A method for establishing a PK-PD model of multi-class cardiac effect components of a traditional Chinese medicine compound

Abstract

The application discloses a method for establishing a traditional Chinese medicine compound multi-class cardiac effect component integrated PK-PD model. The method comprises the following steps: establishing a PK-PD model of each cardiac effect component monomer; classifying the components according to the chemical structure type and the pharmacokinetic behavior characteristics; classifying the components with similar structures by using a weight coefficient method for intra-class integration, and independently modeling the components with special pharmacokinetic behaviors; and establishing the integrated PK-PD model based on the combined drug concentration and the monomer model calculation and prediction of the pharmacodynamic effect and accumulation. Through the hierarchical integration strategy, the application effectively solves the problem that the contribution of a high-efficiency low-exposure component is covered due to the simple weighted summation of the prior art, realizes accurate characterization of the synergistic effect of the multi-class components of the traditional Chinese medicine compound, significantly improves the overall pharmacodynamic prediction accuracy, and can be used for explaining the prescription principle and guiding clinical rational drug use.

Description

Technical Field

[0001] This invention relates to the field of medical and health technology, specifically to a method for establishing a PK-PD model integrating multiple cardiotonic components of a traditional Chinese medicine compound. Background Technology

[0002] Pharmacokinetic-pharmacodynamic (PK-PD) combined models are effective tools for studying the quantitative relationship between dose and drug effect, providing a scientific basis for elucidating drug action mechanisms and guiding rational drug use in clinical practice. For complex traditional Chinese medicine compound formulas, establishing multi-component integrated PK-PD models has become an important direction in traditional Chinese medicine pharmacology research in recent years.

[0003] Currently, there are several studies on the establishment of pharmacokinetic-pharmacodynamic (PK-PD) models for multiple components of traditional Chinese medicine (TCM). For example, Chinese invention patent CN101046831A discloses a method for constructing, calculating, and fitting a mathematical model of pharmacokinetic-pharmacodynamic combination for multiple components of TCM. This method uses the area under the effect curve (AUC) of each effective component as a weighting coefficient to calculate the comprehensive pharmacokinetic parameters and fit the overall PK-PD model. This method provides a way for multi-component PK-PD research of TCM compound preparations without prior determination of the bioavailability of each component. However, its weight determination is mainly based on the area under the effect duration, which does not adequately consider the differences in structural types and pharmacokinetic characteristics among multiple components.

[0004] Chinese invention patent CN117497202A proposes a weighted integration pharmacokinetic (PK) method for multi-component integration of traditional Chinese medicine cardiovascular formulas to assess their anti-myocardial ischemia (anti-MI) effects. This method uses the reciprocal of the minimum effective dose for each effector's anti-MI effect as a weighting coefficient, incorporating pharmacodynamic intensity information into the integration weights. While this method improves upon weighting based solely on AUC, its weighting design primarily targets a specific pharmacodynamic effect (anti-MI), and it lacks a hierarchical integration mechanism that considers the pharmacokinetic characteristics of the components themselves when dealing with multiple components from different sources and with significantly different structural types within the same formula.

[0005] Chinese invention patent CN117334261A discloses a method for establishing an overall pharmacokinetic-pharmacodynamic (PK-PD) model for multiple cardiotonic components. This method involves simultaneous collection of blood samples and pharmacodynamic indicators, establishing PK-PD models for each individual component, and then utilizing integrated pharmacokinetic principles based on AUC. 0-∞A custom weighting coefficient is used to sum the blood drug concentrations of each component, and then these sums are added to the respective pharmacodynamic model formulas to predict the overall efficacy. However, this method uses a uniform AUC weight to weight and integrate all components, failing to fully consider the significant differences in in vivo exposure levels, retention times, and potency of active ingredients with different chemical structures (such as steroidal cardiac glycosides, alkaloids, and triterpenoid saponins) in traditional Chinese medicine compound formulas. This simple weighted summation strategy may mask the important contribution of high-potency, low-exposure components (such as alkaloids) to the overall efficacy, making it difficult to accurately describe the synergistic effects between different categories of components, thus limiting the model's accuracy in predicting the overall efficacy of the compound formula and its ability to analyze the contributions of different components.

