WO2021124143A1

WO2021124143A1 - System for evaluating a parameter related to the adequacy of a drug depending on genetic factors

Info

Publication number: WO2021124143A1
Application number: PCT/IB2020/062020
Authority: WO
Inventors: Fabio Sallustio; Giuseppe Castellano; Gesualdo LORETO; Giuseppe DALFINO; Angela PICERNO
Original assignee: Persongene Srl
Priority date: 2019-12-16
Filing date: 2020-12-16
Publication date: 2021-06-24
Also published as: IT201900024150A1

Abstract

System (100) for evaluating a parameter related to the adequacy of a drug depending on genetic factors comprising: - a block (101) for storing parameters chosen between: markers chosen for each drug SNP; number of published studies Ns; Impact Factor IF; value of statistical significance P; ethnicity of studied population E; - a block (102) for analyzing a weight of each parameters; - a block (106) for combining an index related to effectiveness, an index related to toxicity or an index related to dosage, based on the genetic outcome of each SNP; - a block (107) for generating a parameter of adequacy based on the outcome of the combination performed by block (106); and - a block (108) for classifying the drugs according to the parameter of adequacy.

Description

System for evaluating a parameter related to the adequacy of a drug depending on genetic factors The present invention relates to a system for determining an adequacy parameter of a drug as a function of genetic factors. The present invention also relates to a method for determining an adequacy parameter of a drug as a function of genetic factors. In particular, the present invention relates to a system and a method for determining an adequacy parameter of a drug as a function of genetic factors, of the type usable for drug dosage based on genetic tests and on studies of the variability response to drugs in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and / or mechanisms of action of a drug in the body. An important field of application is, for example, that of solid organ transplantation, since the success of the procedure depends on a delicate balance in immunosuppressive treatment, which includes the administration of appropriate doses of immunosuppressive drugs, especially in the early post-transplant period. It is known that genomic science, and in particular the wide characterization of individual DNA, can respond to the need to transform pharmacological treatment to make it more effective and economical, significantly reducing risks and costs, but above all allowing to choose an optimal treatment on the basis of individual genetic characteristics that modulate the ability to interfere with drug action, patient metabolism and drug transport. For example, individuals with a particular genetic variant may not be able to metabolize certain drugs and therefore may have a higher risk of adverse reactions or harmful drug interactions. In other cases, some gene variants can cause some drugs to be metabolized too rapidly, resulting in partial ineffectiveness of the current treatment. Both the lack of therapeutic response and adverse drug reactions are a major problem. In fact, the costs of non-efficacy and toxicity of the treatments are very high, both in clinical and economic terms. There are some types of genetic tests that analyze the likelihood of a clinical response to a particular drug or drug mix. Pharmacogenomic tests are available for various diseases such as tumors, neuropsychiatric diseases, cardiovascular diseases etc. The tests can be configured either on a single drug or on groups of drugs, concerning one or more pathologies. A first patent application WO2016018499A1 relates to a method for providing an optimized specific or personalized drug therapy for a single subject or a group of subjects and based, at least in part, on one or more genetic profiles of the subject, the pharmacogenomic profile of the subject and / or the evaluation of possible drug interactions. In various embodiments specific systems are provided for carrying out one or more steps of the mentioned methods. Another example is described in patent application US2017147779A1 which relates to methods of pharmacological treatment through the use of a combination of genetic and non-genetic information to adapt the dose of the drug to the patient. One of the methods described comprises receiving a pharmacological profile comprising the therapeutic range of the drug; receiving patient data including demographic and clinical data; determination of the patient's genotype by coding a cytochrome P450 gene selected from the group consisting of CYP2D6, CYP1A2, CYP2C19, CYP2C9 and CYP2E1, each gene locus containing one or more genetic variants; the generation of a first pharmacokinetic (PK) model of the area under the temporal concentration curve (AUC) based on patient data, genotype and drug profile; the administration to the patient of a first dosage regimen based on the first PK model; the determination of a blood level of the drug in the patient; the generation of a second PK model that incorporates the blood level of the drug; the administration of a second dosage regimen of the drug to the patient according to the second PK model. Another solution is provided in patent application US2009138286 which describes a customized management software to determine a series of recommended doses of a drug for a patient. The software contains a code to receive information on a combination of at least one genetic factor and patient personal data that are predictive of the patient's reaction to a series of drug doses. Using a predictive mathematical model specific to the drug under consideration, the code calculates the series of recommended doses specific to the patient's genetic factor. The series of recommended doses is issued. In a preferred embodiment, the output is provided by an interactive display which allows a user, typically a healthcare professional, to enter actual doses and patient responses. The next set of recommended doses is preferably adapted, in real time, to account for actual doses and the patient's actual responses. Another example of a known method is described in WO2019/211308A1 that disclosed a method and software for visualizing a model-based prediction on a matrix display. In the training data set that the method described consider there are a lot of subjective parameters (authors, publications date, authors network) and the method refers to the drug effectiveness in the total population. A problem of the described method is that its