CN109754858B - Methotrexate dosing regimen determination device, storage medium and apparatus - Google Patents
Methotrexate dosing regimen determination device, storage medium and apparatus Download PDFInfo
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Abstract
The application relates to a method, a device, a storage medium and equipment for determining a methotrexate dosing scheme, wherein a methotrexate intracellular metabolic dynamics model is established, the influence of different contents of methotrexate metabolism-related enzymes (folate polyglutamate synthetase and gamma-glutamyl hydrolase) on methotrexate metabolic rate parameters in the model is considered in a combined manner, and the metabolic condition of methotrexate is simulated through the model, so that the corresponding dosing scheme can be determined according to the methotrexate metabolic simulation condition, namely the dosing scheme is determined by combining the content difference of the methotrexate metabolism-related enzymes of different patient individuals, the dosing scheme is more scientific and reasonable, and the accurate dosing for different patient individuals is realized.
Description
Technical Field
The application relates to the technical field of medicine, in particular to a methotrexate dosing regimen determination device, a storage medium and equipment.
Background
Methotrexate (MTX) is a drug applied to clinical treatment of diseases such as acute lymphocytic leukemia, malignant lymphoma, osteosarcoma and the like, after MTX enters cells, intracellular MTX is connected with glutamic acid (PG) one by one under the action of folyl-polyglutamate synthase (FPGS) to form polyglutamate Methotrexate (MTX-PGs, 2-7) which is a main active ingredient, and the MTX-PGs block a folic acid metabolic pathway by competitively inhibiting intracellular dihydrofolate reductase (DHFR), thereby playing a role in apoptosis of cancer cells.
In the prior art, when determining the MTX dosage of a patient, a universal clinical dosage is adopted, and then a dosage scheme is adjusted according to the MTX blood concentration condition of the patient and an international universal MTX safe blood concentration judgment standard. However, because the correlation between the concentration of MTX-PGs in cells and the blood concentration of MTX is poor, the drug administration scheme can not be accurately determined only by determining the drug administration scheme according to the blood concentration of MTX, and thus, the drug administration scheme of methotrexate in the prior art has certain irrationality.
Disclosure of Invention
In view of the above, there is a need to provide a more accurate and reasonable method, device, storage medium and apparatus for determining methotrexate dosing regimen.
A method for determining a dosing regimen for methotrexate comprising:
obtaining the expression conditions of folate polyglutamate synthetase and gamma-glutamyl hydrolase in a target patient;
obtaining corresponding methotrexate metabolic rate parameters according to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase, wherein the methotrexate metabolic rate parameters represent the conversion rate of methotrexate and polyglutamate methotrexate;
and substituting the methotrexate metabolic rate parameters into a methotrexate intracellular metabolic dynamics model, and determining the methotrexate administration scheme of the target patient through the methotrexate intracellular metabolic dynamics model.
In one embodiment, obtaining expression of folate polyglutamate synthetase and γ -glutamyl hydrolase in a subject comprises:
obtaining the content test result of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase in the body of the target patient;
and obtaining the expression conditions of the folic acid polyglutamic acid synthetase and the gamma-glutamyl hydrolase according to the content test result.
In one embodiment, the corresponding methotrexate metabolic rate parameters are obtained according to the expression of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase, and comprise:
and determining the methotrexate metabolic rate parameter corresponding to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase through a corresponding relation model of the methotrexate metabolism related enzyme content and the methotrexate metabolic rate parameter according to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase.
In one embodiment, the process of establishing the corresponding relation model of the methotrexate metabolism-related enzyme content and the methotrexate metabolism rate parameter comprises the following steps:
obtaining metabolic sample data for methotrexate, the metabolic sample data comprising: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate, the content change time of intracellular compounds, the content of intracellular folate polyglutamic acid synthetase and the content of intracellular gamma-glutamyl hydrolase;
obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the content of the intracellular methotrexate, the content change time of the intracellular compound and the content of the intracellular polyglutamic acid methotrexate;
performing correlation analysis treatment according to the conversion rate parameter, the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase to obtain an effect parameter of the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase on the conversion rate parameter;
and constructing a corresponding relation model of the content of the enzyme related to the methotrexate metabolism and the methotrexate metabolism rate parameter according to the content of the intracellular folate polyglutamate synthetase and the action effect parameter of the content of the intracellular gamma-glutamyl hydrolase on the conversion rate parameter.
In one embodiment, the establishment process of the methotrexate intracellular metabolic kinetic model comprises the following steps:
obtaining metabolic sample data for methotrexate, the metabolic sample data comprising: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate and the content change time of intracellular compounds;
obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the content of the intracellular methotrexate, the content change time of the intracellular compound and the content of the intracellular polyglutamic acid methotrexate;
and constructing a methotrexate intracellular metabolic dynamics model according to the conversion rate parameters of the methotrexate and polyglutamic acid methotrexate.
In one embodiment, the methotrexate dosing regimen for the target patient is determined by the methotrexate intracellular pharmacokinetic model, comprising:
acquiring the content index of the polyglutamic acid methotrexate of the target patient;
according to the methotrexate content index of polyglutamic acid, obtaining a corresponding methotrexate content index through the intracellular metabolic dynamics model of methotrexate;
and determining the methotrexate administration scheme of the target patient according to the methotrexate content index.
