Pharmacovigilance and Pharmacogenetics: Considerations for the Present and the Future

Inter-individual variability in drug response is one of the most relevant issues for the proper management of patients in clinical practice. The team of health professionals is faced with possible unexpected variations in individual responses to medicinal products responsible for therapeutic failures and adverse reactions, many of which are clinically relevant. The observation that the same drug administered at the same dose may be effective in the majority of subjects treated, but poor effectiveness and/or inducing side effects, sometimes serious ones, in some patients is a problem that has always been detected but that today is amplified in virtue of the increased use of polytherapy.
Although once pharmacokinetic and pharmacodynamic variability was predominantly related to the influence of non-genetic factors (such as age, sex, nutritional status, renal and hepatic function, alcohol abuse, smoking, concomitant intake of other drugs and the presence of comorbidities), around the 1950s the scientific community saw a significant component of diversity in the individual response to drugs in hereditary factors, thus attributing to genes the ability to influence the variability of reaction to a given active ingredient, including the absence of a clinical response or the appearance of adverse drug reactions (ADRs). This has led over the years to the development of studies on the pharmacogenetic aspects understood as allelic variations in genes correlated with absorption, distribution, metabolism, excretion and biological action of the drug that can influence its action.

The fourth cause of death

ADRs are the fourth leading cause of death in the United States, a figure that persists year after year despite the increasing attention the issue receives. The significant clinical impact of ADRs requires targeted strategies aimed at minimising the risk of the onset of a drug-induced adverse event which, in addition to significantly undermining the patient’s health, contributes to considerable increases in healthcare costs. An approach to ADR that also includes a pharmacogenetic analysis can provide valuable information by allowing the prevention or minimisation of the damage associated with the adverse effects related to the administration of a specific drug.

The effects of genetics

From the pharmacogenetic point of view we can consider two types of effects of the genetic component on the drugs responsible for an ADR, including the lack of efficacy in the definition of ADR. A first effect is hypersensitivity reactions essentially linked to polymorphic variants of the major histocompatibility complex; a second is the positive or negative modulations of the response to a drug due to allelic variants in the genes responsible for the absorption, distribution, metabolism and excretion of the drug or in the primary therapeutic target of the drug such as receptors and enzymes. In the field of oncology, the situation is further complicated by the fact that even somatic variants, typical of tumours, can contribute to influence the response to therapy.
Modern molecular biology techniques make it easy to identify these polymorphisms, often at lower costs than common diagnostic tests. The identification of a particular polymorphism, associated with adverse reactions, before the administration of a drug, would allow the choice of alternative therapeutic strategies that could include:

1. the use of a drug of the same class whose action is not influenced by polymorphism
2. adjustment of the dose of the initially selected drug
3. a more in-depth and prolonged monitoring of the drug and the patient
4. the use of an alternative drug.

Studies on inter-individual variations

Studies from pharmacogenetic research on inter-individual variations in the DNA sequence make it possible to predict a patient’s response to a medicine based on a pharmacogenetic test, thus avoiding incurring serious ADRs and contributing significantly to optimising the patient’s pharmacological management. Several studies have shown that the correct use of pharmacogenetics is useful for the Italian Health Service (it improves the prescriptive approach and increases treatment compliance). To date, many tests have entered daily clinical practice in several countries because they are supported by a solid and consistent scientific literature (including HLA-B * 5701 for abacavir, HLA-B *1502 and HLA-A*3101 for carbamazepine, CYP2C9 and VKORC1 for warfarin, TPMT for thiopurines, UGT1A1*28 for irinotecan, DPYD for fluoropyrimidines, CYP2D6 and CYP2C19 for tricyclic antidepressants and SSRIs, CYP2D6 for tamoxifen and codeine, CYP3A5 for tacrolimus, CYP2C19 for voriconazole, CYP2B6 for efavirenz). To cite the example of the United States, where the FDA has added pharmacogenomics information in the clinical fact sheet of over 150 drugs, mandatory pharmacogenetic tests required are 56. In Italy the only mandatory test, if we exclude the field of the analysis of somatic variations on the tumour tissue, involves the search for the allelic variant HLA-B * 5701 before starting treatment with the antiretroviral drug abacavir. The hypersensitivity reaction to abacavir typically manifests with erythematous, confluent macopapular rash with possible involvement of one or more internal organs. It is certainly a serious reaction that justifies the pharmacogenetic test. However, there are other situations of similar danger with other drugs for which the pharmacogenetic test should be introduced.
Among the drugs involved in the onset of serious genetically determined undesirable effects, allopurinol is an exemplary case of what has been said in light of the fact that its wide use in clinical practice is one of the most frequent causes of ADRs: the anti-gout agent is responsible for 5% of all cases of drug hypersensitivity syndrome. The presence of the HLA-B*5801 allele (in 1-6% of the Caucasian population) gives an increased risk of severe allopurinol-induced skin reactions (SCARs), including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).
Another example of the possible interrelations between pharmacogenetics and pharmacodynamics with important clinical repercussions involves warfarin therapy. The considerable variability in the response to this drug in some subjects leads to haemorrhagic complications. These complications are related to the presence of polymorphisms in the VKORC1 gene, which results in a lower clotting capability of VKORC1, the drug’s target enzyme, and consequent greater sensitivity to the inhibitory action of warfarin (and coumarin drugs in general) with increased bleeding risk. Although it is true that the current monitoring through the measurement of the INR (International Normalized Ratio) is to be considered sufficient, several studies have shown that if it is accompanied by the pharmacogenetic test there is a further reduction of ADRs leading to hospitalisation, because a better defining of the optimal dosage is obtained.

