Genotyping for HLA Risk Alleles to Prevent Drug Hypersensitivity Reactions: Impact Analysis

Human Leukocyte Antigen (HLA) variants can be a risk factor for developing potentially fatal drug hypersensitivity reactions. Our aim was to estimate the potential impact of genotyping for the HLA risk alleles incorporated in the Dutch Pharmacogenetics Working Group (DPWG) guidelines in The Netherlands. We estimated the number of hypersensitivity reactions and associated deaths that can be avoided annually by genotyping for these HLA risk alleles. Additionally, the cost-effectiveness was estimated. Nationwide implementation of genotyping HLA risk alleles before initiating drugs with an actionable drug–gene interaction can potentially save the life of seven allopurinol initiators and two flucloxacillin initiators each year in The Netherlands. Besides these deaths, 28 cases of abacavir hypersensitivity, 24 cases of allopurinol induced SCARs, 6 cases of carbamazepine induced DRESS and 22 cases of flucloxacillin induced DILI can be prevented. Genotyping HLA-B*5701 in abacavir initiators has a number needed to genotype of 31 to prevent one case of abacavir hypersensitivity and is cost-saving. Genotyping HLA-B*5801 in allopurinol initiators has a number needed to genotype of 1149 to prevent one case of SCAR but is still cost-effective. Genotyping before initiating antiepileptic drugs or flucloxacillin is not cost-effective. Our results confirm the need for mandatory testing of HLA-B*5701 in abacavir initiators, as indicated in the drug label, and show genotyping of HLA-B*5801 in allopurinol initiators should be considered.

Factors Affecting Voriconazole Trough Concentration and Optimal Maintenance Voriconazole Dose in Chinese Children

Voriconazole is a triazole antifungal agent commonly used for the treatment and prevention of invasive aspergillosis (IA). However, the study of voriconazole's use in children is limited. The present study was performed to explore maintenance dose to optimize voriconazole dosage in children and the factors affecting voriconazole trough concentration. This is a non-interventional retrospective clinical study conducted from 1 January 2016 to 31 December 2020. The study finally included 94 children with 145 voriconazole trough concentrations. The probability of achieving a targeted concentration of 1.0–5.5 µg/mL with empiric dosing increased from 43 (45.3%) to 78 (53.8%) after the TDM-guided adjustment. To achieve targeted concentration, the overall target maintenance dose for the age group of less than 2, 2 to 6, 6 to 12, and 12 to 18 years old was approximately 5.71, 6.67, 5.08 and 3.31 mg·kg−1/12 h, respectively (p < 0.001). Final multivariate analysis found that weight (p = 0.019), dose before sampling (p < 0.001), direct bilirubin (p < 0.001), urea nitrogen (p = 0.038) and phenotypes of CYP2C19 were influencing factors of voriconazole trough concentration. These factors can explain 36.2% of the variability in voriconazole trough concentration. Conclusion: In pediatric patients, voriconazole maintenance doses under the target concentration tend to be lower than the drug label recommended, but this still needs to be further studied. Age, body weight, dose, direct bilirubin, urea nitrogen and phenotypes of CYP2C19 were found to be influencing factors of voriconazole concentration in Chinese children. The influence of these factors should be taken into consideration during voriconazole use.

All You Need to Know About UGT1A1 Genetic Testing for Patients Treated With Irinotecan: A Practitioner-Friendly Guide

Irinotecan is an anticancer agent widely used for the treatment of solid tumors, including colorectal and pancreatic cancers. Severe neutropenia and diarrhea are common dose-limiting toxicities of irinotecan-based therapy, and UGT1A1 polymorphisms are one of the major risk factors of these toxicities. In 2005, the US Food and Drug Administration revised the drug label to indicate that patients with UGT1A1*28 homozygous genotype should receive a decreased dose of irinotecan. However, UGT1A1*28 testing is not routinely used in the clinic, and specific reasons include lack of access to concise information on this wide issue as well as mixed recommendations by regulatory and professional entities. To assist oncologists in assessing whether and when to use UGT1A1 genetic testing in patients receiving irinotecan-based therapies, this article provided (1) essential knowledge of UGT1A1 polymorphisms; (2) an update on the impact of UGT1A1 polymorphisms on efficacy and toxicity of contemporary irinotecan-based regimens; (3) dosing adjustments based upon the UGT1A1 genotypes, and (4) recommendations from currently available guidelines from the US and international scientific consortia and major oncology societies.