In one embodiment, the methotrexate dosing regimen for the target patient is determined by the methotrexate intracellular pharmacokinetic model, comprising:
acquiring the content index of the polyglutamic acid methotrexate of the target patient;
obtaining a plurality of polyglutamic acid methotrexate content predicted values corresponding to a plurality of preset drug delivery schemes through the methotrexate intracellular metabolic kinetics model;
and screening the predicted value of the polyglutamic acid methotrexate content meeting the polyglutamic acid methotrexate content index, and taking the corresponding preset administration scheme as the methotrexate administration scheme of the target patient.
A methotrexate dosing regimen determination device comprising:
the information acquisition module is used for acquiring the expression conditions of folate polyglutamate synthetase and gamma-glutamyl hydrolase in a target patient body;
the parameter determination module is used for obtaining corresponding methotrexate metabolic rate parameters according to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase, and the methotrexate metabolic rate parameters represent the conversion rate of methotrexate and polyglutamate methotrexate;
and the scheme determining module is used for substituting the methotrexate metabolic rate parameters into a methotrexate intracellular metabolic dynamics model and determining the methotrexate administration scheme of the target patient through the methotrexate intracellular metabolic dynamics model.
A computer device comprising a memory storing a computer program and a processor implementing the steps of the method described above when executing the computer program.
A computer-readable storage medium, on which a computer program is stored, which, when being executed by a processor, carries out the steps of the method as described above.
According to the method, the device, the storage medium and the equipment for determining the methotrexate dosing scheme, the methotrexate intracellular metabolic dynamics model is established, the influence of different contents of methotrexate metabolism-related enzymes (folate polyglutamate synthetase and gamma-glutamyl hydrolase) on the methotrexate metabolic rate parameters in the model is considered, and the metabolic condition of methotrexate is simulated through the model, so that the corresponding dosing scheme can be determined according to the methotrexate metabolism simulation condition, namely the dosing scheme is determined according to the difference of the contents of the methotrexate metabolism-related enzymes of different patient individuals, the methotrexate dosing scheme is more scientific and reasonable, and the accurate dosing for the different patient individuals is realized.
Drawings
FIG. 1 is a schematic flow chart of a method for determining a dosing regimen of methotrexate in one embodiment;
FIG. 2 is a schematic flow chart illustrating modeling of methotrexate intracellular metabolism kinetics in one embodiment;
FIG. 3 is a schematic flow chart illustrating modeling of the correlation between the content of enzymes associated with methotrexate metabolism and the metabolic rate of methotrexate in one embodiment;
FIG. 4 is a schematic in vivo metabolism of methotrexate;
FIG. 5 is a schematic representation of a model of the metabolic process of methotrexate in one embodiment;
fig. 6 is a schematic structural view of the methotrexate dosing regimen determination device in one embodiment.
Detailed Description
In order to make the objects, technical solutions and advantages of the present application more apparent, the present application is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
In one embodiment, as shown in fig. 1, a method for determining a methotrexate dosing regimen is provided and is illustrated as applied to a processor that can determine a methotrexate dosing regimen, the method comprising the steps of:
step S110, obtaining the expression conditions of folate polyglutamate synthetase and gamma-glutamyl hydrolase in the body of a target patient;
after the drug (methotrexate) enters the body of a patient, drug metabolism is required to exert the corresponding drug effect. Drug metabolism refers to the process of changing the chemical structure of a drug under the action of various drug metabolizing enzymes in a patient, which is also called biotransformation. The result of the biotransformation of the drug in vivo has two types, the first is the inactivation of the drug, namely the transformation into the drug without pharmacological activity; the second is drug activation, i.e. the conversion of pharmacologically inactive drugs into pharmacologically active metabolites or the production of toxic metabolites, or the retention of the original pharmacological action after metabolism. In the technical solutions of the embodiments of the present application, drug metabolism is defined uniformly as the process of converting a drug into a corresponding primary active ingredient.
Clinical research shows that the individual difference of MTX curative effect and toxic side effect is great. MTX can enter cells actively via Reduced Folate Carrier (RFC)1, Proton Coupled Folate Transporters (PCFT) and 2, Organic Anion Transport Polypeptide (OATP)1B1, or by passive diffusion (MTX plasma concentrations above 20X 10-6 mol/L). Connecting intracellular MTX with glutamic acid (PG) under the action of folic acid polyglutamate synthetase (FPGS) one by one to form polyglutamate methotrexate (MTX-PGs, 2-7); MTX-PGs are hydrolyzed by gamma-glutamyl hydrolase (GGH) to MTX, and then discharged. MTX and its main active metabolite MTX-PGs mainly block the metabolic pathway of folic acid through the competitive inhibition of dihydrofolate reductase (DHFR) in the cell, make cancer cell die, wherein because MTX blood concentration will decline rapidly after administering, and MTX-PGs dissociation rate is slow, it is bad to go out the cytogenetic property, with dihydrofolate reductase (DHFR), thymine synthetase, two amide ribonucleotide converting enzyme and aminoimidazole amide carboxylase, etc. have stronger affinity, so MTX-PGs are MTX exerts potency and produces the major active form of the oxic side effect.
The expression conditions of drug metabolizing enzymes in different patients are different, and the drug metabolizing enzymes corresponding to methotrexate are phytylpolyglutamate synthetase and gamma-glutamyl hydrolase.
