The research areas pharmacogenomics and individualised pharmacotherapy are concerned with the variability of patients' drug responses that is caused by inborn genetic differences. Research in this area concentrates on expanding the knowledge of molecular, preclinical, and clinical principles in order to arrive at a personalised pharmacotherapy. The aim is to identify the exact causes for individual differences and the variability of desired drug reactions as well as of adverse reactions and interactions of medicinal products. The findings allow the development of modern and personalised treatments and lead to improvements in the patient safety of new medicinal products and therapeutic concepts.

Head of the Research group:

N.N.

Contact:
Dr. Catharina Scholl

Telephone: +49-(0)228-99-307-4309
E-Mail: Catharina.Scholl@bfarm.de

The Research group

Current Research Projects

Artificial intelligence for personalized medicine in depression - analysis and harmonization of clinical research data for robust multimodal patient profiling for the prediction of therapy outcome

Veronica Atemnkeng Ntam, Michael Steffens, Catharina Scholl.

Consortium partners: Institute of Clinical Pharmacology, RWTH University Hospital Aachen (consortium lead); IRCCS Istituto delle Scienze Neurologiche di Bologna; Institute of Psychology, University of Innsbruck; Faculty of Medicine, Tel Aviv University; Center for Psychopharmacology, Diakonhjemmet Hospital Oslo; School of Medicine, University of Zagreb and Zagreb University Hospital Center.

Background:
Personalized medicine aims to predict a patient's response to therapy based on biomarker signatures. This approach is particularly important in the treatment of depressive disorders. Pharmacotherapy of depressive disorders is often associated with difficulties due to low response rates and severe side effects. Numerous studies have been conducted in the field of depression treatment to find personalized treatment options. However, we are still far from being able to determine optimal treatment subgroups diagnostically or to predict the course and individual treatment success of the depressive disorder.

Project Objective:
The aim of this collaborative project is to establish a data and analysis platform that will pool data from existing clinical research projects on individual treatment response in depression. This will serve to identify biomarker profiles for the response to drug therapies for depression using artificial intelligence methods. For this purpose, the partners of the joint project will provide data on therapy course and therapy response from existing clinical research projects. These records will be combined and integrated into a complex data platform for evaluations.

When using AI-supported systems and multimodal biomarker profiles to predict therapy, ethical, legal and regulatory requirements must also be considered. In this context, the task of the BfArM staff involved is, for example, to investigate which regulatory requirements exist to date. Regulatory measures for the use of AI to predict response to drug therapies for depression will be reviewed. Furthermore, it will be of interest to what extent these measures are already being taken into account in the research and development of such algorithms.

Funding:
Within the framework of ERA PerMed by the German Federal Ministry of Health (BMG) Grant no: ZMI5-2522FSB900

Risk assessment and characterisation of novel N-nitrosamines in the context of drug safety and quality

Roland Frötschl, Bodo Haas, Matthias Vogel

Cooperating partners: K. P. Cross¹ , A. Bassan² , I. Brandsma³ , S. Chang⁴ , M. Djuari⁵ , M. Christmann⁶ , U. Deppenmeier⁷ , L. Elenschneider⁵ , J. Fahrer⁸ , G. Johnson⁹ , T. Hansen⁵ , A. Londenberg⁵ , T. Osterlund³ , M. Schulz⁴ , C. Ziemann⁵ , S. E. Escher⁵

¹Instem, Columbus, Ohio, United States of America;² Innovatune, Padova, Italy;³ Toxys, Oegstgeest, Netherlands;⁴ ICCR, Rossdorf, Germany;⁵ Fraunhofer ITEM, Hannover, Germany;⁶ University of Mainz, Mainz, Germany;⁷ University of Bonn, Bonn, Germany;⁸ Technical University of Kaiserslautern, Kaiserslautern, Germany;⁹ Swansea University Medical School, Wales, United Kingdom

Background:
N-nitrosamines (NA) are ubiquitous chemical compounds to which humans may be exposed through environmental factors such as consumption of certain foods. High concentrations of NA can also be found in the inhalation of tobacco smoke. NA are classified as probable carcinogens according to IARC and belong to the group of highly potent mutagenic carcinogens; the so-called "cohort of concern" according to ICH M7 guidance. Since the detection of N-nitrosodimethylamine (NDMA) in 2018 in the active pharmaceutical ingredient valsartan, a European risk assessment procedure has been carried out for drug substances and drug manufacturers have been obliged to assess the risk of NA emergence during manufacturing for their products and, if necessary, to carry out controls for contamination by NA. It was observed that not only low-molecular NA are relevant as impurities, but also active pharmaceutical ingredients themselves can be chemically altered to NA impurities due to possible unfavourable production or storage processes.

