Interview

‘Cost should not affect personalised medicine’

The future of pharmaceutical research is looking at therapies which will be tailor-made to individuals. Harish Padh talks to Katya Naidu about the benefits of pharmacogenomics.

How does the genetic makeup of a person effect the efficacy of a drug?

We have known for ages that drugs are not equally effective in individuals. It was even known that it should have genetic bases for such variability. Genomics in the last decade gave us valuable tools to decipher the individual variations in gene-enzyme make-up of an individual. This combination has resulted in the concept of pharmacogenomics which is an extension of the concept of pharmacogenetics but at larger genomics scale.

It also provided us better understanding of disease processes and drug disposition. Today concepts like genes and genomics are gaining popularity and their conceptual understanding is allowing us to have in-depth knowledge of the cause of disease and drug disposition. Genomics involves the systematic identification of all human genes and gene products, the study of human genetic variations, combined with changes in gene and protein expression over time. Genomics is revolutionising the study of disease processes along with the development and rational use of the drugs. In recently evolved field of pharmacogenomics, attempts are made to determine and quantitate these genetic variations and use them in predicting drug disposition by an individual. Using genotyping, it is possible to consider the consequences of inter-individual variation in given gene encoding drug targets, as well as drug metabolising enzymes and this information can be used both to design new drugs and to individualise drug therapy with existing drugs. Moreover it would help in determining the choice of drug, its dosage and even its delivery mode.

How do genetic differences affect the metabolism of a drug?

Genetic differences which determine the disposition of a given drug in an individual, give differences in drug response. Genetics decide the rate or extent of drug absorption, distribution, metabolism and excretion, in other words how much of a drug is available to an individual and for how long. There are about 20-30 genes (and therefore loci for genotypes) responsible for drug disposition. These genes or loci determine how we respond to most of the therapeutic agents. Variations at these genetic loci determine whether one benefits from given therapy or one is likely to get adverse drug reaction/toxicity. Therefore, understanding alleles at these loci can help us decide the right type of drug and the right dose for the individual.

Genotyping will depend upon the polymorphism of the gene. It will not be same for all the diseases. It will not be same for all the drugs. However, it will be same for a number of drugs metabolised by the same enzyme.

How can genotypes be classified?

Genotyping techniques can be used to predict one's disposition to a given class of drug without doing any phenotypic evaluation, which can subsequently be used for deciding the choice of a drug and its dose. By the use of genotyping methods, an individual can be classified as poor metaboliser (PMs), intermediate metaboliser (IMs), extensive metaboliser (EMs) and ultra rapid metabolizer (UMs) for a given group of drugs. The PM subjects will develop higher serum drug concentrations in comparison with EMs, resulting in increased risk of suffering from concentration dependent side effects when subjected to standard recommended doses. UM subjects, on the other hand, will not reach therapeutic serum concentration upon treatment with standard doses. They may fail to respond to treatment, leading to false accusations of non-compliance. Moreover when the parent compound is a pro-drug, which requires bio-activation by the enzyme to the active drug, the effects of polymorphism can be quite complex in PMs and UMs. Thus, identification of PM and UM subjects can be useful in drug selection and dosage could be tailored to the individual patient from the beginning, which can help avoid adverse reaction or therapeutic failure.

What are the major projects of targeted therapy that are underway at PERD centre and on which diseases?

At PERD we are in the process of genotyping individuals for various cytochromes responsible for metabolism of commonly used drugs such as anti-depressants, neuroleptics, HMG CoA reductase inhibitors, proton pump inhibitors and anti-epileptics. This will help in individualising the therapy.

What are the roadblocks that are underway which will affect the personalised medicine?

Establishing a strong relation between genotype-phenotype along with the technology of mass genotyping are the two roadblocks. Geno-phenotype correlation is well established for many drugs and enzymes with excellent predictive value. However, in other cases both science and technology have to improve to make them globally applicable. There are few issues such as sensitivity and specificity of genotyping method, ethical, legal and behavioural aspects regarding the genotyping.

How will costs affect the operation of personalised medicine?

Costs of wrong therapy is rarely calculated in terms of time, money and missed opportunity. Once we do this analysis scale of technology will bring down the cost to insignificant level. Technology improvement like large scale reliable DNA microarray will help the process. Moreover, it is once in life time testing, so cost should not affect the operation of personalised medicines.

How will pharmacogenomics affect vaccines?

Since vaccines work at immunity level, they should not be affected in the way drugs are through pharmacogenetics. If we find variability in genes involved in immunity, it may be possible to decipher this effect on the efficacy of vaccines. Enzymes involved in drug metabolism are not likely to influence immunity.

Do we need targeted therapy for all the diseases or just for serious and expensive cures like oncology?

Targeted therapy will definitely be useful in situations where there are chances of serious side effects, higher cost of treatment or where there is no time to be wasted like cancer. It will be worth knowing which therapy is likely to work in an individual in a trivial situation as well. It is always desirable if rational approach can replace empirical trial and error therapy.

Personalised medicine will alter the present system of medicine and affect many pharma companies as there will be no blockbuster drug herewith. Do you agree and why?

I agree partially as this will be true in the cases where the drug is not effective because of some particular type of genotype and other drug(s) has(have) to be given for the treatment. However, if only dose adjustment is required because of genotype, it should not be the case. Segmented patient population will not be liked by pharma companies. However, there will be many factors because of which companies will save cost of drug development. For example, fewer patients of right genotype in drug clinical trials.