In this step, when determining the methotrexate administration schedule of the target patient, the processor first obtains the expression of the drug metabolism-related enzymes (drug metabolizing enzymes, i.e., folate polyglutamate synthase and γ -glutamyl hydrolase) corresponding to methotrexate in the target patient. When the processor obtains the expression condition of the drug metabolism related enzyme, the expression condition data of the drug metabolism related enzyme obtained by methods such as testing and the like can be obtained in real time; or individual data of the target patient stored in the server is obtained through network access, and expression condition data of the drug metabolism related enzyme is obtained from the individual data; the expression data of the drug metabolism-related enzyme stored in a storage device such as a memory may be directly acquired.
Step S120, obtaining corresponding methotrexate metabolic rate parameters according to the expression conditions of the folic acid polyglutamate synthetase and the gamma-glutamyl hydrolase, wherein the methotrexate metabolic rate parameters represent the conversion rate of methotrexate and polyglutamate methotrexate;
the drug metabolism process of methotrexate is usually completed by a series of enzymatic reactions, that is, the expression of the drug metabolism-related enzyme has a certain effect on the drug metabolism process of methotrexate, namely, the expression of the drug metabolism-related enzyme directly influences the corresponding drug metabolism rate parameter of methotrexate. That is, since the expression of the drug metabolizing enzyme in different patients varies, the drug metabolism rate parameters (for methotrexate) of different patients vary, and the content of the main active ingredient (for methotrexate, the main active ingredient is polyglutamate methotrexate) of different patients varies with the same dose and the same duration of drug action, and the content of the main active ingredient of methotrexate has an important meaning on the drug action of methotrexate, it is finally shown that the drug actions of different patients vary with the same drug, the same dose, and the same duration of drug action, which is a drawback of the prior art.
In this step, after obtaining the expression conditions of folate polyglutamate synthetase and gamma-glutamyl hydrolase in the target patient, the processor obtains a corresponding methotrexate metabolic rate parameter according to the expression conditions, and the methotrexate metabolic rate parameter characterizes the conversion rate of methotrexate and polyglutamate methotrexate, so that the processor can obtain the content of polyglutamate methotrexate after a preset time period according to the methotrexate metabolic rate parameter and an expected dosage, or the processor can obtain the corresponding methotrexate dosage according to the methotrexate metabolic rate parameter and the expected content of polyglutamate methotrexate after the preset time period, thereby determining the methotrexate administration scheme of the target patient.
And S130, substituting the metabolic rate parameter of the methotrexate into the intracellular metabolic dynamics model of the methotrexate, and determining the methotrexate administration scheme of the target patient through the intracellular metabolic dynamics model of the methotrexate.
Pharmacokinetics (pharmacokinetics) is called pharmacokinetics for short, and mainly studies the dynamic changes of the body's disposition (Disposition) of a drug, including the processes of absorption, distribution, biochemical conversion (or metabolism) and excretion of the drug in the body, and the corresponding model is called a pharmacokinetic model. It should be noted that the pharmacokinetic model used in this application refers specifically to the intracellular pharmacokinetic model of the drug.
In the step, the processor obtains corresponding methotrexate metabolic rate parameters according to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase, substitutes the methotrexate metabolic rate parameters into a methotrexate intracellular metabolic kinetic model, and simulates the drug metabolism process of methotrexate in target cells through the methotrexate intracellular metabolic kinetic model, so that the methotrexate administration scheme of the target patient is determined according to the drug metabolism simulation result.
The embodiment provides a method for determining a methotrexate dosing regimen, which includes the steps of establishing a methotrexate intracellular metabolic dynamics model, considering the influence of different contents of methotrexate metabolism-related enzymes (phytylpolyglutamate synthetase and gamma-glutamyl hydrolase) on methotrexate metabolic rate parameters in the model, and simulating the metabolic condition of methotrexate through the model, so that the corresponding dosing regimen can be determined according to the methotrexate metabolic simulation condition, namely, the dosing regimen is determined according to the difference of the contents of the methotrexate metabolism-related enzymes of different patient individuals, and therefore, the methotrexate dosing regimen is more scientific and reasonable, and accurate dosing for the different patient individuals is achieved.
In one embodiment, when determining the dosing regimen of methotrexate based on individual patient differences, it is first necessary to establish a corresponding model, which in this application includes: a corresponding relation model of the content of the methotrexate metabolism-related enzyme and the methotrexate metabolism rate parameter and a methotrexate intracellular metabolic dynamics model.
In one embodiment, as shown in fig. 2, the process of modeling the intracellular pharmacokinetics of methotrexate includes:
step S210, obtaining the metabolism sample data of methotrexate, wherein the metabolism sample data comprises: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate and the content change time of intracellular compounds;
step S220, obtaining conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content;
and step S230, constructing a methotrexate intracellular metabolic dynamics model according to the conversion rate parameters of methotrexate and polyglutamic acid methotrexate.
In one embodiment, as shown in fig. 3, the process of modeling the correspondence between the content of the enzyme associated with methotrexate metabolism and the parameter of methotrexate metabolism rate includes:
step S310, acquiring metabolic sample data of methotrexate, wherein the metabolic sample data comprises: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate, the content change time of intracellular compounds, the content of intracellular folate polyglutamic acid synthetase and the content of intracellular gamma-glutamyl hydrolase;
step S320, obtaining conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content;
step S330, performing correlation analysis processing according to the conversion rate parameter, the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase to obtain the effect parameters of the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase on the conversion rate parameter;
and step S340, constructing a corresponding relation model of the methotrexate metabolism related enzyme content and the methotrexate metabolism rate parameter according to the intracellular folate polyglutamate synthetase content and the action effect parameter of the intracellular gamma-glutamyl hydrolase content on the conversion rate parameter.
