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Pharmacogenomics and individualised pharmacotherapy

ADRED – Adverse drug reactions (ADR) leading to emergency department (ED) visits: Causality analysis and preventability rate of the ADRs

Principal Investigator: Prof. Dr. J. Stingl; study coordination: Marlen Schurig; BfArM employees: Marlen Schurig, Katharina Schneider, Michael Steffens, Miriam Böhme et al.

Cooperating emergency departments: Hospital Fürth (Prof. H. Dormann), University Hospital Ulm (Prof. T. Seufferlein), Interdisciplinary Emergency Department of the University Hospital Bonn (Dr. I. Gräff, Prof. G. Baumgarten), Emergency Department of the Robert Bosch Hospital Stuttgart, IKP Stuttgart (Prof. Dr. M. Schwab)

Background:
International studies and data analyses have shown that 5-10% of the admissions to emergency departments (ED) are due to adverse drug reactions (ADR). These ADRs can be classified as either preventable or not preventable drug-related events. Furthermore, literature reports regarding the distribution ratio of the preventability of such ADRs vary considerably. This study intends to support the knowledge base on the occurrence of ADRs in hospital emergency units in Germany by gaining insight into the causality of drug-related emergency hospital admissions. This could yield information on how high the rate of preventable side effects and medication errors is in the total group of cases.

Purpose:
The ADRED study addresses the issue of drug-related hospital admissions in emergency departments. The total number of suspected ADRs is assessed in a prospective case cohort in order to estimate the proportion of potentially preventable drug-related events that could be classified as medication errors. Additionally, the occurrence of a suspected ADR in the total population of patients in the emergency departments is determined. Patient-related risk factors of ADRs, e.g. age, comorbidity and polypharmacy as well as demographic data are collected. These clinical and molecular risk factors include the pharmacogenetic profile of the individual patient which is determined by taking DNA from blood or saliva samples from the patients with ADR. Information about diagnoses, treatments and interventions at the hospital, duration of illness/injury as well as the number of deaths are assessed for pharmacoeconomical analyses.

Methods:
The ADRED trial is a multicenter, prospective observational case study which will only include suspected drug-related cases that necessitate treatment. Potential medication errors are not considered, nor are ADRs that were not the reason for admission to the emergency department. The necessity of treatment in an emergency department is considered an indicator of the level of severity/seriousness of the adverse drug event. Therefore, the study sites involved the ED of major regional centers, maximum care facilities and university hospitals from different parts of Germany. The period observed covers a total of one year for each center.

Each suspected ADR case in the study center is assessed by the hospital clinician using the WHO-UMC system of causality criteria. Preventability assessment according to the Schumock scale is used to identify medication errors. In the case of a preventable medication-related event it is identified at which stage of the process it occurred (e.g. during prescription, dispensing, administration or monitoring) and what could have caused it. Thus, medication errors are classified on this level as different types of error.

The study cases are then documented in electronic case report forms. ADRs with potentially preventable causes or patient-related risk factors are collected in the database. Individual patient factors such as pharmacogenetic polymorphisms in drug metabolism may increase the risk of experiencing an ADR. In cases where patient risks factors are identified as having contributed to the occurrence of the ADR, the case is classified as an ADR that is not preventable. DNA from all patients with ADR is collected for further research in this field of safety pharmacogenetics. Additionally, pharmacoeconomic analyses of ADRs and preventable medication errors are performed using parameters such as the duration of hospitalizations and the number of diagnostic or medical interventions.

Each study center's ED has an annual average of 30,000 patients treated. If the underlying assumption of a 10% rate of ADRs is correct we can expect about 3,000 drug-related cases from each study center. The clinical course, severity and consequences of the ADRs as well as the number of deaths are documented.

First results:
Currently, four study centers have been initiated, two of which are involved actively. A further center is expected to start with the recruitment of ADR cases towards the end of 2016. As a standard procedure the medication of each ED visitor is evaluated; if the case is considered an ADR, the medication is also collected in an electronic medical documentation system. These data are analyzed when the documentation of all cases has been completed.

Funding:
This study was financially supported by a research grant from the BMG AMTS (Kapitel 15 02 Titel 686 05).

