Drugs for individuals rather than diseases - that’s what Julia Kirchheiner from the University of Ulm is striving for. The 37-year-old is one of only a few German experts working in pharmacogenetics research, a field of research that investigates the genetic causes of individual differences in people’s response to drugs. Kirchheiner’s objective is to find ways to make it possible to treat individual patients with the drug and dose that suits them best.
Lofty goals? Absolutely not, said the pharmacologist, referring to figures obtained in an international survey carried out by American and European institutes, according to which the side effects of drugs are the fifth most frequent cause of death in the USA. Another survey puts side effects of drugs as the seventh most frequent cause of death. The American regulatory authority for the approval of new drugs (FDA) has set up a work group, of which Kirchheiner is part, to finalise the guidelines for the carrying out of pharmacogenetic tests in the drug discovery process. “These guidelines will also have a huge impact on our work,” said the pharmacologist.
According to Kirchheiner, it has been known for more than 30 years that individual patients respond differently to the same drug in the way they absorb, process and eliminate (metabolise) the drug. About 20 years ago, researchers discovered that certain gene variants are the cause of these differences.
"Much is known about the genetic mechanisms of drug effects, but nobody puts this knowledge into practice," said Kirchheiner, who is determined to change all this by providing the necessary information to patients and doctors.
Kirchheiner became interested in pharmacogenetics very early on; her doctoral thesis dealt with the genetic mechanisms of cancer development. She did her practical medical training in the Department of Psychiatrics at the Free University of Berlin, and was also part of a large pharmacogenetic trial in which she investigated the effects and side effects of drugs for the treatment of schizophrenia. From 1999 to 2003, she worked at the Institute of Clinical Pharmacology at the Charité in Berlin (Prof. Ivar Roots).
At the Charité, Kirchheiner carried out a systematic meta-analysis of studies on antidepressants and came up with suggestions on the drug doses required. She found that numerous drugs caused up to twenty-fold differences in the concentration of drugs in the blood of ultra rapid and ultra slow “drug metabolisers”. Kirchheiner explained that it takes a very long time before patients suffering from depression respond to the psychopharmaceutical drugs given to treat the disorder and she hopes that pharmacogenetics will help in this area: “Doctors would very much like to know whether they have prescribed the right dose and even more so whether the prescribed drug is the best for a particular patient, or whether a different one should have been chosen.”
Pharmacogenetic knowledge is useful for long-term therapies whose effect is difficult to measure, or can only be measured at a very late stage. These therapies include secondary preventive therapies for patients suffering from cardiovascular diseases (e.g., beta blockers, blood fat reducers), long-term drug therapies of mental diseases and cancer.
Kirchheiner uses cancer therapy to illustrate the importance of customising the treatment to the individual requirements of patients or their tumours. Kirchheiner also wants the therapy of tumours to take into account the individual drug tolerability of patients and the properties of tumour cells. German foundations (e.g., Carreras, Sander) are attaching increasing importance to such approaches and hence to pharmacogenetics. (Link to Sander Foundation: "Does the genotype have an effect on EGF-R inhibitors?" https://www.gesundheitsindustrie-bw.dewww.bio-pro.de/en/region/ulm/magazin/05223/index.html)
Individualised drug therapy plays a far greater role in the USA than in Germany. In the USA, the FDA has already changed the product information of some drugs, it also recommends pharmacogenetic tests and encourages drug producers to offer such tests. The Ulm scientist is pleased that the regulatory authorities now promote personalised medical treatments.
Tamoxifen, approved by the FDA for the preventive treatment of breast cancer, is ineffective in seven per cent of patients who use the drug due to a gene variant. According to Kirchheiner, this is an excellent example of the benefit of using pharmacogenetic tests with well established methods and that are reimbursed by the health insurance companies. But what does a genotype tell the doctor, what needs to be tested, is the gene variant also of relevance for additional drugs whose effects have not been specifically tested? Answers to these questions are found on a case-by-case discussion basis only. This, according to Kirchheiner, is the greatest bottleneck in the process of transferring research findings to bedside application.
This is why Kirchheiner attaches great importance to informing general practitioners, hospital doctors and patients about the benefits of pharmacogenetic testing. Nowadays, medical students and young doctors are also given better insights into the subject. Kirchheiner is personally aware of this improved dissemination of knowledge as she has contributed to a new pharmacology textbook (USA) that devotes a whole chapter to the subject of pharmacogenetics. Kirchheiner aims her own research more closely at the patient. She has conducted numerous studies to test the effect of antidepressants or antidiabetic drugs on different patient genotypes. Driven by the conviction that these findings must enter clinical application, Kirchheiner has prepared systematic studies on pharmacogenetics-based dose recommendations for psychopharmaceuticals, anti-cancer and other drugs. She will put her expertise to good use at the institute of the American FDA where she has been invited to spend a six-week sabbatical starting in spring 2009.
Julia Kirchheiner knows that individualised patient therapy is far more than just molecular tests. In cooperation with the Department of Paediatrics and Adolescent Psychiatry at the University Hospital of Ulm she has just commenced a study on patients’ medical beliefs. The researchers are investigating people’s beliefs in the healing power of plant drugs compared to chemical drugs. Working with Thomas Seufferlein, gastroenterologist from Halle and former colleague at Ulm University, Kirchheiner hopes to receive funds to be able to carry out a study to assess whether green tea or green tea extracts are suitable for the prevention of colon cancer. Many public funding institutions still have reservations about Kirchheiner’s approach. Therefore, the bulk of her financial support comes from the EU and private foundations. In the meantime she is gathering together further information aimed at the improvement of personalised patient therapy.
Kirchheiner’s team has just commenced studies on the improved prediction of the individual effect of antidepressants which are known to be ineffective in one third of patients. If it were possible in future to modify the use of antidepressants to individual patient requirements, this would considerably decrease the time before a palpable effect could be seen, explained Kirchheiner.In the case of cancer, Kirchheiner is investigating pharmacogenetic mechanisms that might be the cause of the severe side effects some of these strong drugs have on some patients. Some patients experience a strong reduction in normal blood cells, which results in a high risk of contracting infections such as pneumonia. The time required by the normal blood cells to recover from the therapy varies from patient to patient. Currently, no biomarkers are known that would help predict the duration of the changes of the blood picture.
Kirchheiner supports the broader use of the term pharmacogenetics, which not only takes into account the metabolism and the transport of drugs, but also deals with far more complex drug action structures. Kirchheiner is investigating genetic mechanisms that affect the side effects of growth factor receptor inhibitors (EGF-R) used to treat tumours and she is achieving important insights from finding out whether patients develop a skin rash or not in reaction to the drugs.