In one embodiment, aiming at the action mechanism of methotrexate and the defects of clinical medication, a method for realizing the individualized administration of the methotrexate is constructed, namely, an intracellular methotrexate metabolic kinetic model is established, a kinetic model parameter k of methotrexate metabolic related protein is introduced, in-vitro lymphocytes and the like are utilized to research the dynamic change process of intracellular MTX and MTX-PGs (2-7) under the action of main proteins FPGS and GGH, and the relation between the parameter k and the protein expression quantity is determined. Therefore, the concentrations of intracellular MTX and MTX-PGs (2-7) are predicted by measuring the expression quantity of MTX metabolism related proteins in different patients, calculating a parameter k and combining a linear kinetic equation, the curative effect and the toxic and side effect of the medicament are reflected, the administration dosage is further determined, and individualized dosage adjustment is realized.
Specifically, as shown in fig. 4, the metabolic processes of methotrexate in vivo mainly include: methotrexate after intravenous injection enters blood circulation and then is distributed in blood cells, lymphocytes and peripheral tissues, and MTX and glutamic acid (PG) are connected to form polyglutamate methotrexate (MTX-PGs, 2-7) under the action of folate polyglutamate synthetase (FPGS) in cells; under the action of gamma-glutamyl hydrolase (GGH), MTX-PGs are hydrolyzed to MTX.
As shown in FIG. 5, the concentrations of MTX-PGs (1-7) were each designated as X by modeling according to the metabolic process of methotrexate1～X7All data are obtained from experimental measurements and the time of change of the intracellular concentration of each compound is denoted as t. When intracellular MTX concentration is high: under the dual action of FPGS and GGH, the whole process is shown to proceed in the downward direction of the figure, and the constant of the conversion rate from MTX-PG1 to MTX-PG2 is recorded as k12For the same reason, there is k23To k is67. When intracellular MTX concentration is low: under the dual action of FPGS and GGH, the whole process is shown to proceed in the upward direction of the figure, and the constant of the conversion rate from MTX-PG2 to MTX-PG1 is recorded as k21For the same reason, there is k32To k is76。
Since MTX-PG7 interconverts only with MTX-PG6, X7Subject to X only6The influence of (a) is:
simplifying to obtain:
the same principle is as follows:
due to X1～X7It is known that k can be obtained by calculation67、k76And further calculating to obtain all k parameters.
In addition, the parameters of the effect of FPGS and GGH on different metabolic processes are respectively denoted as kFPGSAnd kGGHDuring the interconversion between MTX-PG1 and MTX-PG2, the corresponding effect parameter is kFPGS,12And kGGH,21. Due to k12And k21Is the result of the combined action of FPGS and GGH, thus:
k12＝kFPGS,12-kGGH,21
k21＝kGGH,21-kFPGS,12
by analogy, we can obtain:
kn,n+1＝kFPGS,n,n+1-kGGH,n+1,n
kn+1,n＝kGGH,n+1,n-kFPGS,n,n+1
after all the k parameters are obtained through calculation, the action effect constants k of the FPGS and the GGH for different conversion processes can be obtained through calculation according to the relationFPGS,n,n+1And kGGH,n+1,n. Obtaining all the k parameter effect constants kFPGS,n,n+1And kGGH,n+1,nAnd then, a methotrexate intracellular metabolic dynamics model and a corresponding relation model of the content of the methotrexate metabolism-related enzyme and the methotrexate metabolic rate parameter can be established.
In one embodiment, further comprising: the method comprises the steps of screening out characteristic peptide segments of FPGS and GGH by applying the principle of targeted proteomics (QTAP), determining ion channels of the two characteristic peptide segments, synthesizing corresponding isotope peptide segments as internal standards to reduce system errors, establishing a method for quantifying protein, carrying out methodology verification, and quantifying the protein in target cells by utilizing the established method.
In one embodiment, obtaining expression of folate polyglutamate synthetase and γ -glutamyl hydrolase in a subject comprises: obtaining the content test result of folate polyglutamate synthetase and gamma-glutamyl hydrolase in the body of a target patient; and obtaining the expression conditions of the folic acid polyglutamic acid synthetase and the gamma-glutamyl hydrolase according to the content test result.
In determining the dosing regimen of methotrexate to a subject patient, the levels of drug metabolism-related enzymes corresponding to methotrexate, i.e., folate polyglutamate synthase and γ -glutamyl hydrolase, in target cells of the subject patient are first measured. Specifically, the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase can be determined according to the enzyme content test result obtained by the UPLC-MS/MS method.
In one embodiment, the corresponding methotrexate metabolic rate parameters are obtained according to the expression of folate polyglutamate synthetase and gamma-glutamyl hydrolase, and comprise: and determining the methotrexate metabolic rate parameter corresponding to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase according to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase by a corresponding relation model of the methotrexate metabolism related enzyme content and the methotrexate metabolic rate parameter. After the expression condition of the methotrexate metabolism-related enzyme is obtained, the corresponding methotrexate metabolism rate parameter can be determined through establishing a corresponding relation model of the content of the methotrexate metabolism-related enzyme and the methotrexate metabolism rate parameter.