BMG GHP - Global Health Programme of the Federal Ministry of Health

Project Lead: Prof. Dr. Julia Stingl; Project Coordination: Dr. Nadina Stadler; Training Lead/In-House DQA Training: Dr. Jochen Norwig (Department 6)
BMG GHP Team Members: Ms. Sibylle Matz, Ms. Regine Lehnert, Dr. Birgit Ewert (Department 3); Dr. Michael Steffens, Dr. Katja Just, Dr. Catharina Scholl, Dr. Matthias Vogel (Research Division 5)

Background:
In 2016 following the G7 summit, the German Federal Ministry of Health launched the Global Health Programme (BMG GHP). The Robert Koch Institute, the Federal Institute for Drugs and Medical Devices (BfArM), the Paul Ehrlich Institute for Vaccines and Biomedicines (PEI) and the Bernhard Nocht Institute for Tropical Medicine (BNITM) are partners in the implementation of the BMG GHP/consortium.

At BfArM, two highly-collaborative, long-term projects have been developed to support partner countries in Africa in strengthening activities relevant to implementation of more resilient healthcare and regulatory systems. Several colleagues in the divisions/departments 3, 5 and 6 are collaborating and contributing significant know-how to the following training modules/capacity building projects:

MODULE 1 - CLINPHARANTIBIOTICS
Combating Antimicrobial Resistance by Promoting Judicious/Rational Use of Anti-infective Drugs

Partner Countries: Zimbabwe, Zambia, Malawi
Key Collaborator on the Project: Prof. Collen Masimirembwa, African Institute of Biomedical Science and Technology (AiBST), Harare, Zimbabwe

Overall aim:
This project will facilitate a situation analysis of antibiotic use/prescription practices and resistance in healthcare facilities in Zimbabwe, Malawi and Zambia and strengthen transfer of knowledge on optimal and judicious use of antimicrobial agents. The emphasis is on scientific training. ClinPharAntibiotics will enable knowledge advancement, research and training on principles of rational antibiotic use all the way to precision medicine approaches including specific patient profiles for individualized therapy. We focus on training physicians and other healthcare professionals to deepen their knowledge of antibiotic use and drug safety. Ultimately, ClinPharAntibiotics aims to establish a network for the coordinated optimization of antibiotic use in hospitals, and provide ways to assist healthcare professionals to increase benefits to the individual patient alongside promoting (national) public health.

MODULE 2 - DRUGQUALANALYSIS (DQA)
Training African national drug quality control laboratories in quality assurance and quality management in the context of combating antimicrobial/antibiotic resistance

Partner countries: Zimbabwe, Namibia, Zambia, Malawi, Botswana, Angola, Senegal, Cameroon, Burkina Faso
Partners in the Project: WHO RSS as adviser, InphA Bremen, a prequalified Official Medicines Control Laboratory, national regulatory authorities in the African partner countries

Overall Aim:
The training programme has been developed in collaboration with the Department of Essential Medicine and Health Products of the World Health Organisation (WHO) to address an unmet need. The training at BfArM and InphA will promote skills development, and will assist staff of and national drug quality control laboratories to advance their capacity to monitor the quality of medicinal products. The project will nurture networking and the overall operational capacities required to address and meet (WHO and or ISO) pre/qualification requirements will be further strengthened.

Funding:
BMG GHP receives funding from the Federal Ministry of Health under grant agreement No 323-123002. Duration: 2016-2020

Homepage BMG GHP: coming soon
Additional Information on BMG GHP (in German):
http://www.rki.de/DE/Content/Institut/Internationales/Global_health/Global_health_node.html

EMPAR – Influence of Metabolic Profiles on Drug Safety in Routine Care

Michael Steffens (BfArM), Julia Stingl (BfArM, principal investigator)

Members of consortium: Federal Institute for Drugs and Medical Devices (BfArM), German Center for Neurodegenerative Diseases (DZNE), Scientific Institute of the “Techniker Krankenkasse” (TK)

Aims:
The EMPAR research project investigates the influence of pharmacogenetic factors on the effectiveness and safety of drug therapies in routine health care. Specifically, it addresses the question of whether genetic differences have an impact on the use of statutory health insurance services (hospitalisation, nursing care level, etc.). It may be that poor-metabolizers demand different statutory health insurance services than ultrarapid-metabolizers because they have different experiences with the tolerability and efficacy of therapies. The long-term goal is to implement the use of pharmacogenetic testing of metabolic profiles for side effects and therapy resistance in routine care. This will allow applying drugs more precisely to patients and lead to an improvement in terms of quality of patient care and economic efficiency.

Methods:
The study sample consists of 10,000 elderly patients insured by the TK (60 years and older) who take at least one drug whose metabolism is known to depend on genetic variants. This means, there is clinical evidence that genetic differences have an impact on the pharmacokinetic and/or pharmacodynamic of the drug in question. A panel of pharmacogenetically important markers will be genotyped from buccal swab of each patient. Pharmacogenetic, -epidemiologic and -economic analysis using health care utilization scores (Charlson, Elixhauser, ICD diagnoses, Rx-Risk, chronic disease scores, etc.) will be applied. Machine learning techniques will be used to estimate the benefit of testing metabolic profiles in routine care in terms of prevention of adverse drug reactions and decrease of costs in health insurance services.

Funding:
The project is funded by the Innovation Fund of the Federal Joint Committee (Gemeinsamer Bundesausschuss) under the support code 01VSF16047.

IDRUG - Individualized versus standardized risk assessment in patients at high risk for adverse drug reactions

Katharina Kaumanns, Michael Steffens, Miriam Böhme, Karin Holz, Catharina Scholl, Ann-Kristin Leuchs, Dorothee Wirtz, Norbert Benda, Julia Stingl

Research network partners: Klaus Weckbecker (Institute of General Practice and Family Medicine, University of Bonn), Gunther Hartmann (Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn), Christoph Coch (Study Center Bonn (SZB), University of Bonn), Oliver Schöffski (Study Center Bonn (SZB), University of Bonn)

Background:
Elderly, multimorbid patients are frequently affected by adverse drug reactions (ADR) as they often take several drugs concomitantly. Especially with oral anticoagulants these side effects can be severe, potentially life-threatening and impairing the patients’ quality of life e. g. thromboembolic or bleeding events in the brain or periphery.  We want to investigate, whether a patient-tailored risk information can increase patient safety in high-risk patients. Previously, in clinical practice individualized approaches have often been neglected because proof of a positive cost-benefit-ratio is still missing and cost effectiveness of their clinical implementation has not been shown until now.

Purpose:
Objective of this health services research project is to develop new strategies of improved risk information for patients at high risk for ADR. The study analyzes the benefit of individualized approaches in drug therapy i. e. whether an individual, patient-tailored risk assessment is superior to a standardized information and whether ADR can be reduced in a cost effective way.

Methods:
In cooperation with general practitioners (GP), clinical pharmacologists and pharmacoeconomists we will analyze whether information concerning drug risks respecting the patient’s individual clinical situation is superior to general advising. During a period of 9 months we will observe if knowledge of the own individual risk influences the frequency of GP-consultations, hospital admissions, medication changes and the patients’ quality of life. Genetic reasons for interindividual differences in drug tolerance and metabolism will be determined by additional pharmacogenetic analyses. Furthermore, study participants will be asked to fill in a survey regarding their quality of life and their drug therapy. In total, about 870 patients from 40-80 GP-practices will be enrolled.

First results:
Until now, about 200 patients from 30 GP-practices have been included in the study. Currently, more practices are being recruited and initiated for study participation.

Funding:
Federal Ministry of Education and Research (BMBF) – grant application number 01GY1333A

StemCellFactory III – Investigation of the CNS specific drug metabolism using iPS-cell based cortical
organoids (WP3 and WP4)

Matthias Vogel, Catharina Scholl, Julia Stingl

Participants: Life & Brain GmbH Bonn (Project leadership), Fraunhofer Institute for Production Technology Aachen, University Hospital Aachen, University Hospital Bonn, Lead Discovery Center GmbH Dortmund, P3 aviation GmbH Aachen, Federal Institute for Drugs and Medical Devices Bonn

Background:
In recent years the progression of personalized medicine and individualized drug therapy contribute gaining benefits in patient care and additionally decreasing severe drug side effects. By thoroughly selecting an adequate and effective drug under consideration of the applied dosage is thereby of great importance. Recent developments in the area of cell reprogramming techniques (e.g. induced pluripotent stem cell technology; iPS) facilitate possibilities of examining drug effects by simultaneously including human cells directly obtained from an individual patient. This unique technique of preclinical drug testing evades risks of harming patients by unforeseen reactions and provides insights of future individual pharmacotherapy.

Aims:
The aim of the StemCellFactory III study is to develop an automated process for a safe and standardized production of iPS cells individually derived from patient blood samples with a precending genetic modification. These cells can be further used as platform and model system for personalized stem cell based investigation and examination of drugs. On the basis of neuronal cell models, differentiated from iPS- cells, it is an additional aim of the project to develop an assay useful to investigate the CNS specific CYP450 based drug metabolism.

Methods:
Within the project it is planned to investigate the content and functionality of drug metabolizing enzymes in iPS cell derived cortical organoids. The expression of different CNS specific enzymes will be followed during the differentiation of organoids and the activity of these enzymes will be characterized measuring the metabolism of test substances using LC-MS

Funding:
This project has received funding from the European Union and the state of North Rhine-Westphalia within LifeSciences.NRW, (grant agreement number: EFRE-0800967).

Ubiquitous Pharmacogenomics – Training and education of health care professionals and patients in Pharmacogenomics

Katja Just, Michael Steffens, Julia Stingl (BfArM)

Participants: Academisch Ziekenhuis Leiden - Leids Universitair Medisch Centrum (NL), Royal Liverpool and Broadgreen University Hospitals NHS Trust (UK), Karolinska Institutet (SE), The Golden Helix Foundation (UK), KNMP Holding B.V. (NL), Bio.logis Genetic Information Management GmbH (DEU), Stichting Sint Antonius Ziekenhuis (NL), Medizinische Universität Wien (AUT), Universite Paul Sabatier Toulouse III (FR), Uppsala Universitet (SE), Centro di Riferimento Oncologico di Aviano (IT), Servicio Andaluz de Salud (ESP), University of Patras (GRC), Univerza V Ljubljani (SVN), Robert Bosch Gesellschaft für Medizinische Forschung mbH (DEUHp)

Homepage: http://upgx.eu/, Promotional Video: https://www.youtube.com/watch?v=X2KK_FfsrS4&feature=youtu.be

Background:
Pharmacogenomics (PGx) is the study of genetic variability affecting an individual’s response to a drug. Pharmacogenomics variability counts for a part of adverse drug reactions. The U-PGx consortium will investigate a pre-emptive genotyping approach (that is: multiple pharmacogenomic variants are collected prospectively and embedded into the patients’ electronic record) of a panel of important pharmacogenomic variants as a new model of personalised medicine.
Implementation will be conducted at a large scale in seven existing European health care environments. Knowledge of relevant PGx variation will be immediate accessible. This is accompanied by interpretation and recommendations without any disruption of routine clinical care. Feasibility, health outcome and costeffectiveness will be investigated.

Aims:
Taking into account the diversity in health system organisations and settings in the participating countries, we focus on education and training of pharmacists and physicians. Medical staff can deepen their knowledge on drug risks and safety. The potential of personalised medicine by using PGx in routine clinical care shall be spotlighted.

Methods:
Using the train-the-trainer concept, workshops and a summer school will be organised. Additionally, e-learning programs for medical staff will be established. Further, patients shall be encouraged in knowledge and handling of PGx by electronic information systems.

Funding:
This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 668353.

Pharmacogenomic imaging

Anna Paul, Katharina Kaumanns, Michael Steffens, Martina Wiertz, Roberto Viviani*, Julia Stingl

Aims:
Functional magnetic resonance tomography (fMRT) admits of non-invasive investigation of genetic causes of structural and functional variability in the neuronal networks involved in the process of cognition and sensation of emotions. The study is aimed at determining the inter-individual variability in resting-state brain perfusion and finding out whether, in future, such differences might be used as biomarkers for therapeutic responses to psychotropic drugs. In a first step, the genetic influences in structures modulated by psychotropic drugs are characterised in resting-state brain perfusion (genomic imaging). This is followed by analysing the effects of various pharmaceuticals and identifying the correlation with the therapeutic responses (pharmacological imaging).