A long way to go

These observations are emblematic of the long road that the implementation of pharmacogenetics in our country still has to take. The problems are both structural and cultural. US healthcare sees a strong presence of insurance with a strong focus on cost-benefit ratio. While taking on care of an ADR costs on average between three thousand and five thousand euros depending on the severity, a pharmacogenetic test costs around € 100 per candidate gene.
There is also a cultural problem that is indirectly linked to the history of health in Italy, which has not seen an adequate development of capillary structures of clinical pharmacology: it is rare to find continuing education programmes in medicine in the field of pharmacogenetics directed to health personnel. It is undoubtedly desirable to increase the professional education pathways available to clinicians, in order to increase their awareness and sensitivity in this area, and consequently favour a more vigilant clinical monitoring of patients.
The problem is not only an Italian one, however, pharmacogenetics has entered clinical practice almost twenty years ago, but the tests considered relevant are relatively few even in countries where this discipline is developed. In other words, pharmacogenetics has had a lesser development than initially anticipated. What could be the reasons?
A first problem lies in pharmacogenetics itself; while it is relatively easy to obtain information on yes/no responses, such as those deriving from the association between hypersensitivity and allelic variants of HLA complexes, it is much more difficult to obtain reliable information on polymorphisms that only modulate the response. Out of 18,000 works in the literature on the aspects of modulation of the response, only 10% can suggest a possible causal association between response and polymorphisms and very few associations support the clinical validation. This is not surprising and various factors may have variously contributed to this still limited validity. Methods of analysis in the pre-genome-wide era did not allow an easy analysis of minority variants. Today, genome-wide approaches that make it possible to identify non-hypothetical associations with a pharmacological or enzyme metaboliser target criterion have become possible. Therefore, the combined role of multiple genes responsible for the efficacy or toxicity of one or more drugs can be studied for multi-factorial pharmacological effects.
This will most likely be made possible thanks to the development of international networks that have been established in recent years, for example the Clinical Pharmacogenetics Implementation Consortium (CPIC), a joint consortium of the Pharmacogenomics Research Network of the National Institutes of Health and the Pharmacogenetics Knowledge Base, which has already drawn up guidelines on drug-gene pairs with evidence from randomised trials sufficient to influence prescription; with a caveat: having large databases is important but we must also develop the correct questions when consulting them. This is perhaps the most important challenge for clinical pharmacologists.
A second important step forward has recently been made thanks to the introduction of pharmacogenetics in the drug authorisation process, in accordance with the guidelines issued by the EMA in 2014. In essence, the EMA requires a pharmacogenetic evaluation starting from phase I if there are significant discrepancies in the pharmacokinetics in a defined group of subjects and from phase II in case of adverse reactions for which a pharmacogenetic basis is reasonable. This will allow the introduction of pharmacogenetic tests simultaneously with the marketing of the drug when they are relevant. A third step forward that can be used for research in pharmacogenetics is purely Italian. The recent change in legislation on clinical trials will allow the development of observational studies in which, unlike today, pharmacogenetics will be included. This will allow, if clinical pharmacologists and medical specialists are able to coordinate well, the acquisition of information in real-life conditions, to date not obtainable on the possible association between clinical phenotype and pharmacogenetic variants.
The status of clinical development of pharmacogenetics is therefore still, paradoxically, undergoing expansion. From the new methodologies and strategies mentioned above, a further development is expected; Italy can, thanks to some of its peculiarities, still play a primary role, even if today we are still behind compared to many countries. It would be very important in this regard that the Ministry of Health constituted a round table for discussion between the various protagonists, in order to finalise an ambitious, shared but also sustainable development strategy.

Definitions
Pharmacogenetics - Pharmacogenetics is a branch of pharmacology that studies interindividual variations in the DNA sequence in relation to the response to drugs, both in terms of efficacy and toxicity. These variations may be present in genes that code for proteins involved in the absorption, distribution, metabolism and excretion of the drug (pharmacokinetics) and in those coding for the primary therapeutic target, such as receptors, ion channels, enzymes, etc. (pharmacodynamics). Polymorphisms of genes belonging to these two classes can determine changes in the action of a drug causing the absence of a clinical response to a given treatment or the appearance of adverse reactions.
Pharmacogenomics - The term pharmacogenomics means the set of approaches that, using the information acquired on the genome and its products, aim to identify new therapeutic targets: discover and implement drugs (rational pharmacology) and study the response they produce as a function of the genetic variability of individuals. The term pharmacogenomics does not therefore describe a consolidated scientific discipline, but rather presupposes the well-founded hope that the knowledge gained from completing the characterisation of the human genome and the genome of an increasing number of pathogenic organisms may lead to a new pharmacological science. This should allow to develop targeted drugs and to design rationally personalised and safer therapeutic strategies.