Purpose:
In three research projects, funded by the European Medicines Agency (EMA), the mutagenic effect of different classes of NAs is to be analysed in order to be able to better assess the possible carcinogenicity of individual NAs in the future and from this to improve the development of computer-assisted prediction models. In addition to small-molecular, classical NA, drug-like substances will also be investigated. A special focus will be on the question by which processes the substances can be metabolically activated, whether relevant DNA adducts can be formed and which DNA repair mechanisms are able to reverse these adducts. In addition, in vitro test methods for the detection of genetic alterations are to be optimized for NA. By developing novel in silico and in vitro test systems, the consortium aims to improve risk assessment and facilitate the derivation of threshold values such as tolerable intake levels. The possible formation of drug-derived NA under physiological conditions after oral uptake is also being investigated.

Methods:
Initially, projects will focus on studies of the formation of metabolites from NA, and their ability to damage DNA in the absence of adequate physiological repair. The data obtained will be used to establish correlations between the structure of NA and their potential toxic/mutagenic effects. Using an approach based on quantitative structure-activity relationships (QSAR), tolerable intake levels can thus be derived for compounds for which no suitable in vivo carcinogenicity studies are available, i.e. a prediction based on the "read-across" approach is pursued.

In the further course, the effects of the physiological environment of the digestive tract (including the microbiome) on the formation of NA from drugs or their degradation products will be investigated. Since little is known about nitrosamine formation in the body, the elucidation of possible mechanisms is of utmost importance to assess the risk of NA formation under physiological conditions in patients. The practical research results from these laboratory studies will be pooled and evaluated to develop predictive QSAR models that can be used to predict the tendency of nitrosamine formation for drugs.

Finally, the project will optimize and validate the current bacterial systems for mutagenicity testing (AMES test) as well as further in vitro genotoxicity tests such as the comet assay in liver cell models (primary human and rat liver cells, human liver cell lines) for NA. Metabolic competence will be a key issue here in order to achieve the main goal, namely to identify the mutagenicity and thus possible carcinogenicity of different NA and to be able to derive limit values.

As part of an international consortium, the BfArM contributes significantly to the projects by carrying out state-of-the-art analyses (LC-MS/MS) and toxicological bioassays (Comet Assay).

Funding:
These projects are funded by the European Medicines Agency through the framework contract EMA/2020/46/L1.02.

PSY-KOMO – Improving the health care quality for patients with severe mental illness to reduce somatic comorbidity and prevent increased mortality.

Rebecca Weber, Catharina Scholl, Michael Steffens, Miriam Böhme (all BfArM)

Members of consortium and cooperation partners: Federal Institute for Drugs and Medical Devices (BfArM), Frankfurt/M. University Hospital, Greifswald University Hospital, Christophsbad Clinic Göppingen, Alexius/Joseph Hospital Neuss (St. Augustinus-Group), Institute of Health Services Research and Health Economics, Heinrich-Heine University Düsseldorf (UKD), Institute of General Practice (ifam) (UKD), Department of Psychiatry and Psychotherapy (UKD), Coordination Centre for Clinical Trials (UKD), AOK Rheinland/Hamburg, Psychologische Hochschule Berlin, Central Research Institute of Ambulatory Health Care in Germany, Berlin; Regional Associations of Statutory Health Insurance Physicians (KV) Northrhine, KV Hesse, KV Baden-Württemberg, IGES institute GmbH