Methods:
Various questions concerning different therapies will be dealt with. One is the examination of resting brain perfusion in patients with depressions. The fMRT is searched for changes over time in resting brain perfusion, both under therapy with antidepressants, e.g. changed perfusion due to blockage of serotonin transporter, and under the activation of certain areas during cognitive performances. Finally, we look for associations between the genetic data, the perfusion data, and the therapeutic response data.

First results:
Inter-individual variability is shown in resting-state brain perfusion for certain genetic variations of the polymorphous enzyme Cytochrome P450 2D6 [1]

References:
1. Stingl JC, Brockmöller J, Viviani R (2013) Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry 18(3):273–287
*University of Ulm

Pharmacogenomics of antidepressant drugs in a cell model

Jörg Breitfeld, Anna-Maria Paul, Kristina Stiebel*, Olga Efimkina*, Kerstin Brandenburg, Julia Stingl

Aim:
Pharmaceutical therapies of depressive disorders turn out to be unsatisfactory due to low response rates and severe side effects [1]. Differences in therapy outcome can be attributed to individual neuro-regenerative and neurotoxic antidepressant effects in certain brain areas [2][3]. It is the aim of the project to measure the individual proliferation and toxicity of antidepressant drugs in blood cells in an ex-vivo model in order to identify the individual proliferation pattern as a biomarker for therapeutic response prediction.

Methods:
For a start, dermal fibroblasts and immortalised blood cells are checked for their suitability as model systems for antidepressant effects by investigating whether they can be stimulated to proliferation by antidepressant agents. Cell proliferation and cell toxicity are assayed by flow cytometry and colorimetry. In the further course of the project, methods of molecular biology are applied in genome and transcriptome analyses (DNA sequencing, gene typing, expression analysis).

Results and conclusions:
Previous results show an inter-individual variability, which we have already correlated with clinical parameters. These data will be supplemented with clinical data and disease process data from patients under therapy, and further investigated.

References:
1. Narasimhan S, Lohoff FW (2012) Pharmacogenetics of antidepressant drugs: current clinical practice and future directions. Pharmacogenomics 13(4):441–464
2. Chang EA, Beyhan Z, Yoo MS et al (2010) Increased cellular turnover in response to fluoxetine in neuronal precursors derived from human embryonic stem cells. Int J Dev Biol 54(4):707–715
3. Boldrini M, Hen R, Underwood MD et al (2012) Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression. Biol Psychiatry 72(7):562–571
*University of Ulm

Drug induced skin toxicity

Vivien Hichert, Catharina Scholl, Michael Steffens, Julia Stingl

Aims:
Pharmaceuticals administered in cancer therapies are often targeted at the EGF receptor (epidermal growth factor) since the latter is over-expressed in many tumours. Frequently the targeted cancer therapy is accompanied by acneform skin reactions, which are also associated with a better prognosis [1][2]. In this project, patient material after completed therapy with EGF-receptor inhibitors is analysed for phenotype and genotype to elucidate the molecular basis of epidermal toxicity and to identify potential biomarkers. For it, patient blood samples are analysed for various parameters, e.g. drug plasma concentration, and are then correlated with clinical data. Genetic investigations include the sequencing of genes that are crucial in the EGF receptor-activated signal cascades and immune reactions, e.g., kinases and cytokines. Also the expression of various microRNAs undergoes examination.

References:
1. Hu JC, Sadeghi P, Pinter-Brown LC et al (2007) Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management. J Am Acad Dermatol 56(2):317–326
2. Wacker B, Nagrani T, Weinberg J et al (2007) Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res 13(13):3913–3921

Funding:
Wilhelm Sander Stiftung DERMATOXGEN Nr. 2008.017.2

Inter-individual modes of Ciprofloxacin reception in a cell model

Catharina Scholl, Julia Stingl

Aims:
Ciprofloxacin is a frequently applied antibiotic in the group of fluoroquinolones. Ciprofloxacin can be absorbed by blood cells and kill bacteria intracellularly, e.g. Staphylococcus aureus [1]. The current project investigates ciprofloxacin uptake in lymphoblastoid cells to find out whether differences in ciprofloxacin uptake rates, and thus differences in drug efficacy, are caused by individual genetic variability in drug transport.

