Going through the eye of a needle: Translating research findings into individualised patient treatment
Anyone attempting to assess the importance of pharmacogenetics for drug safety will inevitably end up considering the ambiguous responses of Radio Eriwan. It is true that genetic tests are theoretically able to predict whether an inactive enzyme affects the metabolism of a drug and whether it is necessary to apply a different drug dose. But how can this knowledge be applied in everyday clinical settings when patients with this inactive enzyme are taking three more drugs at the same time that are metabolised through the very same enzymatic pathway?
Julia Stingl from the Ulm-based Institute of Naturopathy and Clinical Pharmacology compares this clinical situation with a blocked sink: the drugs are no longer degraded properly, plasma levels rise and adverse reactions occur. "This is an interaction in which genetics plays a role, but cannot be used to explain everything." Individualised drug therapy is not just a case of directly applying pharmacogenetic findings, if possible, to clinical practice. If a particular patient suffers from liver and kidney insufficiency, the doctor needs to know if he or she is taking other drugs and if so, is he or she doing so at the correct time, in the correct form and the appropriate dose?
Julia Stingl is not saying that her own discipline, pharmacogenetics, does not have any practical, i.e., clinical importance. Stingl, who has treated and trained many patients, knows that a large of number of factors can affect drug safety. Let's take as an example a case that is hardly ever dealt with in clinical studies but is frequently experienced by patients: a patient who metabolises drugs slower than normal for genetic reasons, suffers from adverse drug reactions and decides to see an alternative practitioner because he or she is unsure whether traditional or alternative medical treatment is best. No practitioner in the medical field is able to predict how this twofold therapy will affect the disease in the long term. Demographic data such as the data which the Helmholtz Cohorts are currently collecting would be required in order to assess the effects of double treatment.
Eureka experience when working with the American FDA
During her two-month stay with the American FDA Julia Stingl was frequently confronted with this kind of translation problem. At the FDA, Julia Stingl worked with other experts to revise the “Guidance for pharmacogenetic data submission”. Stingl explains that the guideline was set up to help drug manufacturers include pharmacogenetic aspects in their trials. Julia Stingl also found during her stay in the USA that her “research, which seems somewhat detached, was actually applied”.
The FDA published two product labels, including one for warfarin, which is the most frequent blood thinner used in the USA and has a wide variability in patient response, including the possibility of increased risk of bleeding. The updated warfarin product label includes information in the precautions section that people with variations in two known genes may require a lower initial dose of the drug. As knowledge of a person’s genotype may help in warfarin dosing, people undergoing warfarin treatment in the USA need to undergo genetic testing for optimising dosages in order to minimise dangerous complications and improve the effectiveness and safety of treatment. Julia Stingl notes with satisfaction that one of her research priorities deals with translating pharmacogenetic findings into concrete dosage recommendations.
Adverse drug reactions can be predicted
Pharmacogenetics is set to contribute to a rational individualised drug therapy. Stingl believes that pharmacogenetics is suitable for predicting adverse drug reactions, which are often very clearly defined reactions caused by the drug administered. Some adverse reactions are specifically associated with a drug, said Stingl. "Pharmacogenetics enables us to link a drug effect to a genetic phenotype and hence also to the molecular factors that affect the effect and efficacy of a drug."
Julia Stingl has carried out two studies on the liver enzyme CYP2D6, both of which show the highly complex nature of her work and its usefulness for clinical applications. CYP2D6 acts on around 25% of all prescription drugs, including antidepressants, neuroleptics and betablockers. One of her latest projects dealt with the compound tamoxifen, an anti-oestrogen compound used after breast cancer surgery to prevent invasive cancer growth (metastasis).
A liver enzyme that is always good for surprises
The active compound is a so-called prodrug that is activated by the enzyme CYP2D6 and converted into the metabolite endoxifen, which depends on CYP2D6 activity. Patients with a lower CYP2D6 activity metabolise the drug much slower than normal and respond less to tamoxifen therapy, as too little effective metabolite is produced. It is known from the literature that more than 75% of Caucasians carrying the mutated gene are “poor metabolisers”. Stingl and her colleagues found that the substance was actually effective in patients with a CYP2D6*4 polymorphism who had undergone chemotherapy. These patients had previously been excluded from tamoxifen therapy because it was assumed that this substance did not have any effect.
In April 2010, the researchers from Ulm published another paper on the CYP2D6 enzyme. The results were surprising, not from the pharmacogenetic point of view, but because they showed that there are still many gaps in what is known about this relatively well investigated enzyme. The researchers discovered that CYP2D6 is the only liver enzyme that is also active in the brain, namely in the areas of the hippocampus, thalamus, hypothalamus and cortex. The researchers assume that the enzyme plays a role in brain metabolism and that drugs that exert their effect in the brain are actually also metabolised in the brain, and not only in the liver.
The researchers will now focus on this drug-relevant enzyme in the brain. They are seeking to find out why this enzyme is found in these brain areas and what function it has. Subsequently, they will look into the issue of what effects occur in the seven per cent of the human population who lack this enzyme.
Prospective and multimedication studies are lacking
Julia Stingl is very well aware that research alone is not sufficient to create evidence for clinicians and patients. A lot of explorative research that gives rise to associations is carried out, but Julia Stingl believes that even this is not enough to make predictive statements. She finds that there is a lack of prospective studies that look in greater detail into the results obtained in association studies and she also points out that knowledge about the long-term effect of drug therapies is somewhat incomplete. Stingl feels it is important to expand research to patients who are treated with several compounds concomitantly.
She is sure that this will give rise to important information, for example about statins. This drug class, which is used to treat high blood cholesterol levels, occasionally leads to damage in muscle cells, which in the worst case might lead to severe muscle weakness. It has been known for quite some time that drug transporters deliver the statins into the cells where they are metabolised. Genome-wide investigations of patients suffering from severe muscle weakness have shown that the “old” drug transporter that transported the compound from the liver was the cause of this damage.
Clinical pharmacogenetics on new paths?
Another issue related to the efficacy of drugs is also the lack of communication between treating doctors, clinicians and patients. Julia Stingl believes that too little information is given to patients and complex and complete databases are of no benefit to clinicians and patients.
Stingl has found that in Germany the traditional subject of clinical pharmacology is becoming less important. Her stay with the FDA has given her an insight into what the future of this subject could be, given that what was once the FDA’s Department of Clinical Pharmacology is now called “Office for Translational Science”.
If clinical pharmacogenetics is just a case of measuring drug blood concentrations, it is no longer as important as it once was. However, it is extremely important in terms of translating research results into clinical settings, dealing with individual patient cases and in particular with the effect medicinal therapies can have in different people.
Stingl, J.; Huber-Wechselberger, A. et al.: Impact of CYP2D6*4 genotype on progression free survival in tamoxifen breast cancer treatment, in: Current Medical Research & Opinion 2010, online: doi: 10.1185/03007995.2010.518304.
Kirchheiner, J.; Seeringer, A. et al.: CYP2D6 in the brain: genotype effects on resting perfusion, in: Molecular Psychiatry (2010), 1-9 (doi:10.1038/mp.2010.42.