Background:
The care of physical illnesses of people with severe mental illness (SMI) poses a particular challenge for health systems. On the one hand, reasons for this can be found on part of practitioners who may overlook somatic problems by focusing on psychiatric illnesses (so-called Overshadowing), on the other hand, this group of patients may have specific problems to make use of existing structures of care. However, life expectancy of SMI-patients is reduced by an average of six to twelve years due to somatic comorbidities of heart, lung, liver and other organs. Therefore, an adequate treatment of these somatic comorbidities is enormously important. Many psychopharmacological drugs have a high potential for adverse drug reactions (ADR), which is challenging for the pharmacological therapy of SMI-patients. The risks for drug-drug interactions (DDI) is especially high with additional treatment of a somatic comorbidity. This leads to a burden for the patient and may result in a discontinuation of therapy. The PSY-KOMO-project is intended to meet those challenges by making use of a new form of care, which will improve the quality of care for this group of patients.Participating in this project, scientists at BfArM will analyze the medication prescribed to the patients during the project period. A special focus will be put on the interaction of psychotropic and somatic medication for which individual variability in drug metabolism may be of considerable importance. The scientists at BfArM also participate in pharmacological training of participating practitioners at the study centers and are in contact with the staff of the Department of Psychiatry and Psychotherapy in Düsseldorf, who offer a telephone consultation for psychiatrists taking part in the study.

Purpose:
Aim of the project is to improve the quality of care for patients with severe mental illness. Thereby the quality of treatment and processes in the care of physical comorbidities and optimal adjustment of psychopharmacotherapy with somatic medication are of particular importance. In order to meet this goal a cross-sectoral and medically interdisciplinary network is created. The aim is to overcome barriers on the side of healthcare providers through targeted counseling and information of physicians and caregivers.  Specially trained health care companions provide patients with targeted support in making use of existing and newly established care services. Specific telemedical consultations are offered to physicians participating in the project supporting an optimized medication for both, psychiatric as well as somatic disease and thus reduce drug-drug interactions. During the project period, physicians will be supported in recognizing drug-drug interactions and make adjustments to medication if necessary. This should improve guideline-based therapy of patients and increase the safety of pharmaceutical therapy.

Methods:
In our cooperating study centres several thousand patients with severe mental illness are expected to be integrated into the new form of care and monitored during the project. Retrospectively, matching control groups will be selected on the basis of routine data of medical insurance companies in order to allow statistically proven statements concerning a possible improvement of detection and treatment of comorbidities and to evaluate the use of telephone or telemedical consultations. The medication analysis is intended to contribute to the development of the new form of care in a way that the benefits this analysis could bring to the care of mentally ill patients and the treatment of their comorbidities (e.g., by reducing their risk for ADR) is evaluated during the course of the project.

Funding:
The project is funded by the Innovation Fund of the Federal Joint Committee (Gemeinsamer Bundesausschuss) under the support code 01NVF19019.

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

Miriam Böhme, Catharina Scholl, Michael Steffens (all BfArM), Prof. Julia Stingl (RWTH Aachen, cooperation partner)

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) Emergency Department Klinikum Ingolstadt (Dr. Florian Demetz), Emergency Department University Hospital Augsburg (PD Dr. Markus Wehler)

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..

References:
1) Schurig AM et al. (2018), Adverse Drug Reactions (ADR) and Emergencies. Dtsch Arztebl Int., Apr 13;115(15):251-258
2) Just KS et al. (2019), Personalising drug safety-results from the multi-centre prospective observational study on Adverse Drug Reactions in Emergency Departments (ADRED). Eur J Clin Pharmacol., Dec 12

Funding:
This study was financially supported by a research grant from the BMG AMTS (ZMVI5-2514ATA004, ZMVI1-2514ATS004)

GHPP

Background:
The Federal Ministry of Health launched the Global Health Protection Programme (GHPP) in 2016 as a result of the decisions taken at the G7 summit. In Germany, the Federal Institute for Drugs and Medical Devices (BfArM), the Bernhard Nocht Institute for Tropical Medicine, the German Central Committee for the Control of Tuberculosis, the Borstel Research Centre, the Friedrich Loeffler Institute, the Paul Ehrlich Institute and the Robert Koch Institute are involved in implementing the programme.

The BfArM has been involved in the programme since 2016 as part of various projects with the aim of supporting and strengthening local healthcare systems in Africa.

GHPP LabTrain
Partner countries: Gambia, Ghana, Liberia, Sierra Leone

Partner organisations: Institute for Pharmaceutical and Applied Analytics (InphA), World Health Organisation (WHO), University of Würzburg (JMU), Institute of Pharmacy and Food Chemistry

Project objective: The LabTrain project aims to increase the competence of African national drug regulatory authorities and their quality control laboratories (QCLs) through various measures.