[0006] Qili Qiangxin Capsules are a widely used traditional Chinese medicine compound preparation for the treatment of heart failure. Its cardiotonic effect is contributed by a variety of active ingredients with different structural types. Currently, there is a lack of a method to establish an integrated PK-PD model that reflects the differences and synergistic effects among these multi-chemically structured cardiotonic components. Therefore, developing an integrated PK-PD model applicable to multiple cardiotonic components in traditional Chinese medicine compound preparations is of great significance for elucidating the material basis of compound drug efficacy, improving the accuracy of efficacy prediction, and guiding rational drug use in clinical practice. Summary of the Invention

[0007] To address the aforementioned shortcomings in the existing technology, the present invention aims to provide a method for establishing an integrated PK-PD model of multiple cardiotonic components in traditional Chinese medicine compound formulas. This method performs hierarchical integrated modeling based on the chemical structure type and pharmacokinetic characteristics of the active ingredients, thereby achieving an accurate description of the overall exposure-effect relationship and efficacy prediction of multiple cardiotonic components in traditional Chinese medicine compound formulas.

[0008] To achieve the above-mentioned objectives, the technical solution adopted by this invention is as follows: A method for establishing an integrated PK-PD model of multiple cardiotonic components in traditional Chinese medicine compound prescriptions is provided, comprising the following steps: (1) Establish PK-PD model of each cardiotonic component monomer: Each cardiotonic component monomer was given to the experimental subjects, and blood drug concentration data and pharmacodynamic index data were collected at different time points to establish a quantitative relationship model between blood drug concentration and pharmacodynamics of each monomer component. (2) Obtain pharmacokinetic data after combined administration: Mix multiple cardiotonic components in proportion and administer them to the experimental subjects, and collect blood drug concentration data at different time points; (3) Determine the integration strategy: Based on the chemical structure type and / or pharmacokinetic behavior characteristics of each cardiotonic component, classify multiple cardiotonic components into at least two categories; for component categories with the same structural type or similar pharmacokinetic behavior, use the weighting coefficient method for intra-class integration; for components with significant differences in pharmacokinetic behavior or special pharmacodynamic contribution characteristics, model them independently. (4) Establish an integrated PK-PD prediction model: Based on the integration strategy determined in step (3), the blood drug concentration data after combined administration obtained in step (2) and the single PK-PD model established in step (1) are used to calculate the predicted efficacy of each component and sum all the predicted efficacy to obtain the overall predicted efficacy, thereby establishing an integrated PK-PD model.

[0009] Preferably, the structural types described in step (3) include glycosides, alkaloids and triterpenoid saponins.

[0010] Preferably, the integration strategy described in step (3) is as follows: classify the glycosides into one category and use the weighting coefficient method for intra-category integration; and model the alkaloids and triterpenoid saponins independently.

[0011] Preferably, the weighting coefficient method described in step (3) specifically involves calculating the area under the pharmacokinetic curve (AUC) of each component in this class of components. 0-∞ This category accounts for the total AUC of the components. 0-∞ The proportion of each component is used as the weighting coefficient of each component; the weighting coefficient of each component is multiplied by its blood drug concentration at each time point after combined administration to obtain the weighted integrated blood drug concentration of that type of component.

[0012] Preferably, the quantitative relationship model described in step (1) is an S-type E max The model and formula are as follows: Where E is the rate of change of the efficacy index relative to the baseline, E max C represents the maximum effect value; C is the blood drug concentration at a certain time; EC is the maximum effect value. 50 The blood drug concentration at which half of the maximum effect is achieved; γ is the Hill coefficient.