input data could be combined but are chosen essentially arbitrarily by MLL, and they were not weighted for importance. Furthermore, input is not based on an objective biological data as the DNA reading of specific biomarkers for a specific subject. Although they are advantageous in several respects, the main problem of the known methods is that they are not accurate and reliable in the personalized optimization of the initial dosage and maintenance of a drug treatment for a single individual. In fact, known methods do not start from a biological objective parameter, as the DNA analysis of a specific subject. Furthermore, the known solutions, when analysing pharmacogenomic markers (genetic variants), never analyse more markers for the same drug but are limited to the use of single markers of single genes. Furthermore, the known solutions are not able to combine genetic information with data deriving from the scientific literature and inherent to the same pharmacogenomic markers. Furthermore, known solutions never use a system, computerized method or algorithm capable of using and combining genetic data together with scientific literature data to select a drug while taking into account the drug output, toxicity and dosage results simultaneously. The purpose of the present invention is to provide a system and a method for determining an adequacy parameter of a drug as a function of genetic factors, capable of optimizing the initial and maintenance dosage of various widely used drugs, capable of predicting the efficacy of a drug as a function of genetic factors, able to predict the toxicity of a drug as a function of genetic factors, to reach target concentrations more quickly and limit dose- related adverse reactions, thus having characteristics such as to overcome the limits of current known systems and methods. According to the present invention, a system is provided for determining an adequacy parameter of a drug as a function of genetic factors, as defined in claim 1. According to the present invention, a method is also provided for determining an adequacy parameter of a drug as a function of genetic factors, as defined in claim 3. For a better understanding of the present invention, a preferred embodiment is now described, purely by way of non-limiting example, with reference to the attached drawings, in which: - Figure 1 shows a block diagram of a system for determining an adequacy parameter of a drug as a function of genetic factors, according to the invention; - Figure 2 shows experimental results obtained using the system and method of Figure 1, according to the invention; - Figures 3a – 3e show further experimental results obtained using the system and method of Figure 1 on five subjects. With particular reference to Figure 1, a system 100 for determining an adequacy parameter of a drug as a function of genetic factors is shown, according to the invention. More precisely, the system 100 includes: - a block 101 for storing parameters selected from the group consisting of: - selected markers for each drug, indicated with SNP (Single nucleotide polymorphism), - number of published studies, indicated with Ns, - impact factor, or Impact Factor, of the journal indicated with IF, - value of statistical significance, indicated with P, - ethnicity of the population studied, indicated with E; - a block 102 for analysing the weights of the aforesaid parameters in a set of drugs belonging to the same category, starting from N determined and selected pharmacogenomic markers; - a block 103 for determining an index relating to the effectiveness of each drug; - a block 104 for determining a toxicity index of each drug; - a block 105 for determining an index relating to the dosage for each drug; - a combination block 106 of the index relating to the efficacy of each drug, the toxicity index of each drug or the index relating to the dosage for each drug, based on the genetic result of each SNP, which can be summarized with good or negative genetic predisposition to take that drug for toxicity, outcome, dosage, depending on the SNP considered; - a block 107 for generating a parameter (index) of adequacy of a drug based on the result of the combination performed by block 106; - a block 108 for classifying drugs according to a ranking that goes from best to worst based on the results of the DNA analysis, ordering in descending order the parameter (index) of adequacy of each drug. To be clearer, in this description of the invention with the word ‘weight’ ore ‘Weights’ are considered objective parameters, as Impact factor, statistical P value, ad so on. According to one aspect of the invention, the adequacy parameter is between the values -1 and +1. As previously mentioned, the invention also refers to a method for determining an adequacy parameter of a drug as a function of genetic factors, as shown in Figure 2. The method includes the steps of: - store parameters chosen in the group consisting of: - selected markers for each drug, indicated with SNP (single nucleotide polymorphism), - number of published studies, indicated with Ns, - impact factor, or Impact Factor, of the scientific journal that published the study, indicated with IF, - value of statistical significance, indicated with P, - ethnicity of the population studied, indicated with E; - analyze the weights of the above parameters in a set of drugs belonging to the same category, starting from N determined and selected pharmacogenomic markers; - determine an index relating to the effectiveness of each drug; - determine a toxicity index (Itox) of each drug; - determine a dosage index (Idos) for each drug; - combine the index relating to the efficacy of each drug, the toxicity index of each drug or the index relating to the dosage for each drug, calculated for each relative SNP analyzed, with the genetic result of each SNP (which can be synthesized with good or negative genetic predisposition to take that drug for toxicity, outcome, dosage, depending on the SNP considered); - generating an adequacy parameter of a drug based on the result of the combination performed by block 106; - classify the drugs according to a ranking of suitability ranging from best to worst based on the results of DNA analysis by assigning a toxicity score (Tscore), a dosage score (Dscore) and an efficacy score (Oscore). According to one aspect of the invention, the step of determining the toxicity index (Itox) of each drug includes calculating it, for each pharmacogenomic marker (SNP) related to the drug, according to the following formula:

where: N = number of SNPs selected for each drug Ns = number of published studies IF = journal impact factor P = P value of statistical significance Np = number of patients in the study E = ethnicity of the population studied k = number of SNPs per category (toxicity or outcome) The Itox will then be multiplied by +1 or -1 depending on whether the genetic result of each SNP of that drug for genetic predisposition to toxicity is positive or negative, respectively. According to another aspect of the invention, the step of determining the dosage index (Idos) for each drug comprises calculating it, for each pharmacogenomic marker (SNP) relating to the drug, according to the following formula:

where: N = number of SNPs selected for each drug Ns = number of published studies IF = journal impact factor P = P value of statistical significance Np = number of patients in the study E = ethnicity of the population studied k = number of SNPs per category (toxicity or outcome) The Idos will then be multiplied by +1 or -1 depending on whether the genetic result of each SNP of that drug due to genetic predisposition to the dosage provides for a reduction in dosage or an increase in dosage, respectively. According to an aspect of the invention, the step of generating an efficacy index (Iout) of each drug comprises calculating it, for each pharmacogenomic marker (SNP) related to the drug, according to the following formula:

where: N = number of SNPs selected for each drug Ns = number of published studies IF = journal impact factor P = P value of statistical significance Np = number of patients in the study E = ethnicity of the population studied k = number of SNPs per category (toxicity or outcome) The Iout will then be multiplied by +1 or -1 depending on whether the genetic result of each SNP of that drug for genetic predisposition to efficacy is positive or negative, respectively. According to another aspect of the invention, the step of classifying the drugs according to a ranking that goes from best to worst, or by efficacy, or by toxicity, or by dosage, based on the results of the DNA analysis comprises determining the score of Oscore efficacy according to the following fo

the Tscore toxicity score according to the following formula:

the score for the Dscore assay according to the following formula:

And the total adequacy score of the drug TOTscore according to the following formula:

A classification is then made for both toxicity, efficacy and dosage, and drug adequacy by ordering in descending order, for each drug considered, the Oscore, Tscore, Dscore and TOTscore scores, respectively. The Applicant has performed experimental tests using statins as drugs. DNA was analyzed for 4 different drugs falling into the statin category: Atorvastin, Rosuvastatin, Pravastatin, Simvastatin. Based on the scientific literature, we chose to analyze 3 genes for Atorvastin (two for dosage and one for toxicity), 3 for Rosuvastatin (1 for toxicity, 1 for outcome, and 1 for dosage), 4 for Pravastatin (3 for outcome and 1 for dosage) and 5 for Simvastatin (2 for outcome and 3 for toxicity). The system and method were able to accurately classify the most suitable drugs according to their genotype (SNPs analyzed), taking into account efficacy, toxicity and dosage. By way of example, but not exhaustively, by analyzing the DNA of 5 different subjects, a ranking of the 4 drugs was obtained, from best to worst, different for each of the subjects analyzed. DNA was analyzed for each of the 5 subjects for pharmacogenomic markers (SNPs) rs7412, rs4693075, rs20455, rs4149056, rs2231142, rs4149015, rs17244841, rs2032582, rs1346268, rs1719247. The results of the application of the system and the method for the 5 subjects taken as an example are summarized in Figure 3. Taking as reference the adequacy index (TOTscore, or Total score) it was possible to classify the most suitable statins for each of the subjects analyzed. For the subject n ° 1, SIMVASTATIN, PRAVASTATIN, ROSUVASTATIN, ATORVASTATIN were more suitable, from best to worst. For subject no. 2, PRAVASTATIN, ATORVASTATIN, ROSUVASTATIN, SIMVASTATIN were more suitable, in descending order. For subject no. 3, PRAVASTATIN, ROSUVASTATIN, ATORVASTATIN, SIMVASTATIN were more suitable, in descending order. For subject no. 4, ATORVASTATIN, ROSUVASTATIN, PRAVASTATIN, SIMVASTATIN were more suitable, in descending order. For subject no. 5, PRAVASTATIN and ROSUVASTATIN were more suitable, in descending order, in the same way, ATORVASTATIN, SIMVASTATIN. As can also be seen from Figure 3, it is possible to obtain 5 different profiles for the 5 subjects taken into consideration and therefore to customize and classify the most correct pharmacological profile in a precise manner. Furthermore, it is possible to classify and identify, for each of the subjects considered, the drugs from lesser to greater toxicity (Tscore or Toxicity score) and those from greater to lesser efficacy (Oscore or Outcome score), as can be seen in Figure 3. The method according to the invention, is based on pharmacogenomics that is the study of the role of the genome in drug response and analyses how the genetic makeup of an individual affects his/her response to drugs. It deals with the influence of acquired and inherited genetic variation on drug response in patients by correlating SNP with pharmacokinetics (drug absorption, distribution, metabolism, and elimination) and pharmacodynamics (effects mediated through a drug's biological targets). The principal input of the method according to the invention is the individual SNP and the method is applied to evaluate the efficacy of a drug on a specific individual and not, as in prior art, on the population in general. So, the principal input of the method according to the invention is a real analysis of genetic factors. Advantageously according to the invention, the method starts from the real DNA analysis of an individual. All the mathematical steps give rise from an objective data that is the DNA base of the considered polymorphism (SNP) presents in the Genome of the analysed subject. The bases of the polymorphisms can always be of three different type, depending on the person being analysed. The remaining data that could be subjective (for example publications that are selected), are in fact selected by means of objective parameters and data such as Impact factor score of the paper, the value of statistical significance, the ethnicity, and so on, that is with objective data. Advantageously, the invention allows to evaluate the toxicity of a drug on a single subject based on his DNA (Personalized Medicine) as the method according to the invention uses the DNA analysis of the single subject considered. Therefore, system and method for determining an adequacy parameter of a drug as a function of genetic factors according to the invention are precise. Furthermore, the system and method for determining an adequacy parameter of a drug as a function of genetic factors according to the invention allow a classification of drugs so that they are optimized based on specific data of the treated patient. Furthermore, the system and method for determining an adequacy parameter of a drug as a function of genetic factors according to the invention makes it possible to take into account, as a whole, both the information relating to toxicity and that relating to pharmacological efficacy. , and those relating to the assay, combining them with the results of the DNA analysis (genotype, SNP) and enclosing them in a single classification index (adequacy index, TOTscore). Finally, the system and method for determining an adequacy parameter of a drug as a function of genetic factors according to the invention allow to optimize a drug treatment based on both genetic data and additional parameters). Finally, it is clear that the system and the method for determining an adequacy parameter of a drug according to the genetic factors according to the invention described and illustrated herein, can be modified and varied without thereby departing from the protective scope of the present invention, as defined in the attached claims.

