Pharmacogenetics

What is a drug

A drug is any active physicochemical substance that interacts with and modifies the body to cure, prevent or diagnose a disease. Drugs regulate pre-existing functions but are not capable of creating new ones [1].

 

Drug action

Generally, a drug is introduced (administered) into the body at a location away from the intended site of effect. After absorption into the circulatory system, various organs and tissues transport and absorb the drug throughout the body, including its target sites (distribution). Some medicines must be metabolized by the body before they can carry out their activities; others are metabolized after their action at the indicated site, and others are not metabolized. Finally, the drug is eliminated from the body (excretion) [2]. Knowing the metabolic pathways that process each drug and determining which ones are critical before launching it on the market helps reduce the variability of drug response in the population and the risk of adverse side effects. [3].

General factors in determining drug treatment 

The main factors when studying a drug and defining its use are given by the determined relationship between the amount of a medication administered (dose), the resulting concentrations of the drug in the body (exposure), and the intensity of the pharmacological effects caused by these concentrations, beneficial and/or toxic (response) [4].

 

Changes in effect between individuals 

There is a significant difference between people in terms of their response to drugs, both in effectiveness and toxicity. Thus, different patients respond dissimilarly to the same medication [5]. This difference lies in genetic and non-genetic factors. The latter are very varied and can change throughout a person’s life, such as the influence of sex, age, diet, type of disease or drug interaction. Genetic factors are more conditioning, as they tend to remain constant and related to the variability between individuals in the expression of the genes responsible for processing the drug, given by different genotypes [6], [7]. A genotype is an inherited genetic information stored in our DNA that is located in the genes and determines the specific characteristics that define a person’s traits, in this case, susceptibility to a drug. These genotypes show variations, which basis is the so-called single nucleotide polymorphisms (SNP: single nucleotide polymorphism), which information is identified by two letters (nucleotide bases) that we carry along with the DNA. SNPs occurring in genes can influence the functioning of proteins responsible for drug processing [8]. These SNPs are primarily responsible for differences in drug response between individuals. In a broader sense, some genetic variations occur more frequently in some ethnic groups, making them more or less likely to have a better overall response to a drug [8].

 

What it takes

The difference between one person and another in response to the same drug leads to prescribing drugs without really knowing their effects in a particular patient, which results in “trial and error” by the healthcare professional, trying different medicines and doses until the proper treatment is found. This carries a high risk of possible adverse reactions and high toxicity levels in the patient, not to mention the inefficiency caused by the time and budget invested by the health service [9].

 

What is pharmacogenetics?

Pharmacogenetics is the study of the role of individual genetic variations on the pharmacological response of the individual, both in terms of treatment efficacy and adverse effects, thus preventing toxicity and therapeutic failure [5], [6].

 

Objectives of pharmacogenetics

Pharmacogenetics aims to optimize pharmacological treatment, knowing a priori the efficacy, tolerance and effects of drugs in each patient [6]. In other words, to achieve a much safer and more efficient personalized therapy that allows the healthcare professional to choose the right drug, with the correct dose and with the lowest risk of adverse effects possible for a given patient [6], [7], [9].

It is worth mentioning that, in 2018, retail pharmaceuticals (excluding those used during inpatient treatment) accounted for about one-sixth of all healthcare spending and were the third-largest spending component in EU countries, after inpatient and outpatient care.

 

Advantages

Pharmacogenetics makes it possible to avoid delays in the administration of effective therapy, unnecessary risks of adverse reactions and large expenditures on ineffective treatments, which can lead to an overall reduction in the cost of health care by reducing:

  • the number of adverse drug reactions
  • the number of failed drug trials
  • the time it takes for a drug to be approved
  • the length of time patients are on medication
  • the number of drugs patients have to take to find an effective therapy
  • the effects of a disease on the body through early cure. [9]

 

Example: Mercaptopurine and the NUDT15 gen 

Mercaptopurine is the mainstay of curative treatment of multiple cancers, primarily acute lymphoblastic leukemia. Prolonged daily exposure to mercaptopurine during maintenance therapy is the mainstay of most current treatment regimens for acute lymphoblastic leukemia and is indisputable for curing this disease. In addition, it is also used for the treatment of other diseases such as ulcerative colitis and Crohn’s disease. A comprehensive genetic study conducted in 2015 on 1028 patients with this disease, subjected to mercaptopurine treatment regimens, identified variants associated with a predisposition to present toxicity to this drug in the NUDT15 gene [12], recognized to be involved in the control mechanisms for the correct functioning of DNA [13]. Among the results reported, the patients who responded worse to treatment because they were susceptible to the drug and, consequently, had a higher risk of toxicity and adverse effects to the medication, were those who carried a specific genotype (CT, and especially TT). In comparison, those with CC genotype had a lower risk. Therefore, mercaptopurine doses have to be adjusted according to toxicities during treatment. Thus, as in Figure 1, the appropriate regulated dose amount was determined for each patient with a specific genotype, reducing dose intensity in those patients with CT and TT genotypes. Thus, taking into account the genotype and its susceptibility to produce adverse effects, it can be considered a priori whether the drug is the most suitable for treatment and what should be the convenient dose to carry it out [12].

Figure 1. Mercaptopurine dose intensity modulated from genotypes in the NUDT15 gene.