[0013] Preferably, the pharmacodynamic parameters in step (1) include left ventricular systolic pressure (LVSP) and left ventricular diastolic pressure (LVDP).

[0014] Preferably, the traditional Chinese medicine compound is Qili Qiangxin Capsules, and the cardiotonic components include cypermethrin, cypermethrin derivative, cypermethrin N, cypermethrin M, aconitine, and astragaloside A.

[0015] Preferably, the integration strategy specifically involves: treating aliquots, aliquots glycosides, aliquots aglycone, aliquots N, and aliquots M as aliquots, and using AUC...0-∞ A custom weighting coefficient method was used for intra-class integration; aconitine and astragaloside A were modeled independently.

[0016] The beneficial effects of this invention are as follows: 1. This invention classifies components according to structural type (e.g., glycosides, alkaloids, saponins), and integrates groups with similar structures and pharmacokinetic behaviors (e.g., glycosides) within each group, simplifying the model while reflecting their overall contribution. Components with significantly different pharmacokinetic or pharmacodynamic characteristics (e.g., aconitine, astragaloside A) are modeled independently. This strategy of classification and integration combined with independent modeling better aligns with the scientific concept of synergistic effects of multiple components and targets in traditional Chinese medicine compound formulas, achieving precise characterization of the differences and synergistic effects of different categories of components.

[0017] 2. This invention provides a complete technical solution from monomeric PK-PD modeling, component classification, integrated weight determination to overall model establishment and verification. This method is not only applicable to Qili Qiangxin Capsules, but can also provide a methodological reference for integrated PK-PD modeling of other traditional Chinese medicine compound formulas, effective parts and compatibility preparations with multiple cardiotonic components or similar complex component systems. It helps to elucidate the pharmacodynamic material basis of traditional Chinese medicine and guide the optimization of clinical dosing regimens. Attached Figure Description

[0018] Figure 1 This is a three-dimensional relationship diagram of the time-mean blood drug concentration-mean efficacy index of the seven cardiotonic components in the embodiments of the present invention; Figure 2 This is the pharmacokinetic curve of the combined intravenous administration of the seven cardiotonic components of QLQX in this embodiment of the invention; Figure 3 This is a fitted curve of the measured effect and the predicted effect in rats after combined intravenous administration in an embodiment of the present invention; Figure 4 This is a fitted curve of the measured effect and the predicted effect in rats after combined intravenous administration in the comparative example of this invention. Detailed Implementation

[0019] The specific embodiments of the present invention are described below to enable those skilled in the art to understand the present invention. However, it should be understood that the present invention is not limited to the scope of the specific embodiments. For those skilled in the art, various changes are obvious as long as they are within the spirit and scope of the present invention as defined and determined by the appended claims. All inventions utilizing the concept of the present invention are protected.

[0020] Example Animal experiments on intravenous administration of the cardiotonic component of 1 Qili Qiangxin Capsules (QLQX) Sixty-three male SD rats (weighing 320–360 g) were randomly divided into seven groups: an intravenous bolus injection group of aconitine, aconitine aglycone, astragaloside A, aconitine N, aconitine glycoside II, and aconitine M, and an intravenous infusion group of aconitine. The dosages for each group were 0.5 mg / kg, 0.5 mg / kg, 2 mg / kg, 1 mg / kg, 0.4 mg / kg, 1.5 mg / kg, and 0.015 mg / kg, respectively. The bolus injection volume was 2 mL / kg, the infusion rate was 4 mL / h, and the infusion time was 0.075 h / kg. The rats were first injected intraperitoneally with 45 mg / kg of 2% sodium pentobarbital solution. After the righting reflex disappeared, subsequent procedures were performed.