In one embodiment, the methotrexate dosing regimen for the target patient is determined by a methotrexate intracellular metabolic kinetics model comprising: acquiring the content index of the polyglutamic acid methotrexate of a target patient; obtaining a corresponding methotrexate content index through a methotrexate intracellular metabolic dynamics model according to the polyglutamic acid methotrexate content index; and determining the methotrexate administration scheme of the target patient according to the methotrexate content index.
Specifically, when the methotrexate administration scheme of the target patient is determined, the methotrexate administration scheme can be determined in a 'reverse derivation' mode, namely, the obtained content index of polyglutamate methotrexate is substituted into a methotrexate intracellular metabolic kinetics model, so that the corresponding intracellular methotrexate content, the plasma methotrexate content and the methotrexate administration amount are reversely derived, and the target patient can be accurately administered.
In another embodiment, the dosing regimen of methotrexate for a target patient is determined by a methotrexate intracellular metabolic kinetics model comprising: acquiring the content index of the polyglutamic acid methotrexate of a target patient; obtaining a plurality of polyglutamic acid methotrexate content predicted values corresponding to a plurality of preset dosing schemes through a methotrexate intracellular metabolic kinetics model; and screening the predicted value of the content of the polyglutamic acid methotrexate, which meets the content index of the polyglutamic acid methotrexate, and taking the corresponding preset administration scheme as the methotrexate administration scheme of the target patient.
Specifically, when the methotrexate administration scheme of the target patient is determined, the methotrexate administration scheme can also be determined in a forward derivation mode, namely, a plurality of preset administration schemes are substituted into a methotrexate intracellular metabolic dynamics model to obtain a plurality of corresponding predicted values of polyglutamate methotrexate content, the predicted values are compared with indexes of the polyglutamate methotrexate content of the target patient, and the predicted values meeting the indexes are screened out, so that the methotrexate administration scheme meeting the requirements is obtained, and the accurate administration of the target patient is realized.
It should be understood that although the various steps in the flow charts of fig. 1-3 are shown in order as indicated by the arrows, the steps are not necessarily performed in order as indicated by the arrows. The steps are not performed in the exact order shown and described, and may be performed in other orders, unless explicitly stated otherwise. Moreover, at least some of the steps in fig. 1-3 may include multiple sub-steps or multiple stages that are not necessarily performed at the same time, but may be performed at different times, and the order of performance of the sub-steps or stages is not necessarily sequential, but may be performed in turn or alternating with other steps or at least some of the sub-steps or stages of other steps.
In one embodiment, as shown in fig. 6, there is provided a methotrexate dosing regimen determination device comprising: an information acquisition module 110, a parameter determination module 120, and a scenario determination module 130.
The information acquisition module 110 is used for acquiring the expression conditions of folate polyglutamate synthetase and gamma-glutamyl hydrolase in the body of the target patient;
the parameter determination module 120 is configured to obtain corresponding methotrexate metabolic rate parameters according to expression conditions of folate polyglutamate synthetase and γ -glutamyl hydrolase, where the methotrexate metabolic rate parameters characterize the conversion rate of methotrexate and polyglutamate methotrexate;
the protocol determination module 130 is configured to substitute the methotrexate metabolic rate parameter into the methotrexate intracellular pharmacokinetic model, and determine a methotrexate administration protocol of the target patient through the methotrexate intracellular pharmacokinetic model.
In one embodiment, the information obtaining module 110 is further configured to obtain the results of the content test of folate polyglutamate synthetase and gamma-glutamyl hydrolase in the target patient; and obtaining the expression conditions of the folic acid polyglutamic acid synthetase and the gamma-glutamyl hydrolase according to the content test result.
In one embodiment, the parameter determining module 120 is further configured to determine a methotrexate metabolic rate parameter corresponding to the expression of the folate synthase and the γ -glutamyl hydrolase according to the expression of the folate synthase and the γ -glutamyl hydrolase by a corresponding relationship model of methotrexate metabolism-related enzyme content and the methotrexate metabolic rate parameter.
In one embodiment, the apparatus further comprises: the model building module is used for obtaining the metabolism sample data of the methotrexate, and the metabolism sample data comprises: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate, the content change time of intracellular compounds, the content of intracellular folate polyglutamic acid synthetase and the content of intracellular gamma-glutamyl hydrolase; obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content; performing correlation analysis treatment according to the conversion rate parameter, the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase to obtain the acting effect parameters of the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase on the conversion rate parameter; and constructing a corresponding relation model of the methotrexate metabolism related enzyme content and the methotrexate metabolism rate parameter according to the intracellular folate polyglutamate synthetase content and the action effect parameter of the intracellular gamma-glutamyl hydrolase content on the conversion rate parameter.
In one embodiment, the model building module is further configured to obtain metabolic sample data for methotrexate, the metabolic sample data comprising: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate and the content change time of intracellular compounds; obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content; and (3) constructing a methotrexate intracellular metabolic kinetic model according to the conversion rate parameters of methotrexate and polyglutamate methotrexate.
In one embodiment, the protocol determination module 130 is further configured to obtain an index of the amount of methotrexate polyglutamate in the target patient; obtaining a corresponding methotrexate content index through a methotrexate intracellular metabolic dynamics model according to the polyglutamic acid methotrexate content index; and determining the methotrexate administration scheme of the target patient according to the methotrexate content index.
In one embodiment, the protocol determination module 130 is further configured to obtain an index of the amount of methotrexate polyglutamate in the target patient; obtaining a plurality of polyglutamic acid methotrexate content predicted values corresponding to a plurality of preset dosing schemes through a methotrexate intracellular metabolic kinetics model; and screening the predicted value of the content of the polyglutamic acid methotrexate, which meets the content index of the polyglutamic acid methotrexate, and taking the corresponding preset administration scheme as the methotrexate administration scheme of the target patient.
Specific limitations of the methotrexate dosing regimen determination device can be found in the limitations of the methotrexate dosing regimen determination method described above, and are not described herein again. The various modules in the above-described methotrexate dosing regimen determination device can be implemented in whole or in part by software, hardware, and combinations thereof. The modules can be embedded in a hardware form or independent from a processor in the computer device, and can also be stored in a memory in the computer device in a software form, so that the processor can call and execute operations corresponding to the modules.
In one embodiment, a computer device is provided, comprising a memory and a processor, the memory having a computer program stored therein, the processor implementing the following steps when executing the computer program: obtaining the expression conditions of folate polyglutamate synthetase and gamma-glutamyl hydrolase in a target patient; obtaining corresponding methotrexate metabolic rate parameters according to the expression conditions of the folic acid polyglutamate synthetase and the gamma-glutamyl hydrolase, wherein the methotrexate metabolic rate parameters represent the conversion rate of methotrexate and polyglutamate methotrexate; and substituting the methotrexate metabolic rate parameters into the methotrexate intracellular metabolic dynamics model, and determining the methotrexate administration scheme of the target patient through the methotrexate intracellular metabolic dynamics model.
In one embodiment, the processor, when executing the computer program, further performs the steps of: obtaining the content test result of folate polyglutamate synthetase and gamma-glutamyl hydrolase in the body of a target patient; and obtaining the expression conditions of the folic acid polyglutamic acid synthetase and the gamma-glutamyl hydrolase according to the content test result.
In one embodiment, the processor, when executing the computer program, further performs the steps of: and determining the methotrexate metabolic rate parameter corresponding to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase according to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase by a corresponding relation model of the methotrexate metabolism related enzyme content and the methotrexate metabolic rate parameter.
In one embodiment, the processor, when executing the computer program, further performs the steps of: obtaining metabolic sample data of methotrexate, wherein the metabolic sample data comprises: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate, the content change time of intracellular compounds, the content of intracellular folate polyglutamic acid synthetase and the content of intracellular gamma-glutamyl hydrolase; obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content; performing correlation analysis treatment according to the conversion rate parameter, the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase to obtain the acting effect parameters of the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase on the conversion rate parameter; and constructing a corresponding relation model of the methotrexate metabolism related enzyme content and the methotrexate metabolism rate parameter according to the intracellular folate polyglutamate synthetase content and the action effect parameter of the intracellular gamma-glutamyl hydrolase content on the conversion rate parameter.
In one embodiment, the processor, when executing the computer program, further performs the steps of: obtaining metabolic sample data of methotrexate, wherein the metabolic sample data comprises: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate and the content change time of intracellular compounds; obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content; and (3) constructing a methotrexate intracellular metabolic kinetic model according to the conversion rate parameters of methotrexate and polyglutamate methotrexate.
In one embodiment, the processor, when executing the computer program, further performs the steps of: acquiring the content index of the polyglutamic acid methotrexate of a target patient; obtaining a corresponding methotrexate content index through a methotrexate intracellular metabolic dynamics model according to the polyglutamic acid methotrexate content index; and determining the methotrexate administration scheme of the target patient according to the methotrexate content index.
In one embodiment, the processor, when executing the computer program, further performs the steps of: acquiring the content index of the polyglutamic acid methotrexate of a target patient; obtaining a plurality of polyglutamic acid methotrexate content predicted values corresponding to a plurality of preset dosing schemes through a methotrexate intracellular metabolic kinetics model; and screening the predicted value of the content of the polyglutamic acid methotrexate, which meets the content index of the polyglutamic acid methotrexate, and taking the corresponding preset administration scheme as the methotrexate administration scheme of the target patient.
In one embodiment, a computer-readable storage medium is provided, having a computer program stored thereon, which when executed by a processor, performs the steps of: obtaining the expression conditions of folate polyglutamate synthetase and gamma-glutamyl hydrolase in a target patient; obtaining corresponding methotrexate metabolic rate parameters according to the expression conditions of the folic acid polyglutamate synthetase and the gamma-glutamyl hydrolase, wherein the methotrexate metabolic rate parameters represent the conversion rate of methotrexate and polyglutamate methotrexate; and substituting the methotrexate metabolic rate parameters into the methotrexate intracellular metabolic dynamics model, and determining the methotrexate administration scheme of the target patient through the methotrexate intracellular metabolic dynamics model.
In one embodiment, the computer program when executed by the processor further performs the steps of: obtaining the content test result of folate polyglutamate synthetase and gamma-glutamyl hydrolase in the body of a target patient; and obtaining the expression conditions of the folic acid polyglutamic acid synthetase and the gamma-glutamyl hydrolase according to the content test result.
In one embodiment, the computer program when executed by the processor further performs the steps of: and determining the methotrexate metabolic rate parameter corresponding to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase according to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase by a corresponding relation model of the methotrexate metabolism related enzyme content and the methotrexate metabolic rate parameter.
In one embodiment, the computer program when executed by the processor further performs the steps of: obtaining metabolic sample data of methotrexate, wherein the metabolic sample data comprises: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate, the content change time of intracellular compounds, the content of intracellular folate polyglutamic acid synthetase and the content of intracellular gamma-glutamyl hydrolase; obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content; performing correlation analysis treatment according to the conversion rate parameter, the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase to obtain the acting effect parameters of the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase on the conversion rate parameter; and constructing a corresponding relation model of the methotrexate metabolism related enzyme content and the methotrexate metabolism rate parameter according to the intracellular folate polyglutamate synthetase content and the action effect parameter of the intracellular gamma-glutamyl hydrolase content on the conversion rate parameter.
In one embodiment, the computer program when executed by the processor further performs the steps of: obtaining metabolic sample data of methotrexate, wherein the metabolic sample data comprises: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate and the content change time of intracellular compounds; obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content; and (3) constructing a methotrexate intracellular metabolic kinetic model according to the conversion rate parameters of methotrexate and polyglutamate methotrexate.
In one embodiment, the computer program when executed by the processor further performs the steps of: acquiring the content index of the polyglutamic acid methotrexate of a target patient; obtaining a corresponding methotrexate content index through a methotrexate intracellular metabolic dynamics model according to the polyglutamic acid methotrexate content index; and determining the methotrexate administration scheme of the target patient according to the methotrexate content index.
In one embodiment, the computer program when executed by the processor further performs the steps of: acquiring the content index of the polyglutamic acid methotrexate of a target patient; obtaining a plurality of polyglutamic acid methotrexate content predicted values corresponding to a plurality of preset dosing schemes through a methotrexate intracellular metabolic kinetics model; and screening the predicted value of the content of the polyglutamic acid methotrexate, which meets the content index of the polyglutamic acid methotrexate, and taking the corresponding preset administration scheme as the methotrexate administration scheme of the target patient.
It will be understood by those skilled in the art that all or part of the processes of the methods of the embodiments described above can be implemented by hardware related to instructions of a computer program, which can be stored in a non-volatile computer-readable storage medium, and when executed, the computer program can include the processes of the embodiments of the methods described above. Any reference to memory, storage, database, or other medium used in the embodiments provided herein may include non-volatile and/or volatile memory, among others. Non-volatile memory can include read-only memory (ROM), Programmable ROM (PROM), Electrically Programmable ROM (EPROM), Electrically Erasable Programmable ROM (EEPROM), or flash memory. Volatile memory can include Random Access Memory (RAM) or external cache memory. By way of illustration and not limitation, RAM is available in a variety of forms such as Static RAM (SRAM), Dynamic RAM (DRAM), Synchronous DRAM (SDRAM), Double Data Rate SDRAM (DDRSDRAM), Enhanced SDRAM (ESDRAM), Synchronous Link DRAM (SLDRAM), Rambus Direct RAM (RDRAM), direct bus dynamic RAM (DRDRAM), and memory bus dynamic RAM (RDRAM).
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (8)
1. A methotrexate dosing regimen determination device comprising:
the information acquisition module is used for acquiring the expression conditions of folate polyglutamate synthetase and gamma-glutamyl hydrolase in a target patient body;
the parameter determination module is used for obtaining corresponding methotrexate metabolic rate parameters according to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase, and the methotrexate metabolic rate parameters represent the conversion rate of methotrexate and polyglutamate methotrexate;
the scheme determination module is used for substituting the methotrexate metabolic rate parameter into a methotrexate intracellular metabolic dynamics model and determining the methotrexate administration scheme of the target patient through the methotrexate intracellular metabolic dynamics model;
the parameter determination module is also used for determining the methotrexate metabolic rate parameter corresponding to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase through a corresponding relation model of the methotrexate metabolism related enzyme content and the methotrexate metabolic rate parameter according to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase;
the device also comprises a model building module used for obtaining the metabolism sample data of the methotrexate, wherein the metabolism sample data comprises: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate, the content change time of intracellular compounds, the content of intracellular folate polyglutamic acid synthetase and the content of intracellular gamma-glutamyl hydrolase; obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content; performing correlation analysis treatment according to the conversion rate parameter, the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase to obtain the acting effect parameters of the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase on the conversion rate parameter; constructing a corresponding relation model of the content of the relevant enzyme of the methotrexate metabolism and the methotrexate metabolism rate parameter according to the content of intracellular folate polyglutamate synthetase and the action effect parameter of the content of intracellular gamma-glutamyl hydrolase on the conversion rate parameter;
the model building module is further used for obtaining metabolic sample data of methotrexate, and the metabolic sample data comprises: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate and the content change time of intracellular compounds; obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content; and (3) constructing a methotrexate intracellular metabolic kinetic model according to the conversion rate parameters of methotrexate and polyglutamate methotrexate.
2. The apparatus according to claim 1, wherein the information acquisition module is further configured to acquire the results of the assay of the levels of folate polyglutamate synthetase and γ -glutamyl hydrolase in the subject; and obtaining the expression conditions of the folic acid polyglutamic acid synthetase and the gamma-glutamyl hydrolase according to the content test result.
3. The device of claim 1, wherein the protocol determination module is further configured to obtain an index of the level of methotrexate polyglutamate in the target patient; obtaining a corresponding methotrexate content index through a methotrexate intracellular metabolic dynamics model according to the polyglutamic acid methotrexate content index; and determining the methotrexate administration scheme of the target patient according to the methotrexate content index.