92 Eligibility and reimbursement of SGLT2 inhibitors in a heart failure outpatient cohort

Aims In patients affected by heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fraction, sodium–glucose cotransporter type 2 inhibitor drugs (SGLT2i) have shown unexpected and extraordinary results, regardless of the co-presence of diabetes mellitus (DM). The results of the clinical trials have recently allowed the national drug agency (AIFA) to summarize and simplify SGLT2i indications for treatment; however, the reimbursement of these drugs is currently only ensured to diabetic patients, who represent a small subgroup of heart failure (HF) population. The study aims to determine eligibility for SGLT2i in HF outpatients, according to the inclusion criteria of the main clinical trials, comparing the drug label proposed by EMA/AIFA with the current reimbursement criteria. Methods and results In this retrospective, observational study, 206 HF outpatients were enrolled from September 2018 to September 2019. The percentages of eligible patients according to the DECLARE-TIMI 58, EMPA-REG OUTCOME, DAPA-HF, EMPEROR REDUCED, and EMPEROR PRESERVED inclusion criteria were analysed, comparing the indications proposed by the EMA/AIFA label and the current reimbursement criteria. Among the 206 patients enrolled, the mean age was 71 ± 12 years, 24% were diabetic, the mean MDRD eGFR was 61 ± 22 ml/min/1.73m2, the mean ejection fraction (LVEF) was 38 ± 11% (LVEF &lt;40 in 65% of the whole cohort). According to EMA/AIFA indications, eligible patients for SGLT2i in this cohort are 66%, representing almost the entire HFrEF population. This percentage, which is far higher than the eligibility of the main clinical trials, is motivated by the more stringent inclusion criteria proposed by the latter, in which the prevailing limiting factors were NYHA class and NTproBNP values. The reimbursement of these drugs is currently only ensured for diabetic patients with eGFR &gt; 60 ml/min/1.73 m2; in our study only 8% of patients met these criteria. Assuming soon to extend the EMA/AIFA indication to HFpEF patients, wider eligibility for SGLT2i is expected for most patients with HF, irrespective of DM and LVEF. Conclusions Two-thirds of our HF population is currently eligible for SGLT2i prescription, according to the drug label proposed by EMA/AIFA; this eligible cohort includes almost all HFrEF patients. When the indications will be updated according to the results of HFpEF trials on SGLT2i, eligibility will be extended almost to the entire cohort of HF outpatients. Most eligible patients are not diabetic, however, they have not currently access to drug reimbursement. The constant updating of the SGLT2i label and reimbursement criteria is the main limiting factor in current clinical practice.

Knowledge of Rational Drug Use Among Village Health Volunteers in a Municipal Hospital in Thailand

Village health volunteers (VHVs) are key factors to improve and maintain health status in the Thai population, especially in rural areas. Knowledge in rational drug use of VHVs is essential to help Thai people use medicines appropriately. Therefore, this study aimed to investigate the literacy of VHVs relating to rational drug use in a municipal hospital, Nakhon Si Thammarat province, Thailand. The literacy score was assessed using the questionnaire that was developed based on the Rational Drug Use Manual by the Ministry of Public Health. This questionnaire consists of 5 aspects, including the understanding of drug labels, advertisement evaluation, drug purchasing and using, understanding the meaning of medical terms, and access to drug information. The results were analyzed and described as frequency and percentage. Of all 139 VHVs who participated in the questionnaires, the average score of rational drug use literacy was 16.51 (SD = 5.79) out of 28 (58.96%), which was defined as poor level. Considering by aspects, it was found that the scores in the drug label literacy and understanding of the medical terms were at good levels. Drug purchasing and using aspect was at a moderate level. The advertisement assessment aspect was at a poor level. In conclusion, the results in this study indicated that VHVs in a municipal hospital, Nakhon Si Thammarat province, Thailand, should strengthen the knowledge relating to evaluation of advertising media and purchasing and using of drugs.

Comparison of Online Patient’s Reviews and National Pharmacovigilance Data for Tramadol-Related Adverse Events: Comparative Observational Study (Preprint)

BACKGROUND Tramadol is known to cause fewer adverse events (AE) than other opioids. However, recent research has raised concerns about various safety issues. OBJECTIVE We aimed to explore these new AE related to tramadol using social media and conventional pharmacovigilance data. METHODS This study used two datasets, one from patients’ drug reviews on WebMD and one from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). We analyzed 2,062 and 29,350 patient reports from WebMD and FAERS, respectively. Patient posts on WebMD were manually assigned the preferred terms of the Medical Dictionary for Regulatory Activities (MedDRA). To analyze AE from FAERS, a disproportionality analysis was performed with three measures: the proportional reporting ratio (PRR), the reporting odds ratio (ROR), and the information component (IC). RESULTS From the 869 AE reported, we identified 125 new signals related to tramadol use not listed on the drug label that satisfied all three signal detection criteria. In addition, 20 serious AE were selected from new signals. Among new serious AEs, vascular disorders had the largest signal detection criteria value. Based on the disproportionality analysis and patients’ symptom descriptions, tramadol-induced pain might also be an unexpected AE. CONCLUSIONS This study detected several novel signals related to tramadol use, suggesting newly identified possible AE. Additionally, this study indicates that unexpected AEs can be detected using social media analysis alongside traditional pharmacovigilance data. CLINICALTRIAL N/A

Variability of Pharmacogenomics Information in Drug Labels Approved by Different Agencies and Its Ethical Implications

Aims: The aim of this study was to determine if there are discrepancies among various agency-approved labels for the same active ingredient and where the labels approved by the Turkish Medicines and Medical Devices Agency (TMMDA) stand regarding the inclusion of PGx and discuss these ethical implications. Background: The efficacy and safety of drugs can be improved by rational prescription and personalization of medicine for each patient. Pharmacogenomics information (PGx) in drug labels (DL) is one of the important tools for the personalization of medications because genetic differences may affect both drug efficacy and safety. Providing adequate PGx to patients has ethical implications. Objective: To evaluate PGx in the DLs approved by TMMDA and other national agencies provided by the Pharmacogenomics Knowledgebase. Methods: DL annotations from the Pharmacogenomics Knowledgebase and DLs approved by the TMMDA were analyzed according to information and action levels, which are “testing required”, “testing recommended”, “actionable”, and “informative”. Results: There are 381 drugs listed in PharmGKB drug label annotations with pharmacogenomics information and 278 of these have biomarkers. A total of 242 (63.5%) drugs are approved and available in Turkey. Of these, 207 (85.5%) contain the same information as in or similar to that in the labels approved by the other agencies. The presence and level of information varied among the DLs approved by different agencies. The inconsistencies may have an important effect on the efficacy and the safety of drugs.