Two-drug combination in-vitro pharmacokinetics / pharmacodynamics simulation system
By designing a two-drug combined with in vitro pharmacokinetic/pharmacodynamic simulation system including a central chamber and two dosing tanks, the problem of difficulty in simulating the pharmacokinetic and pharmacodynamic processes in the combination of antibacterial drugs is solved in the prior art, and the precise simulation and bactericidal effect of drug concentration changes are achieved.
Patent Information
- Application Number
- CN202411739352.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-29
- Publication Date
- 2025-03-21
AI Technical Summary
The prior art is difficult to accurately simulate the pharmacokinetic and pharmacodynamic processes when two antibacterial drugs are used in combination, especially complex changes in the stages of rising drug concentration and elimination.
A two-drug combined with in vitro pharmacokinetics/pharmacodynamics simulation system is designed, including a central chamber and two dosing tanks, to control the change of drug concentration through an infusion pump, simulate the increase and elimination process of drug concentration in the body.
In vitro pharmacokinetic/pharmacodynamic simulation of the combination of two antibacterial drugs is achieved, which can accurately simulate the changes in drug concentration, help study the bactericidal effects of antibacterial drugs and optimize the dosing regimen.
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Figure CN119662367A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of in vitro pharmacodynamics of antibacterial drugs, and particularly relates to an in vitro pharmacokinetic / pharmacodynamic simulation system of two drugs combined. Background Art
[0002] With the continuous development of pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial drugs, PK / PD research plays an increasingly important role in the pharmacodynamic evaluation of antimicrobial drugs, the formulation and optimization of dosing regimens, and the reduction of bacterial resistance. At present, there are many in vitro PK / PD research methods for antimicrobial drugs. In addition to the traditional in vitro pharmacodynamic research methods of antimicrobial drugs (minimum inhibitory concentration determination, static bactericidal curve, etc.), in vitro PK / PD models are also developing. The in vitro PK / PD model of antimicrobial drugs refers to a method that uses in vitro devices to simulate the pharmacokinetic process of antimicrobial drugs in the human body and study the changes in its efficacy in this process; compared with the traditional in vitro pharmacodynamic research method of antimicrobial drugs, the biggest difference between this method and the traditional in vitro pharmacodynamic research method of antimicrobial drugs is that its drug concentration changes according to the pharmacokinetic law of the human body, rather than a constant concentration, which is more in line with the situation of the drug in the human body and can be maintained for 72 hours; at the same time, a single or multi-stage flow rate can be set, which is highly controllable and can fully simulate the single-chamber or multi-chamber pharmacokinetic behavior process of the human body.
[0003] Conventional PK / PD studies are usually only applied to the metabolic kinetics and pharmacodynamics of a single antibacterial drug. However, with the development of medical technology, combined drug use, such as two-drug antibacterial combination, is becoming more and more common. Correspondingly, the metabolic kinetics and pharmacodynamics of two-drug combination also require a simulation system to confirm the antibacterial efficacy of the two-drug combination. When a single drug is infused, there is only one drug in the dosing tank. Correspondingly, when combined, there are two drugs in the dosing tank. However, the two drugs in combination may not reach peak concentration at the same time, and the concentrations of the two drugs rise at different rates, and there may not be a certain linear relationship. Therefore, it is difficult to accurately simulate the actual concentration change process of the two drugs with only one dosing tank containing two drugs. There is another method to add two antibacterial drugs to two dosing tanks separately. Not only does it require more infusion pumps to control the concentrations of different dosing tanks separately, but its simulation method is inconsistent with the single drug simulation method. Because the pharmacokinetic characteristics of the two drugs may be quite different in actual situations, the flow rate often produces difficult-to-achieve results, which is not conducive to simulating the drug concentration of combined drug use. Summary of the invention
[0004] The technical problem to be solved by the present invention is to provide an in vitro pharmacokinetic / pharmacodynamic simulation system for the combination of two drugs, so as to provide experimental support for the in vitro pharmacokinetic / pharmacodynamic simulation of the combination of two drugs.
