptor-1 (PD-1), and programmed death-ligand 1(PD-L1). One of the most known complications of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs). In this chapter, we will focus on selected rare or very rare irAEs, shedding the light on the other side of the coin of personalized cancer immunotherapy. We will also discuss general management approach of irAEs with an in-depth look on each one of these rare irAEs. The chapter will also cover principles of immunotherapy rechallenge post-occurrence of irAEs, and the impact of irAEs incidence on the efficacy of ICI. We will discuss some of the rare or very rare irAEs including cutaneous irAEs, immune-mediated Hypophysitis, hematological irAEs, ophthalmic irAEs, checkpoint inhibitor pneumonitis (CIP), neurologic irAEs, infectious irAEs, and cardiac irAEs. This chapter tried to highlight the significance of identifying emerging rare and very rare irAEs while considering initial assessments and management approaches identified in various clinical practice guideline and primary literature data

The design and implementation of an undergraduate health professional degree elective course on scientific writing, peer assessment, and critical appraisal

Background and purpose: Strong writing skills are critical to the pharmacy profession. This paper describes the design, delivery, and impact of a course intended to develop pharmacy students' scientific writing, peer assessment, and critical appraisal skills. Educational activity and setting: The course was offered in the final year of an undergraduate pharmacy program with students whose first language is not English. In this course, students write two structured pharmacy review articles (PRA) based on assigned scientific research articles and peer assess each others' written PRAs. Students also critically appraise scientific research articles on a weekly basis, complete one pre-journal club written reflective critique based on a assigned scientific research article, and moderate one journal club session. Findings: Course rubrics were developed and validated by the course coordinators. A survey administered to students enrolled in the course identified that 85% of the students perceived that they gained adequate writing skills in the course. More than 70% of the students indicated they had the necessary skills to evaluate their peers' written assessments, and 93% felt comfortable providing and receiving feedback from peers. More than 90% of the students indicated that writing PRAs and the peer assessment improved their critical and analytical skills. This course improved students' scientific writing, peer assessment, and critical appraisal skills. Further practice is required to reinforce the skills learned and to strengthen the writing skills of students