[0021] The first step is endotracheal intubation to ensure unobstructed breathing in the rats during the experiment and reduce the risk of death. The second step is jugular vein cannulation for timely blood collection from the rats. The third step is left ventricular cannulation, connected to a pressure sensor, for collecting drug efficacy indicators in the rats using the MadLab bioinformatics medical signal acquisition and processing system. The fourth step is left femoral vein cannulation, connected to an infusion pump for model establishment, used to intravenously inject the model-inducing drug verapamil into the rats. The fifth step is exposing the right femoral vein before drug administration to facilitate intravenous injection of cardiotonic drugs after model establishment. The sixth step involved collecting blood samples from the jugular vein into heparin sodium centrifuge tubes at time points 5 min, 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, and 4 h after drug administration (for guanosine M, at 2 min, 5 min, 10 min, 15 min, 30 min, 45 min, and 1 h after administration; and for aconitine, at 2 min, 7 min, 15 min, 30 min, 1 h, 2 h, 3 h, and 4 h after intravenous infusion). Pharmacodynamic parameters, including LVDP and LVSP, were collected simultaneously. After biological sample pretreatment, the blood drug concentrations at each time point were determined using liquid chromatography-mass spectrometry (LC-MS / MS). A temperature-controlled heating pad was used throughout the experiment to maintain a constant body temperature in the rats, and respiratory rate was monitored.

[0022] 2. Animal experiments on the combined intravenous administration of the cardiotonic component of QLQX Ten male SD rats (weighing 320-360 g) were anesthetized by intraperitoneal injection of 2% sodium pentobarbital solution. The experimental procedure was performed according to the above-mentioned procedure. The dosage of the seven components was 0.5 μmol / kg, except for aconitine, which was 5 nmol / kg. Blood was collected from the jugular vein into heparin sodium anticoagulant tubes at 5 min, 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, and 4 h after administration, and pharmacodynamic parameters were collected at the same time.

[0023] 3. A method for determining the content of seven cardiotonic components in Qili Qiangxin Capsules using liquid chromatography-mass spectrometry (LC-MS / MS). 3.1 Experimental Apparatus Quantitative analysis was performed using an ultra-high performance liquid chromatography-tandem mass spectrometer (UPLC-MS / MS): AcQuity, manufactured by Waters Corporation, USA. TM The UPLC series liquid chromatograph is connected in series with an AB Sciex API 5500 Qtrap mass spectrometer. The chromatography system software is Empower 3.0, and the mass spectrometry system software is Analyst 1.6.3. Other equipment includes a Thermo Fisher benchtop centrifuge (Germany); a -70 °C ultra-low temperature freezer (Haier, China); a nitrogen dryer (Techne, USA); a KQ-300B ultrasonic cleaner (Kunshan Ultrasonic Instrument Co., Ltd.); and a CV200 vacuum centrifuge concentrator (Beijing Jiam Technology Co., Ltd.).

[0024] 3.2 Sample Pretreatment Accurately pipette 50 μL of rat plasma, add 150 μL of acetonitrile (IS 0.5 ng / mL), vortex at 1500 rpm for 5 min, sonicate in an ice-water bath for 10 min, centrifuge at 12000 rpm for 5 min at 4 ℃, and collect 150 μL of the supernatant. Concentrate to dryness by vacuum centrifugation at 37 ℃. Reconstitute the dried product with 50 μL of 30% acetonitrile, vortex at 1500 rpm for 5 min, sonicate in an ice-water bath for 5 min, centrifuge at 12000 rpm for 5 min at 4 ℃, and inject the supernatant for analysis.

[0025] 3.3 Preparation of Standard Curve Samples Take 45 μL of blank plasma and add 5 μL of a series of 10× standard curve working solutions. Vortex at 1500 rpm for 30 s to mix, obtaining standard curve samples with concentrations ranging from 1 to 1000 ng / mL for astragaloside A; 0.5 to 500 ng / mL for aconitine, aconitine N, and aconitine M; 0.2 to 200 ng / mL for aconitine aglycone and aconitine glycoside II; and 0.02 to 20 ng / mL for aconitine. The subsequent processing of the standard curve samples and quality control samples is the same as described in section “3.2”.

