Pharmacogenetic Information Reflected in Cpic and Dpwg Guideline and its Application on Drug Labels

Posters

A. Akici1; V. Aydin1; E. Kadi2; F. Isli2; and H. Gursoz2 1 Department of Pharmacology, Marmara University School of Medicine, Istanbul, Turkey; and 2Turkish Medicines and Medical Devices Agency, Ministry of Health, Ankara, Turkey Background:  Treatment with anti-tumor necrosis factor alpha (antiTNF-α ) drugs is known to increase the risk of granulomatous diseases, leading to development of risk management strategies at either national or global level. This study aimed to determine the relative risk of developing tuberculosis (RRDT) due to anti-TNF-α  usage in patients with rheumatologic diseases (RD) in Turkey. Methods:  This retrospective cohort study included patients with RDs (rheumatoid arthritis, ankylosing spondylitis, juvenile arthritis, and psoriatic arthritis) that treated with or without anti-TNF-α  agents, as registered in the Prescription Information System (PIS) of the Turkish Medicines and Medical Devices Agency between 1 April 2013 and 31 December 2015. One-year RRDT after anti-TNF-α  usage was estimated. Results:  The number of tuberculosis cases among all 898,718 RD patients was 422, yielding an incidence of 46.9/100,000 patients. Most common diagnosis in all population was rheumatoid arthritis (81.3%), followed by ankylosing spondylitis (14.7%). Mostly prescribed anti-TNF-α  drug was etanercept (38.7%), followed by adalimumab (24.9%), infliximab (19.7%), golimumab (15.3%), and certolizumab (1.4%). There were 7,925 patients who received at least two separate doses of anti-TNF-α (study group) and 690,930 patients who had never used anti-TNF-α  (control group) due to RD during 1 year of follow-up. Mean age of the groups were 42.1 ± 13.3 and 52.1 ± 17.4, respectively. Percentages of woman in study and control groups were 45.4% and 69.5%, respectively. Seven patients in the study group developed tuberculosis compared to 131 patients in the control group (88.3 vs 19.0 cases per 100,000 patients, respectively) with a RRDT of 4.66 (95% CI, 2.18-9.96, p< 0.0001). Conclusions: This is the first study to show increased RRDT in patients who were treated with anti-TNF-α  drugs due to their rheumatologic condition in a PIS-based nationwide cohort study in Turkey. The study confirmed necessity of the current risk management strategy regarding tuberculosis in these patients. Key words:  rheumatologic disease; anti-TNF-α , tuberculosis, drug safety.

E. Gomez-Dominguez15; R. Andrade1,*; and M.I. Lucena1,* Instituto de Investigación Biomédica de Málaga -IBIMA, Hospital Universitario Virgen de la Victoria. Universidad de Málaga *CIBERehd, Málaga, Málaga, Spain; 2Hospital Torrecardenas, Almeria, Málaga, Spain; 3Hospital de Mendaro, Guipuzcoa, Spain; 4Hospital Morales Meseguer, Murcia, Spain; 5 Hospital Universitario y Politécnico La Fe. CIBERehd, Valencia, Spain; 6Hospital Germans Trias i Pujol , Badalona, Spain; 7 Hospital de la Santa Creu i Sant Pau. CIBERehd, Barcelona, Spain; 8Agencia Sanitaria Costa del Sol , Málaga, Spain; 9Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional de Málaga, Málaga, Spain; 10Hospital Universitario de Canarias, Tenerife, Spain; 11Hospital Clinic de Barcelona. CIBERehd, Barcelona, Spain; 12Hospital Universitario Basurto, Bilbao, Spain; 13Complejo Hospitalario de Albacete, Albacete, Spain; 14Hospitales Universitarios Virgen Macarena-Virgen del Rocío. CIBERehd, Sevilla, Spain; and 15Hospital 12 de Octubre, Madrid, Spain Background:  Idiosyncratic drug induced liver injury (DILI) is a rare adverse drug reaction that poses major challenges to healthcare practitioners and regulatory agencies. We aimed to update the clinical characteristics and outcomes of DILI patients, and the drugs frequently implicated in hepatotoxicity in Spain. Methods:  We analyzed 915 DILI cases (842 single episodes, 55 rechallenges, 18 double-episodes due to different drugs) in 857 patients included in the Spanish DILI Registry from 1994 to 2015. Cases were adjudicated using expert clinical judgment/RUCAM scale and compared according to pattern of liver damage (hepatocellular, HC; cholestatic, Chol or mixed, Mix). Results:  The cohort median age was 57 years (range: 11-90 y) with a mean body mass index of 25.8 ± 3.8 kg/m2. Male gender predominated (52%). HC, Chol and Mix patterns of liver damage were identified in 65%, 18% and 17% of cases, respectively. More than half of the cases were of moderate severity (58%). Patients with Chol and Mix pattern were older (median 64 y and 62 y, respectively) than HC patients (median 52 y), p< 0.001. Anti-infectives, central nervous system, cardiovascular and anti-inflammatory agents were the most commonly implicated therapeutic classes accounting for 37%, 14%, 11% and 9% of cases, respectively. Amoxicillin/clavulanate remains the agent responsible for the highest number of DILI (21% of cases). Substantial increase in anabolic androgenic steroid-induced hepatotoxicity was observed in recent years. A cluster of DILI cases reported to the registry (i.e. ebrotidine, tetrabamate, nimesulide, amoxicillin-clavulanate, Exolise®, Epistane®) contributed to adoption of regulatory measures. Conclusions: The pioneering prospective Spanish DILI Registry proved to be very valuable for in-depth clinical phenotyping of hepatotoxicity, providing consistent figures in clinical characteristic outcomes and implicated drugs. It also constitutes an important tool for public health promotion in postmarketing drug surveillance. Funding:  Research grants from AEMPS and FEDER (PI15/01440, PI 16/01748). CIBERehd by ISCIII.