Based on a needs analysis of the national drug authorities in Ghana, Liberia, Sierra Leone and The Gambia, the Federal Institute for Drugs and Medical Devices (BfArM) and the Institute for Pharmaceutical and Applied Analytics (InphA) will provide technical advice and support for the establishment and further development of QCLs. In addition, basic training courses and an exchange of information will be organised to cover all the recommendations of the WHO guidelines for good practice in pharmaceutical QCLs. In addition, customised training will be developed for the partner laboratories and other GHPP DQA alumni countries, which will be complemented by structure-building measures to improve the laboratory quality management system.

In addition, the project supports national QCLs by contributing to the WHO International Pharmacopoeia (Ph. Int.). The BfArM will support the WHO in the preparation of monographs for medicinal products for the treatment of leishmaniasis and amoebiasis, which are particularly widespread in parts of Africa. In view of the increasing importance of mRNA vaccines worldwide, the quality of the lipid excipients used for the production of lipid nanoparticles to coat the mRNA must also be ensured. In joint research activities of the BfArM, the WHO and the University of Würzburg, quality testing procedures and specifications are being developed for the lipid derivatives used as excipients in mRNA vaccines.

Project staff:
Department 5: Prof. Dr Britta Hänisch (project lead), Andrea Stanglmair (project coordinator, deputy project lead), Claudia Stärk (doctoral student)

Department 4, FG 45: Dr Yvonne Urbach (project lead), Dr The Hung Vu (researcher, deputy project lead), Benjamin Winnerling (researcher)

Funding:
The project is funded by the Federal Ministry of Health. Funding period: 2023-2025.

Completed projects:

GHPP CPA and PLUS - Combating antimicrobial resistance - Scientific training on rational anti-infective use (2017-2022)

Countries involved: Zimbabwe, Zambia, Malawi

Partner in Zimbabwe: Prof Collen Masimirembwa, African Institute of Biomedical Science and Technology (AiBST), Harare, Zimbabwe

Partner in Zambia: Dr Derick Munkombwe, Department of Pharmacy, School of Health Sciences, University of Zambia

GHPP DQA and PLUS - Quality assurance and quality management training of African quality control laboratories in the framework of the Global Action Plan on Antimicrobial Resistance (2017-2022)

Participating countries: Armenia, Botswana, Burkina Faso, Burundi, Cameroon, Egypt, Ethiopia, Ghana, Kenya, Malawi, Namibia, Nigeria, Rwanda, Senegal, Sierra Leone, Tanzania, Uganda, Zambia, Zimbabwe

Project partner: World Health Organisation (WHO); Institute for Pharmaceutical and Applied Analytics, Bremen (InphA)

GHPP LEARN (2020-2022)

Cross-project survey of E-LEARNing concepts to support sustainable capacity building within the framework of GHPP

Project partner: GHPP office at the Robert Koch Institute (RKI)

Further information:

BfArM Website: GHPP projects at the BfArM

GHPP Website: Global Health Protection Programme

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

Michael Steffens, Tatjana Hübner (study coordinator), Jochen Fracowiak (all BfArM), Julia Stingl (RWTH Aachen, cooperation partner)

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 adult patients insured by the TK (18 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.

RegCDx - Regulatory Research on Companion Diagnostics

Project strand II (BfArM, Division 5): Tatjana Hübner, Catharina Scholl, Michael Steffens

Cooperation partners project element I (BfArM, Division 9): Camilla Lambertz, Kathrin Lange, Wolfgang Lauer

Background:
The development of pharmacogenomic and genetic diagnostics for personalised drug therapy has made enormous advances over the past ten years. Meanwhile, the number of drug approvals requiring the investigation of genetic markers that influence the individual safety and efficacy of drugs is increasing. Accordingly, the regulations for the market launch of in vitro diagnostics have been adjusted to the evolving demands. The European Regulation for In Vitro Diagnostics (IVDR) and the Regulation for Medical Devices (MDR) officially came into force on 25 May 2017 and will replace the existing medical device directives after a transitional period of 5 years. The RegCDx project supports this transition in order to meet the scientific and regulatory challenges associated with the assessment of companion diagnostics in the context of the new IVDR.