[0026] 3.4 Analysis Conditions 3.4.1 Chromatographic conditions An ACQUITY UPLC® HSS T3 column (1.8 μm particle size, 100 mm × 2.1 mm) was used at a column temperature of 40 ℃, with an injection volume of 5 μL. The mobile phase consisted of water-0.1% formic acid-0.1 mM ammonium formate (A) and acetonitrile-0.1% formic acid (B), and the gradient elution program is shown in Table 1.

[0027] Table 1 Liquid phase elution program 3.4.2 Mass Spectrometry Conditions Mass spectrometry analysis was performed using an ESI source in positive ion multiple reaction monitoring (MRM) mode. The mass spectrometry detection parameters for each compound are shown in Table 2. Ion source parameters were set as follows: temperature, 500°C; gas 1 and gas 2, 50 psi; curtain gas, 35 psi; spray voltage, 5500 V; collision gas: Medium; inlet potential: 10 V; collision cell outlet potential: 14 V.

[0028] Table 2 Mass spectrometry detection conditions for analytes and IS 3.5 Data Analysis The calculation of pharmacokinetic parameters and the construction of the PK-PD model were performed using Phoenix. ® WinNonlin ® Software (USA).

[0029] 4. Establishment of the PK-PD model of the cardiotonic component of QLQX The three-dimensional relationship between "time-mean blood drug concentration-mean efficacy index" of the seven cardiotonic components in QLQX is shown in the figure. Figure 1 In this figure, the X-axis represents time, the Y-axis represents the mean blood drug concentration, and the Z-axis represents the mean efficacy index. The bottom is the drug-time curve, the left side is the concentration-effect curve, and the back side is the time-effect curve. The three-dimensional curves represent the relationship between the three, reflecting a dynamic correlation. The filled area is only for visualization and has no actual quantitative significance. As can be seen from the figure, in rats with heart failure, the efficacy indices decrease as the blood concentration of each drug component decreases.

[0030] In this study, the change in efficacy index at each time point after drug administration relative to the time of modeling was used as the evaluation index. That is, the percentage was calculated by the ratio of the difference between the two to the index at the time of modeling, and defined as the efficacy variable E used for fitting, as shown in formula (1).

[0031] (1) E in the formula t E represents the efficacy indicators at various time points after drug administration. m These are indicators used during modeling.

[0032] Since the efficacy indicators were collected simultaneously with the plasma samples, no phenomenon was observed where the change in efficacy lagged behind the blood drug concentration. Therefore, the PK-PD direct connection model was used to mathematically describe the relationship between blood drug concentration C and efficacy E. After repeated comparisons of various models, the S-type Emax model was finally selected for fitting, as shown in formula (2).

[0033] (2) In the formula, E is the pharmacodynamic variable defined by "Formula (1)"; E max C represents the maximum effect value; C is the blood drug concentration at a certain time; EC is the maximum effect value. 50 The blood drug concentration at which half of the maximum effect is achieved; γ is the Hill coefficient, used to describe the steepness of the concentration-response curve.

[0034] After organizing the relevant data such as time, C, and E, the data were imported into the software for fitting to construct a monomeric PK-PD model. The Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC) displayed on the software results page were used as the main criteria for model selection. The model with lower values ​​for both criteria was selected as the better fit model. Simultaneously, the parallelism between the curves in the residual plot and the x-axis was observed. Model analysis results showed that, except for aconitine, which is a one-compartment model, the pharmacokinetic processes of the other components were more suitable for a two-compartment model. In terms of pharmacodynamics, each component was described using an S-type Emax model, and then jointly fitted with the corresponding pharmacokinetic model. The resulting parameters are shown in Table 3. Parameter comparison showed that aconitine had the lowest EC50 value, indicating a relatively strong binding ability to the receptor mediating cardiotonic effects.

