One of the big challenges in drug development is our limited ability to identify potential adverse reactions associated with new therapeutics. Pharmacogenomics provides a great opportunity in understanding the mechanisms of action of drugs and predict not just their adverse reactions but also their efficacy. But as all opportunities it has some limitations too. In this review we will discuss the usage of pharmacogenetics in drug development and adverse reactions prediction.
But let’s start with what is adverse reaction and why it is important in drug development. Adverse drug reactions include a range of expected (and unexpected) toxicities to therapeutic failures and rare, severe reactions. Monitoring and preventing these reactions is top priority in drug development. How much we can predict the adverse reactions depends on various factors. In some cases where the nature of the studied drug is known there are some anticipated adverse reactions; similarly if the metabolic pathway of the drug is known there are some expected adverse reactions.
How could pharmacogenomics contribute in monitoring drug safety?
For example, codeine is activated to morphine by liver enzyme CYP2D6, however if the patient has multiple copies of active CYP2D6 gene they may be exposed to higher doses of morphine. If the enzyme is with low activities, on the other side, patients will have lower levels of active drug. This same enzyme is responsible for activating one of the cancer therapeutics – tamoxifen – and patients with low activity of the enzyme could be exposed to lower doses of tamoxifen. So why is this important? Patients with active CYP2D6 could be at risk of overdose when taking codeine; cancer patients who do not metabolise well tamoxifen will have lower doses of active drug and this could affect their treatment.
In some cases the consequences are quite drastic – for example, data from clinical trials with patients with metastatic colorectal cancer show that if the tumor cells active mutation in KRAS gene this leads to lack of effect of the anti-cancer drugs, cetuximab and panitumumab.
All these examples show the importance of genetic information when treating different medical conditions, which is why some clinical trials are collecting biogenetic markers for analysis.
What are the challenges in using pharmacogenetics information?
- There is still limited data regarding many drugs – sometimes this is result of patent protections, in other cases just lack of data or unknown drug action mechanism or metabolic pathway.
- In cases of very limited treatment options for the patients there is an ethical dilemma is patients have to be excluded from treatment because of unfavourable genetic profile.
- Genetic testing is expensive and adds cost to patients’ treatment.
- Collecting information after drug approval is out of drug developers’ control.
While there are challenges in using pharmacogenomics methods in identifying adverse reactions, it will have its place in the future of drug development.
Published on 1 May 2019
Author: Olga Peycheva, Director at Solutions OP Ltd. Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe