While some patients experience adverse drug reactions (ADRs) when taking medicines, others do not, and in some cases, others do not receive therapeutic benefits from treatment regardless of dosage. One reason for this inter-individual variation in response is differences in genes that code for proteins important in drug response. This has given rise to the field of Pharmacogenomics (PGx), which seeks to identify biomarkers that predict drug response and apply them in the provision of PGx-guided precision medicine.
Following years of repeated Pharmacogenomics (PGx) research, which sought to identify biomarkers that predict drug response and apply them to the provision of PGx-guided precision medicine, Zimbabwean biochemist Professor Collen Masimirembwa (Prof ) seems to have cracked the code.
Our Editor, Michael Gwarisa (Q) publication caught up with Professor Masimirembwa to get an insight into this study and explore how such a discovery could be beneficial in and possibly help Africa find the right treatment regimens for its vast population.
Q: Could you give a brief background about yourself. Who is Professor Collen Masimiremwa?
Prof: My training is as a biochemist where I did my PhD in pharmacology at the university of Zimbabwe and went on to also do a PhD in Human genetics at the university at Karnaska university in Sweden thereafter, I went to the pharmaceutical industry for 10 years in Sweden and I had the ambition to set up a pharmaceutical institute in Africa that led me to establish the African Institute for Biomedical Science and Technology in 2002 and me moving back to Zimbabwe in 2008. So I’m currently the President and Chief Scientific Officer of the African Institute of Biomedical Science and Technology, and there I continue to do work in genomics and therapeutics. Recently this effort has been recognised by the Gates Foundation where I’ve been awarded the Calestous Juma Leadership in Science Fellowship, which really I’m using to build a research and development ecosystem on the African continent to promote more translational science where research translates to products and services. And that is also aligned with our national programme of education. And then secondly, I’m involved in expanding the use of genetic testing to inform drug therapy across the continent.
Q: Could you delve into your study where you tested the effectiveness of pharmacogenetic (PGx) testing in reducing incidences of adverse drug reactions (ADRs) and increasing treatment efficacy in African populations?
Prof: For many years, since 1993, I have been studying how genes that called for systems that govern how people respond to medicines vary between populations. So in 1996, I could see that a number of genetic variants which were found in African populations were not found in European populations and vice versa. So, this started to link up with an observation in the clinic that for some drugs, people respond differently depending on the individual as well as their ethnic group. And African people were responding differently compared to Europeans and a good example became the Efavirenz HIV drug, which was introduced around 1999. And in Europe, only a few people experienced serious neuropsychiatric side effects. But when it was introduced in Africa and Zimbabwe specifically, there was an outcry in the hospitals as many people suffered severe nightmares and suicidal tendencies and we wanted to understand what could be the reason for this.
Q: From your studies, what causes some patients to experience adverse drug reactions and others to not get any therapeutic benefit from medications?
Prof: So concerning this question, when a person takes a medicine intending to treat a particular disease, in the clinical trials we find what we think is the dose that will result in a concentration level of the drug in the body that will treat the patient. Now the drug does not stay in the body forever. There are systems in the liver that break down the compound. That is why you take the drug every day because the one you took yesterday will be out of the body. In the liver are enzymes or systems, biological systems that break down the Efavirenz into products that are removed in urine. So you have to take another tablet so that you keep the concentrations high. So a gene is a string of information that will read and produce a protein that does the work we are talking about. Now if that information about the Gen has a change in the chemical configuration, it will then produce a protein that does not function in a normal way.
And in the case of Efavirenz the HIV drug, the enzyme or the protein is called 2B6. The people carrying the genetic variation will produce less active enzyme. When they are given what is considered a standard dose that other people can handle, that person who is carrying a variant will not be able to remove the drug from the body. So each time another dose is given, it accumulates and it goes over the therapeutic level and goes into the toxic level. So the amount of the drug is too much in the body and when it is too much, it then goes and interferes with other systems and in this case for Efavirenz, it will go and affect systems that have to do with your neurological function. So you end up with all these nightmares and the depression and suicidal thinking and other people have actually killed themselves. And it can also go and affect the liver. So you end up with liver toxicity. So this is when we end up saying this dose is too much for this person because they are carrying a certain genetic variant which results in a system with reduced capacity.
We then call it a pharmaco gene, the gene that is influenced. Gene pharmaco refers to the drug Efavirenz . So we are saying Efavirenz levels in the body are determined by the function of an enzyme, which is coded for by a gene of two B6. So this is how we can explain what happens when you have overexposure to the drug in your body and then it causes undesirable adverse drug reactions.
Now, the opposite can happen when you have a genetic variant, let’s say for a drug called Tamoxifen. Now Tamoxifen is given to the patient not as a working compound. We call it a pro drug. It needs to be changed in the liver by another biological system to an active by-product. So it means if your liver is not able to change Tamoxifen to that active component, you will not get the benefits of Tamoxifen. So what we have noticed is that about 34% of people of African descent or African ancestry, carry a genetic variant in the system that is supposed to activate the Tamoxifen to the active by-product called Endoxifen. And we are showing that they will not be able to produce enough Endoxifen. So instead of getting treatment for their breast cancer, the breast cancer will just continue, or after a seizure, it will come back. So that is where the genetic variation is associated with poor treatment outcomes concerning efficacy. So this genetic variation can help the problem of increasing side effects for Efavirenz, it has the problem of under-treatment like in the case of Tamoxifen in breast cancer.
Q: Which African region has the highest burden of ADRs and non-responsiveness to medicines?
Prof: There’s a global organisation which collects reports of adverse drug reactions and it’s it is sponsored by the World Health Organisation (WHO), the programme is located in Upsala. It’s called the Fiji Bass. Now each country has a regulatory authority which looks at the safety of medicines and in those organisations they carry out a programme called pharmacovigilance, which means they ask doctors and or health practitioners to report and decide refers to any drug that is in use. Now, we have we realise that very few African countries submit their data. So we are now trying to do that in the current study we are doing to see whether there is a difference in the frequency and see a variety of side effects in different parts of Africa.
Q: Are there plans to roll out pharmacogenetic (PGx) testing across Africa and where is it being implemented at the moment?
Prof: This is important because we have seen that the genetic variance that predicted risk for adverse drug reactions, they are not uniform across Africa. In Ghana compared to Tanzania, compared to Zimbabwe, they can be different which we think should result in differences in prevalence and severe side effects. Over the past few years, we developed a genetic test that has a number of African-specific genetic variants. We call it Genopharm.
It is such that you can send me a sample or it can be blood or it can be a buckle swab. It comes to my lab, we extract DNA, process it and look for the genetic variance for more than 100 drugs which are on the market. We can get the data, we upload it to the cloud. You can then access it through some passwords we gave you. We can also send you a business card like a safety card, which can tell you which drugs the doctors should prescribe for you and which ones they should not. And the one they are prescribing for you, it will also tell you which dose we should be started at.
In my Calistas Juma Fellowship programme, I’m going to be doing this kind of service to on 6000 patients across African countries, South Africa, Zimbabwe, Kenya and Nigeria and we’re going to do 6000 patients. I have now started with the court in Nigeria where we are using this genetic to try to improve the treatment of sickle cell disease patients. But our tests, are going to help them to know which drug should I start my patient on and what dose I should start with. So far we have done 500 patients and we are aiming to do 1000.
And in Zimbabwe, we are doing different diseases. We are looking at gastrointestinal tumors, that is cancers of the oesophagus, cancers of the colon and stomach cancers. We are trying to see how that medicine that causes severe side effects can be dosed appropriately to reduce the toxicity of the cancer drug.
in Kenya, we are looking at transplant surgery because after you get a new kidney if you don’t have the right dose of drug, which is called an immunosuppressant, you can lose the organ. We want to optimise the drug concentration so that people retain their organs after the transplant. So this is the first multinational rollout effort on pharmacogenetics to see if it can improve treatment outcomes across the African continent.
Q: How equipped are our institutions of learning in Africa to advance research and innovation around precision medicine?
Prof: For a continent with 54 countries and more than 1.3 billion people, we are really under-equipped at every level. At the level of skilled manpower in the healthcare sector who understand and can implement this kind of intervention at an infrastructural level in terms of laboratories that can do the tests. That is why samples are being sent from Nigeria for testing here in Zimbabwe. Then we upload the results into the cloud.
Q: How can precision medicine bridge the gap and offer solutions to the growing burden of AMR and other emerging issues?
Prof: Well, they’re all related in a way and antimicrobial drug resistance and things like that. Of course, they are mainly driven by poor use of these antibiotics and people not completing their course.
But with respect to precision medicine, the way we are doing it is that if you look for HIV, for example, if people are experiencing side effects, they either stop being adherent to the treatment they will probably take. So in a way, in antimicrobial drug resistance, those are some of the ways precision medicine can be involved to say if you don’t give the person the best drug for safety, you might lose efficacy through drug resistance.
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