[0035] Table 3. Mean parameters of the PK-PD model for the 7 cardiotonic components of QLQX 5. Pharmacokinetic and pharmacodynamic studies of the cardiotonic component of QLQX combined with intravenous administration The pharmacokinetic results of the combined intravenous administration of the seven cardiotonic components of QLQX are shown in Table 4 and... Figure 2 .

[0036] Table 4. Pharmacokinetic parameters of the combined administration of the seven cardiotonic components of QLQX (Mean ± SEM, n = 10) Based on the identified seven cardiotonic components, a hierarchical integrated model was constructed, considering their structural types and in vivo pharmacokinetic characteristics. Specifically, the components were divided into three categories: first, aconitine-derived glycosides (aconitine, aconitine derivative, aconitine N, and aconitine M); second, aconitine-derived alkaloids from Aconitum carmichaelii; and third, astragaloside A, a triterpenoid saponin. Among these, five aconitine-derived components exhibited similar structures, all belonging to steroidal cardiotonic glycosides or their related derivatives, possessing similar targets and mechanisms of action, and demonstrating moderate exposure levels, rapid elimination, and rapid onset of action. To reduce the complexity of multi-parameter modeling and reflect their overall synergistic contribution, AUC was used. 0-∞A custom weighting coefficient method was used to integrate the five aconitine derivatives. Although aconitine has a low in vivo exposure level, its relatively long in vivo retention time and clear positive inotropic effect were modeled separately to reflect its high potency and low exposure characteristics. Astragaloside A had the highest exposure level and a relatively long half-life, but mainly exerted a regulatory or synergistic effect; therefore, it was also independently included in the integrated model. AUC 0-∞ The custom weighting method, specifically, uses the AUC of each component... 0-∞ This category accounts for the total AUC of the components. 0-∞ The proportion is used as the weighting coefficient, and the coefficient is multiplied by the blood drug concentration at the corresponding time point to calculate the weighted integrated blood drug concentration of each component, as shown in formula (3) and formula (4).

[0037] (3) in i These represent five different salicylates; The AUC of five salicylic acid components 0-∞ The sum of; W i Indicate the AUC of each component 0-∞ Total AUC of glycosides 0-∞ The ratio, i.e., AUC 0-∞ Custom weighting coefficients.

[0038] (4) In the formula Ci t The blood drug concentrations of the five salicylates at different time points represent the drug concentrations of each of the five salicylates. W i For AUC 0-∞ Custom weighting coefficients Ci r The weighted integrated blood drug concentrations of the five salicylates are given.

[0039] After calculating the weighted integrated blood drug concentration of each component, it was substituted into the single-component PK-PD model formula to obtain the integrated predicted efficacy values ​​of the five cardiotonic glycosides. At the same time, the blood drug concentrations of aconitine and astragaloside A were substituted into their respective PK-PD models to obtain the corresponding predicted efficacy values. Then, the predicted efficacy values ​​of the above seven components were accumulated to obtain the integrated predicted efficacy of the seven cardiotonic components as a whole, which was then compared with the measured efficacy to observe whether the model was successful, as shown in formula (5).

[0040] (5) Where E pPredicted efficacy at various time points; 1-7 represent aconitine, aconitine derivative, aconitine N, aconitine M, aconitine and astragaloside A, respectively; E max EC 50 γ and γ are the parameter values ​​of each individual model, as shown in Table 3; C r C6 represents the weighted integrated blood concentration of aconitine; C7 represents the measured blood concentration of astragaloside A.

[0041] Based on the above model equations, the efficacy at each time point after combined administration was predicted, and compared with the measured results. The results are shown in Table 5. Figure 3 As shown in the charts, the overall trend of the efficacy prediction curves for combined intravenous administration is basically consistent with the measured curves, both gradually decreasing with the extension of time after administration. For LVSP and LVDP, there is good consistency between the model predictions and measured values. Except for the first two sampling time points where the deviation is relatively large, the prediction results at the other time points are basically consistent with the measured data.