Idiosyncratic Drug-Induced Liver Injury: A 20-Year Update of the Cases Enrolled By the Spanish Dili Registry

Pharmacogenetic Information Reflected in Cpic and Dpwg Guideline and its Application on Drug Labels

Conclusions:  Evidence of hepatitis E infection is present in a significant number of patients suspected to have DILI. Seroprevalence of IgG HEV is also very high. Hepatitis E should be ruled out in all patients suspected to suffer from DILI in Spain. Funding: ISCIII, FEDER, (contract numbers: PI15/01440, PI16/01748), Consejería de Salud (PI-0274-2016), AEMPS, CIBERehd, SCReN.

Increased Risk of Tuberculosis in Patients With Rheumatologic Diseases Managed With Anti-Tnf-Α Agents: A Nationwide Retrospective Pharmacoepidemiological Cohort Study in Turkey

M. Slim1; J. Sanabria1; M. Robles-Díaz1,*; I. Medina-Cáliz1; R. Sanjuán-Jiménez1; A. González-Jiménez1; A. Ortega1; M. García-Cortés1,*; B. Garcia-Muñoz1; M.C. Fernandez2; A. Castiella3; E. Zapata3; H. Hallal4; I. Conde5; M. Prieto5,*; E. Montane6; R. María Morillas6; G. Soriano7,*; E. Roman7,*; J.M. Navarro8; M. Jimenez9; A. Aldea10; M. Hernández-Guerra10; P. Gines11; S. Blanco12; J.M. Moreno13; M. Romero-Gomez14,*;

August 2017

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S.W. Lee; S. Yoon; I.J. Jang; K.S. Yu; and S.H. Lee Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea Background:  Genetic polymorphism is one of the major factors that cause inter-individual differences in drug response and adverse drug reactions. Pharmacogenetic information may serve a critical role in personalized medicine. We listed the drugs on the market which

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Clinical Therapeutics included pharmacogenetics-based therapeutic recommendations in their labels and their allele frequencies in Korean population. Methods:  We reviewed the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, and the Dutch Pharmacogenetics Working Group (DPWG) guidelines and crossreferenced it with the drug labels listed by the Food and Drug Administration (FDA; www.fda.gov) and Ministry of Food and Drug Safety of Korea (MFDS; www.mfds.go.kr). The drugs listed by the FDA and MFDS were compared, which reflected either of the CPIC or DPWG guideline. Pharmacogenetic genotype/allele frequencies in Korean, Asian, and Caucasian populations were compared by reviewing the National Center or Biotechnology Information (www. ncbi.nlm.nih.gov) and the supplementary data of CPIC guidelines. Results:  Among the marketed drugs in either Korea or U.S.A., the number of drugs recommended for pharmacogenetics-based therapy by the CPIC and DPWG guidelines were 29 and 34, respectively, while the numbers of drugs of which the labels listed by the FDA and MFDS reflected either the CPIC or DPWG guideline were 12 and 14, respectively. Three of the most commonly referenced genes for pharmacogenetics-based therapy were HLA-B, TPMT, and DPYD. In Korean population, the allele frequencies of HLA-B (*1502, *5701, and *5801) were 0.002 - 0.022, 0.005, 0.001, and that of TPMT (*3C and *6) were 0.009 – 0.018 and 0.003 – 0.013, respectively. However the allele frequencies of DPYD were not yet determined. Conclusions:  More effort have to be made to implement the CPIC and DPWG guidelines to the drug labels in Korea, and at the same time further investigation of allele frequencies in Korean population is needed

Factor XA Inhibitor Attenuates Renal Interstitial Fibrosis in Mice With Unilateral Ureteral Obstruction Y. Horinouchi1; Y. Ikeda1; M. Imanishi1,2; Y. Zamami1,2; Y. Izawa-Ishizawa1; K. Ishizawa1,2; K. Tsuchiya1; and T. Tamaki1 1 Institute of Biomedical Sciences, The University of Tokushima Graduate School, Tokushima, Japan; and 2Tokushima University Hospital, Tokushima, Japan Background:  Renal interstitial fibrosis is a major cause in the progression of chronic kidney diseases (CKD). Recent studies have suggested that Factor Xa (FXa) or its receptor, protease-activated receptor (PAR), plays an important role in the pathophysiology of inflammatory diseases such as diabetic nephropathy and atherosclerosis. However, the involvement of FXa in renal interstitial fibrosis has remained unclear. In this study, we examined the effects of FXa inhibitor on renal interstitial fibrosis by using mice with unilateral ureteral obstruction (UUO), a renal interstitial fibrosis model. Methods:  The C57BL/6J mice were divided into 3 groups: UUO with vehicle, UUO with edoxaban (EDO), a FXa inhibitor, and sham operation with vehicle. Results:  At one week after surgery, the expression levels of FX and receptors for FXa, PAR-1 and PAR-2, increased in the kidney of UUO mice compared sham-operated mice. EDO treatment inhibited UUOinduced upregulation of the expression of the TGF-β ,　collagen I, III and fibronectin. Moreover, UUO-induced upregulation of inflammatory cytokines were also abrogated by EDO treatment. In histological analysis, UUO-induced tubulointerstitial fibrosis and macrophage infiltration were suppressed in EDO-treated mice. Conclusions:  EDO attenuates renal interstitial fibrosis in UUO mice, at least in part by inhibiting pro-inflammatory activation of macrophages. These results indicate that FXa inhibitor, EDO may be particularly beneficial for the management of CKD, in addition to its antithrombotic activity.

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The Pharmacotherapy-Team: A New Intervention Strategy to Improve Rational Pharmacotherapy and Reduce Prescribing Errors in a Hospital Setting J.K. Bekema1,2; D.J. Brinkman1,2; M. Dekker1; M.A. Kuijvenhoven1; M. van Beneden1; and M.A. van Agtmael1,2 1 VU University Medical Center, Amsterdam, The Netherlands; and 2RECIPE (Research & Expertise Center In Pharmacotherapy Education), Amsterdam, The Netherlands Background:  Prescribing errors account for a substantial proportion of medication errors, resulting in patient harm and high costs.1,2 Several interventions to reduce prescribing errors by promoting rational prescribing have been introduced in Dutch primary care.3 Although these interventions are promising, a thorough and structural approach to promote rational prescribing in a hospital setting is still lacking. Given the increasing complexity of patients in hospitals (e.g., polypharmacy, multimorbidity, older age), the demanding working environment, and the large number of drugs prescribed, new strategies to improve rational prescribing in this setting are urgently needed. We developed a new intervention strategy to improve rational prescribing and reduce prescribing errors in a hospital setting. Methods: Because of the complexity of the prescribing process, interventions to improve rational prescribing are more likely to be effective if they include a multidisciplinary and multifaceted strategy. Therefore, we set up a Pharmacotherapy-team consisting of 2 physician-clinical pharmacologists, a hospital pharmacist, an internist, a quality consultant and 2 medical students. We use Participatory Action Research (PAR), combining qualitative and quantitative methods (e.g., medication chart review, online survey) to investigate the complex nature of prescribing in hospital settings. This strategy is characterized by the participation of local employers (senior and junior physicians, nurses) in investigating opportunities to improve practice and the subsequent intervention development and implementation. The Pharmacotherapy-team performs in depth prevalence measurements of prescribing errors on wards before and after the intervention phase. Interventions developed in collaboration with local employers, focus on organization-based (e.g., redesigning working process), discipline-based (e.g., improving guideline accessibility), and individual-based (e.g., education) aspects. Conclusions:  A multidisciplinary Pharmacotherapy-team with active participation of local employers is a new and unique strategy to thoroughly investigate the complex prescribing process. With this tailored approach we hope to develop effective and sustainable interventions to improve rational prescribing in hospital settings.

References 1. Dean B, Schachter M, Vincent C, Barber N. Prescribing errors in hospital inpatients: their incidence and clinical significance. Qual Saf Health Care 2002;11:340-344. 2. Dutch Hospital Pharmacist Association. Central Medication incidents Registration (CMR). Annual rapport 2014. The Hague, The Netherlands. 3. Hazen A, Sloeserwij V, Zwart D, de Bont A, Bouvy M, de Gier J et al. Design of the POINT study: Pharmacotherapy Optimisation through Integration of a Non-dispensing pharmacist in a primary care Team (POINT). BMC Fam Pract 2015;16:76.

How to Deal with Regulation EU 536/2014 on Clinical Trials? A View from the Hospital Clínic Barcelona Research Ethics Committee S. Fernández; N. Riba; J.A. Arnaiz; B. Gómez; A. Bernal; and G. Calvo Hospital Clınic, Barcelona, Spain

Volume 39 Number 8S