Aims:
Project strand I: Implementation of a standard for the exchange of risk-related information regarding Companion Diagnostics (CDx)
Project element I supports the establishment of a continuous exchange of information on the safety and performance of in vitro diagnostics between BfArM, PEI and the IVDR implementation partners involved. The regulatory framework and standards for this procedure will be developed and tested. The project promotes the scientific coordination of the participating experts and serves to accelerate the decision-making processes.

Project strand II: ADR genomics: "Gaining methodological competence through own investigations on high-throughput sequencing in ADR cases"
Project strand II includes a comparison of methods of genetic high-throughput sequencing (e.g. different next-generation sequencing techniques) and the investigation of pharmacotherapy-relevant genes in cases of adverse drug reactions. The aim is to further develop methodological competence in the field of the latest genetic diagnostic techniques and to gain experience with regard to a well-founded, scientific assessment and evaluation of these techniques in regulatory processes.

Methods:
Within the framework of project strand II, based on the case collection of adverse drug reactions (ADRs) built up at the BfArM in recent years, suitable bio-samples will be analysed utilizing the most commonly used and genetic diagnostic methods. The focus is on the comparison of important, clinically relevant pharmacogenetic markers. Different pharmacogenetic techniques using single markers (e.g. microarrays) are compared both with each other and with modern genome sequencing techniques. In addition, a semi-automatic analysis pipeline for the evaluation of pharmacogenetic profiles at BfArM will be established.

Funding:
This project has received funding from the Federal Ministry of Health, grant No.: ZMVI1-2519FSB404.

Pharmgen_Angioedema – Characterization of molecular and external factors of potential impact in bradykinin-mediated angioedema by the example of ACE-inhibitor or angiotensin receptor blocker induced angioedema

Coordination BfArM: Prof. Dr. Bernhardt Sachs; Contributors: Carina Mathey, Dr. Michael Steffens and others, BfArM

Principal investigator Institute of Human Genetics: Prof. Dr. med. Markus Nöthen, coordination: Dr. Christiane Stieber, Institute of Human Genetics, University Hospital of Bonn

Background:
The occurrence of angioedema upon treatment with drugs that affect the degradation of bradykinin, such as ACE-inhibitors or angiotensin receptor blockers (ARBs), is a known risk. The incidence of angioedema in patients treated with ACE-inhibitors is reported to be 0.1 - 0.7 % in Europeans. In Germany the absolute number of ACE-inhibitor induced angioedema is estimated to range between 20,000 and 35,000 cases per year owing to the huge use of ACE inhibitors. The occurrence of these angioedemas is not predictable and depends on the individual characteristics of the patient. Hence this joint research project with the Institute of Human Genetics at the University of Bonn does not focus on the drug, but on the individual risk factors of the patients.

Purpose:
The objective of this study is to characterize pharmacogenetic factors of potential impact in bradykinin-mediated angioedema by the example of ACE-inhibitor or ARB-induced angioedema. The secondary objectives of the study encompass the analysis of the patient’s history, including basic diseases, concomitant medication and lifestyle factors, such as smoking. The study’s high-level aim is to examine whether patient populations with a clearly higher risk can be identified enabling the introduction of appropriate risk-minimizing measures. In addition, the collected data will be used to build up a register for ACE and ARB-induced angioedema (without reference to personal data, initially limited for 20 years).

Methods:
On the genomic level both exploratory and focused analyses will be carried out. The explorative analyses will initially focus on array-based characterizations of frequent DNA sequence variations and their evaluation in genome-wide association studies (GWAS) of angioedema induced by ACE-inhibitors or ARBs. In later investigations, the rarer DNA sequence variations will be analysed in more detail based on exome (entire coding sequence) - or genome-sequencing. The focussed analysis will employ high-resolution investigations of pharmacogenetic candidate genes.
In order to characterize epigenetic factors, initial analysis of the DNA methylation status and further investigations of other epigenetic DNA modifications are planned.

The secondary targets are evaluated descriptively in the cases. For this purpose the following aspects, among others, will be addressed in a questionnaire: family burden with regard to angioedema, co-medication, basic and accompanying diseases, basic epidemiological parameters, smoking, potentially associated factors (operations, stress) and information on the incriminated drug.