[0042] Table 5 Measured and predicted effects of combined intravenous administration in rats (Mean ± SEM, n = 10) Comparative Example: Existing Unified Weighted Integration Strategy To verify the superiority of the layered integration strategy of this invention, the unified AUC in the prior art (such as publication number CN117334261A) is adopted. 0-∞ A comparative model was established using a custom weighting coefficient method. Specifically, without distinguishing between chemical structure types and pharmacokinetic characteristics, the seven cardiotonic components in QLQX (five glycosides, aconitine, and astragaloside A) were treated as a whole, and the AUC of each component was calculated. 0-∞ The total AUC of the 7 components 0-∞ The proportions are used as a unified weighting coefficient. The weight of each component is multiplied by its combined blood drug concentration to obtain the weighted integrated blood drug concentration, which is then substituted into its respective S-type E. max The model formula incorporates predictions of overall drug efficacy. Results are shown in Table 6 and... Figure 4 .

[0043] Table 6. Measured and predicted effects of combined intravenous administration in rats (Mean ± SEM, n = 10) The comparative results show that the unified AUC in the existing technology... 0-∞The custom weighting coefficient method was used to construct an integrated PK-PD model, but the predicted values ​​of each pharmacodynamic index differed significantly from the measured values, making it impossible to accurately predict the cardiotonic effect of QLQX. In contrast, the model constructed by hierarchically integrating the structural types and pharmacokinetic characteristics of each component in this embodiment of the invention has a more accurate prediction effect.

[0044] This invention is not limited to the specific embodiments described above. Without departing from the concept of this invention, those skilled in the art can use the following alternative technical solutions to achieve the same or similar inventive objectives.

[0045] (1) Alternatives to efficacy indicators In this embodiment of the invention, left ventricular systolic pressure (LVSP) and left ventricular diastolic pressure (LVDP) are used as pharmacodynamic evaluation indicators. As an alternative, other pharmacodynamic indicators that can reflect the improvement of cardiac function can also be selected, and each indicator can be used alone or in combination to establish an integrated PK-PD model.

[0046] (2) Alternative methods for blood drug concentration detection This invention uses UPLC-MS / MS to determine the blood concentrations of various cardiotonic components. Alternatively, other analytical methods capable of accurately determining the in vivo exposure levels of the target components can be used. In addition to plasma, the test samples can also include whole blood, serum, tissue homogenate, microdialysis fluid, or other biological samples.

[0047] (3) Alternatives to the PK model This invention uses a compartmental model to establish a single-component PK model. Alternatively, different components can be combined using different PK models to establish an integrated model.

[0048] (4) Alternatives to the PD model This invention adopts S-type E max The model can also be implemented using E. max Different PD models can be used for different components, including effect-room models, indirect response models, and artificial intelligence or machine learning pharmacodynamic prediction models.

[0049] (5) Alternatives to the integration strategy The integration process can be carried out in different ways depending on different research objectives, including but not limited to: integration by chemical structure type; integration by pharmacological mechanism of action; integration by pharmacokinetic characteristics; integration by tissue exposure characteristics; integration by efficacy contribution; integration by network pharmacology targets; weighting by PK or PD parameters; weighting by efficacy intensity; and integration by comprehensive weight. The above integration methods can be used individually or in combination.

[0050] (8) Applicable alternative solutions This invention focuses on Qili Qiangxin Capsules. As an alternative, the method established in this invention is also applicable to: other traditional Chinese medicine compound formulas with cardiotonic effects; multi-component natural drugs; effective parts of traditional Chinese medicine; traditional Chinese medicine compatibility systems; multi-active ingredient combined preparations; and other compound preparations requiring the establishment of an integrated PK-PD model.