Claims

CLAIMS 1. System (100) for evaluating a parameter related to the adequacy of a drug depending on genetic factors comprising: - a block (101) for storing parameters chosen in the group consisting of: - markers chosen for each drug, indicated as SNP (Single nucleotide polymorphism), - number of published studies, indicated as Ns, - Impact Factor of the scientific journal that published the study, indicated as IF, - value of statistical significance, indicated as P, - ethnicity of the studied population, indicated as E; characterized in comprising: - a block (102) for analyzing a weight of each of the aforementioned parameters within a set of drugs included in the same category, starting from N prefixed and selected markers of pharmacogenomics; - a block (103) for evaluating an index related to the effectiveness of each drug; - a block (104) for evaluating an index related to the toxicity of each drug; - a block (105) for evaluating an index related to the dosage of each drug; - a block (106) for combining the index related to the effectiveness of each drug, the index related to the toxicity of each drug or the index related to the dosage of each drug, based on the genetic outcome of each SNP, that can be synthesized as a good or a bad genetic predisposition to take the drug for toxicity, outcome, dosage, depending on the specific SNP; - a block (107) for generating a parameter (index) of adequacy of a drug based on the outcome of the combination performed by the block (106); and - a block (108) for classifying the drugs according to a ranking extending from the best to the worst based on the results of the DNA analysis, ordering in descending order the parameter (index) of adequacy of each drug. 2. System (100) according to claim 1, characterized in that the parameter related to the adequacy is comprised between -1 and +1. 3. Method for evaluating a parameter related to the adequacy of a drug depending on genetic factors comprising the step of: - storing parameters chosen in the group consisting of: - markers chosen for each drug, indicated as SNP (single nucleotide polymorphism), - number of published studies, indicated as Ns, - Impact Factor of the scientific journal that published the study, indicated as IF, - value of statistical significance, indicated as P, - ethnicity of the studied population, indicated as E; characterized in comprising the steps of: - analyzing the weight of each of the aforementioned parameters within a set of drugs included in the same category, starting from N prefixed and selected markers of pharmacogenomics; - evaluating an index related to the effectiveness of each drug; - evaluating an index (Itox) related to the toxicity of each drug; - evaluating an index (Idos) related to the dosage of each drug; - combining the index related to the effectiveness of each drug, the index related to the toxicity of each drug or the index related to the dosage of each drug, evaluated for any analyzed SNP, with the genetic outcome of each SNP; - generating a parameter of adequacy of a drug based on the outcome of the performed combination; and - classifying the drugs according to an adequacy ranking extending from the best to the worst based on the results of the DNA analysis, assigning a toxicity score (Tscore), a dosage score (Dscore) and an effectiveness score (Oscore). 4. Method according to claim 3, characterized in that the step of evaluating the index (Itox) related to the toxicity of each drug includes to evaluate said index, for each pharmacogenomic marker (SNP) related to the drug, according to the following formula:

wherein: N = number of selected SNPs for each drug Ns = number of published studies IF = impact factor related to the journal P = P value related to the statistical significance Np = number of patients object of the study E = ethnicity of the population object of the study k = number of SNP per category (toxicity or outcome) 5. Method according to claim 4, characterized in that the Itox index is multiplied by +1 or -1 depending on the genetic outcome of each SNP of the related drug for genetic predisposition to the toxicity being positive or negative, respectively. 6. Method according to claim 4, characterized in that the step of evaluating the index related to the dosage (Idos) for each drug includes to evaluate said index, for each pharmacogenomic marker (SNP) related to the drug, according to the following formula:

wherein: N = number of selected SNPs for each drug Ns = number of published studies IF = impact factor related to the journal P = P value related to the statistical significance Np = number of patients object of the study E = ethnicity of the population object of the study k = number of SNP per category (toxicity or outcome) 7. Method according to claim 6, characterized in that the Idos index is multiplied for +1 or -1 depending on the genetic outcome of each SNP of the related drug for genetic predisposition to the dosage including a reduction or an increase of said dosage, respectively. 8. Method according to claim 4, characterized in that the step of generating an effectiveness index (Iout) of each drug includes to evaluate said index, for each pharmacogenomic marker (SNP) related to the drug, according to the following formula:

wherein: N = number of selected SNPs for each drug Ns = number of published studies IF = impact factor related to the journal P = P value related to the statistical significance Np = number of patients object of the study E = ethnicity of the population object of the study k = number of SNP per category (toxicity or outcome) 9. Method according to claim 8, characterized in that the Iout index is multiplied for +1 or -1 depending on the genetic outcome of each SNP of the related drug for genetic predisposition to the effectiveness being positive or negative, respectively. 10. Method according to claim 3, characterized in that the step of classifying the drugs according to a ranking extending from the best to the worst, or based on effectiveness, or toxicity, or dosage, based on the outcomes of t uate the effectiveness following formula:

the toxicity score Tscore according to the following formula:

the score related to the dosage Dscore according to the following formula:

and evaluating the overall score related to the adequacy of the drug TOTscore according to the following formula:

11. Method according to claims 3-10, characterized in comprising the step of performing a classification depending both on toxicity, and on effectiveness and dosage, and on adequacy of the drug sorting by descending order, for each drug considered, the Oscore, Tscore, Dscore and TOTscore scores, respectively.