[0005] The technical solution adopted by the present invention to solve the technical problem is: to provide a two-drug combined in vitro pharmacokinetic / pharmacodynamic simulation system, comprising a central chamber with a bacterial culture medium inside and two drug administration tanks, wherein the drug administration tanks are connected to the central chamber through a liquid path provided with an infusion pump, and a waste liquid pipe is connected below the central chamber, and the waste liquid pipe is used to keep the liquid volume in the central chamber unchanged. The method for using the two-drug combined in vitro pharmacokinetic / pharmacodynamic model system comprises the following steps:
[0006] S1: inoculating the study bacteria on the bacterial culture medium in the central chamber;
[0007] S2: Simulating the rising drug concentration stage, adding antimicrobial drugs to the culture medium of the dosing tank according to the antimicrobial drug simulation requirements, starting the infusion pump according to the designed flow rate to make the two dosing tanks continuously infuse into the central chamber, and at the same time, the waste pipe discharges an equal amount of liquid to simulate the rising drug concentration during oral medication or intravenous infusion;
[0008] S3: Simulating drug concentration elimination stage, changing the content of the medication tank according to the drug concentration change simulation requirements, keeping the infusion pump started according to the designed flow rate 2 so that the two medication tanks continue to infuse into the central chamber, and at the same time, the waste pipe discharges an equal amount of liquid;
[0009] S4: Use the drug concentration data obtained clinically or calculated by pharmacokinetic methods as the concentration relationship between the two antibiotics at different times. At the same time, observe the changes in the number of bacteria in the central chamber at different times, correspond the changes in the number of bacteria to the concentration relationship of the antibiotics, and record and study the bactericidal effects of antibiotics when simulating concentration changes in vivo.
[0010] In S2, the antimicrobial drug simulation requirements include: using clinically obtained drug concentration data or drug concentration data calculated by pharmacokinetic methods as drug target concentration data in the central chamber, adding two different antimicrobial drugs to two dosing tanks respectively, or adding two different antimicrobial drugs to two dosing tanks at the same time.
[0011] In S3, the drug concentration change simulation requirements include: using clinically obtained drug concentration data or drug concentration data calculated by pharmacokinetic methods as the drug target concentration data in the central chamber, and continuously infusing into the central chamber from two dosing tanks at the same time, but replacing the culture medium in one of the dosing tanks with a drug-free culture medium to simulate the continuous increase in the concentration of a single drug of the two drugs and the beginning of elimination of the other drug concentration, or, replacing the culture medium in both dosing tanks with a drug-free culture medium to simulate the simultaneous elimination of the two drugs in the body after reaching peak concentrations.
[0012] Preferably, the central chamber is arranged on a magnetic stirrer, and a stirring bar matching the magnetic stirrer is arranged inside the central chamber.
[0013] Preferably, a sampler is provided on the central chamber.
[0014] Preferably, in S2, when the medication tank contains two antibacterial drugs, the drug with the fastest rising speed of drug concentration is drug A, and the other is drug B. When the drug target concentration meets In the case of (F2>0, F1>0), the design flow rate is:
[0015] Wherein, F1 is the flow rate of dosing tank 1; F2 is the flow rate of dosing tank 2; is the concentration of drug A at the current moment; is the concentration of drug B at the current moment; is the concentration of drug A at the previous moment; is the concentration of drug B at the previous moment; Δt is the time interval between moments i-1 and i; F B is the flow rate of drug B from the dosing tank to the central chamber when only a single drug is infused, and F B =F1+F2; V C is the volume of the central chamber; C B The concentration of drug B in the administration tank when only a single drug is infused; The concentration of drug A in the dosing tank 1 when only a single drug is infused; The concentration of drug A in dosing tank 2 when only a single drug is infused.
[0016] Preferably, in S3, when the dosing tank contains two antibacterial drugs, the drug A whose concentration continues to rise is drug A, and the drug B that begins to disappear is drug B. When the drug target concentration meets In the case of (F2>0, F1>0), the design flow rate 2 is:
[0017] Wherein, F1 is the flow rate of dosing tank 1; F2 is the flow rate of dosing tank 2; is the concentration of drug A at the current moment; is the concentration of drug B at the current moment; is the concentration of drug A at the previous moment; is the concentration of drug B at the previous moment; Δt is the time interval between moments i-1 and i; F B is the flow rate of drug B from the dosing tank to the central chamber when only a single drug is infused, and F B =F1+F2; V C is the volume of the central chamber; C BThe concentration of drug B in the administration tank when only a single drug is infused; The concentration of drug A in the dosing tank 1 when only a single drug is infused; The concentration of drug A in dosing tank 2 when only a single drug is infused.
[0018] Preferably, in S3, when the drug administration tanks are replaced with medium without drug, when the drug target concentration meets In the case of (F2>0, F1>0), the design flow rate 2 is:
[0019] Wherein, F1 is the flow rate of dosing tank 1; F2 is the flow rate of dosing tank 2; is the concentration of drug A at the current moment; is the concentration of drug B at the current moment; is the concentration of drug A at the previous moment; is the concentration of drug B at the previous moment; Δt is the time interval between moments i-1 and i; F B is the flow rate of drug B from the dosing tank to the central chamber when only a single drug is infused, and F B =F1+F2; V C is the volume of the central chamber; C B The concentration of drug B in the administration tank when only a single drug is infused; CA2 is the concentration of drug A in dosing tank 1 when only a single drug is infused; CA3 is the concentration of drug A in dosing tank 2 when only a single drug is infused.