4. The device of claim 1, wherein the protocol determination module is further configured to obtain an index of the level of methotrexate polyglutamate in the target patient; obtaining a plurality of polyglutamic acid methotrexate content predicted values corresponding to a plurality of preset dosing schemes through a methotrexate intracellular metabolic kinetics model; and screening the predicted value of the content of the polyglutamic acid methotrexate, which meets the content index of the polyglutamic acid methotrexate, and taking the corresponding preset administration scheme as the methotrexate administration scheme of the target patient.
5. The device of claim 1, wherein the information acquisition module is further configured to obtain a content test result of the enzyme by UPLC-MS/MS method, and determine the expression of the folate polyglutamate synthetase and the γ -glutamyl hydrolase according to the content test result of the enzyme.
6. The device according to claim 1, wherein the action-effect parameters are the action-effect parameters of folate polyglutamate synthetase and gamma-glutamyl hydrolase for different conversion processes.
7. A computer device comprising a memory and a processor, the memory storing a computer program, wherein the processor when executing the computer program implements the steps of:
obtaining the expression conditions of folate polyglutamate synthetase and gamma-glutamyl hydrolase in a target patient;
obtaining corresponding methotrexate metabolic rate parameters according to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase, wherein the methotrexate metabolic rate parameters represent the conversion rate of methotrexate and polyglutamate methotrexate;
substituting the methotrexate metabolic rate parameters into a methotrexate intracellular metabolic dynamics model, and determining the methotrexate administration scheme of the target patient through the methotrexate intracellular metabolic dynamics model;
the obtaining of corresponding methotrexate metabolic rate parameters according to the expression conditions of the folyl polyglutamate synthetase and the gamma-glutamyl hydrolase comprises the following steps: determining the methotrexate metabolic rate parameter corresponding to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase according to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase through a corresponding relation model of the methotrexate metabolism related enzyme content and the methotrexate metabolic rate parameter
Wherein the corresponding relation model of the content of the enzyme relevant to the methotrexate metabolism and the methotrexate metabolism rate parameter is constructed in the following way:
obtaining metabolic sample data of methotrexate, wherein the metabolic sample data comprises: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate, the content change time of intracellular compounds, the content of intracellular folate polyglutamic acid synthetase and the content of intracellular gamma-glutamyl hydrolase; obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content; performing correlation analysis treatment according to the conversion rate parameter, the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase to obtain the acting effect parameters of the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase on the conversion rate parameter; constructing a corresponding relation model of the content of the relevant enzyme of the methotrexate metabolism and the methotrexate metabolism rate parameter according to the content of intracellular folate polyglutamate synthetase and the action effect parameter of the content of intracellular gamma-glutamyl hydrolase on the conversion rate parameter;
the methotrexate intracellular metabolic dynamics model is constructed in the following way:
obtaining metabolic sample data of methotrexate, wherein the metabolic sample data comprises: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate and the content change time of intracellular compounds; obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content; and (3) constructing a methotrexate intracellular metabolic kinetic model according to the conversion rate parameters of methotrexate and polyglutamate methotrexate.
8. A computer-readable storage medium, on which a computer program is stored, which, when being executed by a processor, carries out the steps of:
obtaining the expression conditions of folate polyglutamate synthetase and gamma-glutamyl hydrolase in a target patient;
obtaining corresponding methotrexate metabolic rate parameters according to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase, wherein the methotrexate metabolic rate parameters represent the conversion rate of methotrexate and polyglutamate methotrexate;
substituting the methotrexate metabolic rate parameters into a methotrexate intracellular metabolic dynamics model, and determining the methotrexate administration scheme of the target patient through the methotrexate intracellular metabolic dynamics model;
the obtaining of corresponding methotrexate metabolic rate parameters according to the expression conditions of the folyl polyglutamate synthetase and the gamma-glutamyl hydrolase comprises the following steps: determining the methotrexate metabolic rate parameter corresponding to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase according to the expression conditions of the folate polyglutamate synthetase and the gamma-glutamyl hydrolase through a corresponding relation model of the methotrexate metabolism related enzyme content and the methotrexate metabolic rate parameter
Wherein the corresponding relation model of the content of the enzyme relevant to the methotrexate metabolism and the methotrexate metabolism rate parameter is constructed in the following way:
obtaining metabolic sample data of methotrexate, wherein the metabolic sample data comprises: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate, the content change time of intracellular compounds, the content of intracellular folate polyglutamic acid synthetase and the content of intracellular gamma-glutamyl hydrolase; obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content; performing correlation analysis treatment according to the conversion rate parameter, the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase to obtain the acting effect parameters of the content of the intracellular folate polyglutamate synthetase and the content of the intracellular gamma-glutamyl hydrolase on the conversion rate parameter; constructing a corresponding relation model of the content of the relevant enzyme of the methotrexate metabolism and the methotrexate metabolism rate parameter according to the content of intracellular folate polyglutamate synthetase and the action effect parameter of the content of intracellular gamma-glutamyl hydrolase on the conversion rate parameter;
the methotrexate intracellular metabolic dynamics model is constructed in the following way:
obtaining metabolic sample data of methotrexate, wherein the metabolic sample data comprises: the content of intracellular methotrexate, the content of intracellular polyglutamic acid methotrexate and the content change time of intracellular compounds; obtaining the conversion rate parameters of the methotrexate and the polyglutamic acid methotrexate according to the intracellular methotrexate content, the intracellular compound content change time and the intracellular polyglutamic acid methotrexate content; and (3) constructing a methotrexate intracellular metabolic kinetic model according to the conversion rate parameters of methotrexate and polyglutamate methotrexate.
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