Methods:
One hundred cell lines (immortalised B-lymphocytes) from healthy Caucasians are available for our investigations. They are incubated with varying ciprofloxacin concentrations. The intracellular concentrations are measured by HPLC as a function of time. The results are correlated with pharmacogenetic data from the volunteers. For instance, expression of drug transporters and their polymorphisms is investigated.

First results:
They show inter-individual variations in intracellular ciprofloxacin uptake. After completion of all measurements the data will be correlated with genetic data from the volunteers.

References:
1. Easmon CS, Crane JP, Blowers A (1986) Effect of ciprofloxacin on intracellular organisms: in-vitro and in-vivo studies. J Antimicrob Chemother 18(Suppl D):43–48

Funding:
EU 7th Framework Programme: TINN (TreatInfections in NeoNates: Evaluation of infective agents (ciprofloxacin and fluconazole) for the treatment of infections in preterm and term neonates

Pharmacogenetic research into antidiabetic therapies

Catharina Scholl, Karin Holz, Magdalena Kolbe-Padur, Julia Stingl

Background:
Antidiabetic therapies show a great inter-individual variability in therapeutical effects and side effects. It may be caused by clinical parameters, such as the degree of disease, or by genetic factors. Polymorphisms in the genes of biotransformation, drug transport and drug target structures influence the individual antidiabetic action [1].

Aims:
The project is part of the European research pool DIRECT, which is supported by the “Innovative Medicines Initiative“ (IMI). DIRECT is concerned with research into the impact of genetic variations on the therapy of Type-2-Diabetes mellitus. The aim of these studies is the characterisation of genetic biomarkers for genotype-based therapies. They shall be used in diagnostics to improve the safety and efficacy of oral antidiabetics.

Methods:
Diabetes patients are selected from a clinical course register. The aim is to find genetic markers in patient blood which are potential biomarkers for the development of metformin intolerance or which affect the action of metformin, sulfonyl urea and incretin mimetics.

References:
1. Scholl C, Lehmann ML, Stingl J (2013) Pharmakogenetik oraler Antidiabetika. Pharmakon 1:223–230

Funding:
EU-IMI project: DIRECT: Dabetes REsearCh on patient stratification

Genetic bioinformatics in pharmacogenomics

Michael Steffens, Julia Stingl

Background:
Genetic bioinformatics plays a key role in pharmacogenomics and pharmacogenetics. Thanks to the advance of personalised medicine, the individual genetic profiles of patients and their effects on drug response and drug safety, besides environmental factors, are getting increasingly focussed on. Methods of bioinformatics allow the correlation, and evaluation, of genome and transcriptome data with complex data sets for end points of pharmacological effects, e.g. dose-effect-curves, functional imaging or measurements of cerebral perfusion. A real challenge in this work is the electronic processing of the huge amount of throughput rates as well as the statistic genetic analysis of the surrogate parameters and related genome data employed for the pharmacological phenotypes.

Aims:
Apart from generating appropriate bioinformatic structures for the analysis of genome data from internationally available data bases, like HapMap or the 1000-Genome-project and the sequencing data generated at BfArM, other projects are pursued aimed at the following: i) modelling of pharmacogenetic mechanisms and signal transduction paths in special cell systems, ii) discovery of new biomarkers, e.g. for the definition of new disease subtypes, and iii) investigation of the importance of post-translational modifications for the activation of proteins as target structures for drug therapies.

References:
1. Roukos DH, Ziogas DE, Baltogiannis GG et al (2013) Novel next-generation sequencing and networks-based therapeutic targets: realistic more effective drug design and discovery. Curr Pharm Des
2. Cordero P, Ashley EA (2012) Whole-genome sequencing in personalized therapeutics. Clin Pharmacol Ther 91(6):1001–1009
3. Altman RB (2012) Translational bioinformatics: linking the molecular world to the clinical world. Clin Pharmacol Ther 91(6):994–1000