Source: Yang et al. (2015)

                                  

Next steps

Thanks to the significant advances in the sector during the last decades, its high efficiency and cost-effectiveness, projects for the application of pharmacogenetics in the healthcare system have started to be developed [10], [11], [14]. Of course, the process is slow, and there is still a long way to go, but some countries have already made great strides. This is the case of the great development in the Dutch Health System, where thanks to projects such as the Dutch Pharmacogenetics Working Group (DPWG) [15], health care personnel and pharmacists can, during the prescription and sale of medicines, request available pharmacogenetic data from patients who have given their consent, intending to optimize treatment and care services, providing much more accurate, detailed and efficient care [16]-[17].

Although the routine implementation of pharmacogenetics in healthcare still needs a lot of work to become a reality in most countries, at 24Genetics, we offer you a specialized test, from which you can check your genetic predisposition to dozens of drugs, considering their toxicity in your body, their effectiveness or the necessary dosage level. 24genetics.com/pharma-dna-analysis

 
Bibliography

[1]      World Health Organization, “WHO Expert Committee on Drug Dependence,” in World Health Organization – Technical Report Series, vol. 407, Geneva, 1969.

[2]      N. Mehrotra, M. Gupta, A. Kovar, and B. Meibohm, “The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy,” International Journal of Impotence Research 2007 19:3, vol. 19, no. 3, pp. 253–264, Sep. 2006, doi: 10.1038/sj.ijir.3901522.

[3]      D. M. Grant, “Pharmacogenetics,” Fetal and Neonatal Physiology, pp. 222–229, Jan. 2017, doi: 10.1016/B978-0-323-35214-7.00021-4.

[4]      B. Meibohm and H. Derendorf, “Basic concepts of pharmacokinetic/pharmacodynamic (PK/PD) modelling,” Int J Clin Pharmacol Ther, vol. 35, pp. 401–413, 1997.

[5]      O. Arturo Prior-González, E. Garza-González, H. A. Fuentesde la Fuente, C. Rodríguez-Leal, H. J. Maldonado-Garza, and F. J. Bosques-Padilla, “Farmacogenética y su importancia clínica: hacia una terapia personalizada segura y eficiente,” Medicina Universitaria, vol. 13, no. 50, pp. 41–49, Jan. 2011, Accessed: Nov. 27, 2021. [Online]. Available: https://www.elsevier.es/en-revista-medicina-universitaria-304-articulo-farmacogenetica-su-importancia-clinica-hacia-X1665579611026775

[6]      E. Daudén Tello, “Farmacogenética I. Concepto, historia, objetivos y áreas de estudio,” Actas Dermo-Sifiliograficas, vol. 97, no. 10. Ediciones Doyma, S.L., pp. 623–629, 2006. doi: 10.1016/S0001-7310(06)73482-2.

[7]      A. E. Guttmacher, F. S. Collins, and R. Weinshilboum, “Inheritance and Drug Response,” http://dx.doi.org/10.1056/NEJMra020021, vol. 348, no. 6, pp. 529–537, Oct. 2009, doi: 10.1056/NEJMRA020021.

[8]      S. K. Bardal, J. E. Waechter, and D. S. Martin, “Pharmacogenetics,” Applied Pharmacology, pp. 53–58, Jan. 2011, doi: 10.1016/B978-1-4377-0310-8.00006-3.

[9]      A. T. P, S. S. M, A. Jose, L. Chandran, and S. M. Zachariah, “Pharmacogenomics: The Right Drug to the Right Person,” Journal of Clinical Medicine Research, vol. 1, no. 4, p. 191, 2009, doi: 10.4021/JOCMR2009.08.1255.

[10]    R. Overkleeft et al., “Using personal genomic data within primary care: A bioinformatics approach to pharmacogenomics,” Genes, vol. 11, no. 12, pp. 1–11, Dec. 2020, doi: 10.3390/genes11121443.

[11]    J. Hayward, J. McDermott, N. Qureshi, and W. Newman, “Pharmacogenomic testing to support prescribing in primary care: A structured review of implementation models,” Pharmacogenomics, vol. 22, no. 12. Future Medicine Ltd., pp. 761–777, Aug. 01, 2021. doi: 10.2217/pgs-2021-0032.

[12]    J. J. Yang et al., “Inherited NUDT15 Variant Is a Genetic Determinant of Mercaptopurine Intolerance in Children With Acute Lymphoblastic Leukemia,” Journal of Clinical Oncology, vol. 33, no. 11, p. 1235, Apr. 2015, doi: 10.1200/JCO.2014.59.4671.

[13]    GeneCards – The Human Gene Database, “NUDT15 Gene – Nudix Hydrolase 15,” https://www.genecards.org/cgi-bin/carddisp.pl?gene=NUDT15.

[14]    P. C. D. Bank et al., “Comparison of the Guidelines of the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group,” Clinical Pharmacology and Therapeutics, vol. 103, no. 4. Nature Publishing Group, pp. 599–618, Apr. 01, 2018. doi: 10.1002/cpt.762.

[15]    DPWG, “DPWG: Dutch Pharmacogenetics Working Group,” https://www.pharmgkb.org/page/dpwg.

[16]    P. C. D. Bank, J. J. Swen, R. D. Schaap, D. B. Klootwijk, R. Baak–Pablo, and H. J. Guchelaar, “A pilot study of the implementation of pharmacogenomic pharmacist initiated pre-emptive testing in primary care,” European Journal of Human Genetics 2019 27:10, vol. 27, no. 10, pp. 1532–1541, Jun. 2019, doi: 10.1038/s41431-019-0454-x.

[17]    “Pharmacogenetics – Koninklijke Nederlandse Maatschappij.” https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica/pharmacogenetics-1/pharmacogenetics (accessed Nov. 27, 2021).

 

Written by Dr. André Flores Bello

Geneticist

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