[0051] The above alternatives can be used individually or combined in any way to form new implementation methods. As long as multiple active ingredients are integrated to establish a PK-PD model and achieve overall efficacy prediction and evaluation, they all fall within the protection scope of this invention.

[0052] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

Claims

1. A method for establishing a PK-PD model integrating multiple cardiotonic components of a traditional Chinese medicine compound, characterized in that, Includes the following steps: (1) Establish PK-PD model of each cardiotonic component monomer: Each cardiotonic component monomer was given to the experimental subjects, and blood drug concentration data and pharmacodynamic index data were collected at different time points to establish a quantitative relationship model between blood drug concentration and pharmacodynamics of each monomer component. (2) Obtain pharmacokinetic data after combined administration: Mix multiple cardiotonic components in proportion and administer them to the experimental subjects, and collect blood drug concentration data at different time points; (3) Determine the integration strategy: Based on the chemical structure type and / or pharmacokinetic behavior characteristics of each cardiotonic component, classify multiple cardiotonic components into at least two categories; for component categories with the same structural type or similar pharmacokinetic behavior, use the weighting coefficient method for intra-class integration; for components with significant differences in pharmacokinetic behavior or special pharmacodynamic contribution characteristics, model them independently. (4) Establish an integrated PK-PD prediction model: Based on the integration strategy determined in step (3), the blood drug concentration data after combined administration obtained in step (2) and the single PK-PD model established in step (1) are used to calculate the predicted efficacy of each component and sum all the predicted efficacy to obtain the overall predicted efficacy, thereby establishing an integrated PK-PD model.

2. The method according to claim 1, characterized in that, The structural types mentioned in step (3) include glycosides, alkaloids and triterpenoid saponins.

3. The method according to claim 2, characterized in that, The integration strategy described in step (3) is as follows: classify the glycosides into one category and use the weighting coefficient method for intra-class integration; model the alkaloids and triterpenoid saponins containing a major pharmacological component independently.

4. The method according to claim 1, characterized in that, The weighting coefficient method described in step (3) specifically involves calculating the area under the pharmacokinetic curve (AUC) of each component in this class of components. 0-∞ This category accounts for the total AUC of the components. 0-∞ The proportion of each component is used as the weighting coefficient of each component; the weighting coefficient of each component is multiplied by its blood drug concentration at each time point after combined administration to obtain the weighted integrated blood drug concentration of that type of component.

5. The method according to claim 1, characterized in that, The quantitative relationship model described in step (1) is an S-type E max The model and formula are as follows: ; Where E is the rate of change of the efficacy index relative to the baseline, E max C represents the maximum effect value; C is the blood drug concentration at a certain time; EC is the maximum effect value. 50 The blood drug concentration at which half of the maximum effect is achieved; γ is the Hill coefficient.

6. The method according to claim 1, characterized in that, The pharmacodynamic parameters mentioned in step (1) include left ventricular systolic pressure (LVSP) and left ventricular diastolic pressure (LVDP).

7. The method according to claim 1, characterized in that, The traditional Chinese medicine compound is Qili Qiangxin Capsules, and the cardiotonic components include cypermethrin, cypermethrin derivative, cypermethrin N, cypermethrin M, aconitine, and astragaloside A.

8. The method according to claim 7, characterized in that, The integration strategy specifically involves treating salicylindrica glycoside, salicylindane, salicylinogen, salicylindrica N, and salicylindrica M as salicylindrica glycosides and using AUC... 0-∞ A custom weighting coefficient method was used for intra-class integration; aconitine and astragaloside A were modeled independently.

9. The application of the method according to any one of claims 1-8 in the preparation of software or reagent kits for predicting the overall cardiotonic efficacy of traditional Chinese medicine compound formulas.

10. The application according to claim 9, characterized in that, The aforementioned traditional Chinese medicine compound is a cardiovascular treatment drug containing multiple cardiotonic components.

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