References:
Bulletin zur Arzneimittelsicherheit. Ausgabe 2. Juni 2017. „Arzneimittelinduzierte Angioödeme“ (Seite 13-23) und „Forschungsprojekt zu Arzneimittel-assoziierten Bradykinin-vermittelten Angioödemen“ (Seite 32-35)

Funding:
This project received funding from BfArM’s own resources and the Institute of Human Genetics of the University Hospital Bonn. Period of funding: 2017-2021

Insights in the individual drug transport and metabolism employing cell-based in vitro models

Catharina Scholl, Matthias Vogel (all BfArM)

Background:
Within the field of personalized medicine, the individual pharmacotherapy is increasingly important. Patient specific selection of a dosage or choosing a drug with effectiveness is of utmost importance to obtain positive effects for the patient’s therapy. The interindividual metabolism of drugs is caused by differences in enzyme concentrations located in the liver. As a reason, drugs can be degraded and excreted faster or slower resulting in lower or higher blood concentrations, respectively. Thereby, adverse effects can arise or influence the pharmacotherapy.

Latest research publications also reveal metabolic processes in other tissues (e.g. brain) which may lead to local metabolite adverse or unforeseen reactions. Convincing data, if a drug is metabolized in respective tissues to unknown compound, is part of ongoing research investigations.

In the current study, induced peripheral blood cells can be utilized from individuals to generate neural cells in an early stage and further investigating differences in patient metabolisms. By exploiting the in vitro derived neural cell model, new insights of local pharmacokinetic effects can be gathered. In addition, the early stage of the neural development and fetal metabolism is part of the project and toxic effects due to drug intake during pregnancy can be deduced with the presented cell model.

Methodology:
In the study, the variety of drug metabolizing enzymes and transporter will be investigated. Thereby, the focus lay on specific differences between the phenotypes of patients in correlation with their genotypes. All analytical approaches, in case of enzyme characterization and activity, will be performed by means of modern biotechnological methods (PCR, Western Blot, etc.) and liquid chromatography-mass spectrometry.

Pharmacogenomic imaging

Michael Steffens, Martina Wiertz (all BfArM), Roberto Viviani (University Ulm, cooperation partner), Julia Stingl (RWTH Aachen, cooperation partner)

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.

Reference:
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

Drug induced skin toxicity

Catharina Scholl, Michael Steffens (all BfArM), Sarah Bliersbach (University Hospital Bonn), Julia Stingl (RWTH Aachen, cooperation partner)

Background:
Adverse drug reactions (ADRs) are a major problem in drug therapy. In many cases ADRs occure as drug induced skin reactions. Most of these skin reactions are mild, but in rare cases they can be servere and even life-threatening. The immune system is a major player in the development of drug induced skin reactions, but many factors, which influence the development and severity of these reactions are still not elucidated. In two research projects we try to identify patient specific genetic and epigenetic characteristics associated with the occurance of a drug induced skin reaction.

Project 1: EGF-Receptor inhibiton:
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. 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.

Project 2: Pharmacogenetic and epigenetic profiles of drug-induced skin reactions:
In this project cases from patient suffering from a drug-induced skin reactions are collected and analyzed in cooperation with the Department of Dermatology and Allergy at University Medical Center Bonn. Upon the clinical diagnosis of an drug-induced skin reaction, clinical data concerning the medication of the patient is collected. Additionally, patients are ask to give skin biopsy samples from the affected skin areas. In this samples genetic and epigenetic profiles are analyzed and association with the development of drug-induced skin reactions are investigated. The overall aim of the project is to identify patient individual factors, which could be involved in the development of drug-induced skin reactions.

References:
1) Hichert V et al. (2017), Predictive blood plasma biomarkers for EGFR inhibitor-induced skin rash, Oncotarget, May 23;8(21):35193-35204
2) Steffens M et al (2016), Dosing to rash?-The role of erlotinib metabolic ratio from patient serum in the search of predictive biomarkers for EGFR inhibitor-mediated skin rash. Eur J Cancer., Mar; 55:131-9

Genetic bioinformatics in pharmacogenomics

Michael Steffens

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