[0020] Preferably, when the drug target concentration does not meet In the case of (F2>0, F1>0), according to
[0021] After calculation, it is found that F2>0, but F1<0, according to
[0022] Use the obtained F B After inferring the concentration, use univariate analysis or planning solution to obtain the optimal flow rate F, and set the design flow rates of the two dosing tanks to F as the common elimination phase flow rate of the two drugs.
[0023] The beneficial effect is that: this patent sets two dosing tanks, each containing two drugs. On the basis of traditional single dosing, an additional dosing tank is added to balance the difference in concentration changes of the two drugs, and the method is simple and easy to understand while realizing the in vitro simulation of the combination of two drugs. By controlling the flow rate of the infusion pump, the drug concentration in the central chamber is guaranteed to be consistent with the clinical drug concentration data or the concentration data calculated by the pharmacokinetic method. Then, by sampling or observing the change process of the number of bacteria in the central chamber at different times, the change process of the number of bacteria can be matched with the concentration relationship of the antibacterial drug, which is helpful to study the bactericidal effect of the combination of two antibacterial drugs when simulating the concentration change in vivo. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 This is a schematic diagram of the structure of a two-drug combined in vitro pharmacokinetic / pharmacodynamic simulation system.
[0025] Figure 2 Schematic diagram of the change of drug concentration of the combination of two drugs in vivo over time.
[0026] Figure 3 This is a schematic diagram of the drug concentration changes over time when the concentrations of two drugs are both in the rising phase.
[0027] Figure 4 This is a schematic diagram of the drug concentration changes over time when the concentration of drug A increases and the concentration of drug B decreases when two drugs are combined.
[0028] Figure 5 This is a schematic diagram of the drug concentration changes over time when the two drugs are combined and the concentrations of both drugs are eliminated.
[0029] Among them, 1-central chamber; 2-drug administration tank; 201-drug replenishment port; 3-liquid circuit; 4-infusion pump; 5-waste liquid pipe; 6-magnetic stirrer; 601-stirring bar; 7-sampler.
[0030] The same reference numerals in the various drawings represent the same components. DETAILED DESCRIPTION
[0031] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall within the scope limited by the appended claims of the application equally.
[0032] like Figure 1As shown, the present invention provides a two-drug combined in vitro pharmacokinetic / pharmacodynamic simulation system, comprising a central chamber 1 with a bacterial culture medium inside and two medication tanks 2, wherein the medication tanks 2 are connected to the central chamber 1 through a liquid path 3 with an infusion pump 4, and a waste liquid pipe 5 is connected below the central chamber 1, and the waste liquid pipe 5 is used to keep the liquid volume in the central chamber 1 unchanged. The central chamber 1 should be completely sealed except for the inlet and outlet to avoid affecting the simulation results.
[0033] In a specific embodiment, the central chamber 1 is arranged on the magnetic stirrer 6, and a stirring bar 601 matching the magnetic stirrer 6 is arranged inside the central chamber 1. During the experiment, the magnetic stirrer 6 is turned on, and the stirring bar 601 is located below the liquid surface of the bacterial culture medium. It rotates clockwise through the action of magnetic force, and the bacterial culture medium is continuously mixed, so that the bacteria are evenly distributed, which is convenient for accurate sampling and counting results.
[0034] In a specific embodiment, the central chamber 1 is provided with a sampler 7, which is usually a combination of a heparin cap and a needle. During the experiment, the needle is located below the liquid surface of the bacterial culture medium and is used to absorb liquid from the bacterial culture medium at the sampling time point and perform subsequent operations such as colony counting.
[0035] In order to study the bactericidal effect of antibacterial drugs when simulating changes in in vivo concentration, the method for using the two-drug combined in vitro pharmacokinetic / pharmacodynamic model system provided by the present invention comprises the following steps:
[0036] S1: inoculating the study bacteria on the bacterial culture medium in the central chamber;
[0037] S2: Simulating the rising drug concentration stage, adding antimicrobial drugs to the culture medium of the dosing tank according to the antimicrobial drug simulation requirements, starting the infusion pump according to the designed flow rate to make the two dosing tanks continuously infuse into the central chamber, and at the same time, the waste pipe discharges an equal amount of liquid to simulate the rising drug concentration during oral medication or intravenous infusion;
[0038] S3: Simulating drug concentration elimination stage, changing the content of the medication tank according to the drug concentration change simulation requirements, keeping the infusion pump started according to the designed flow rate 2 so that the two medication tanks continue to infuse into the central chamber, and at the same time, the waste pipe discharges an equal amount of liquid;
[0039] S4: Use clinically obtained drug concentration data or drug concentration data calculated by pharmacokinetic methods as the concentration relationship between the two antimicrobial drugs at different times (see Figure 2 ), and observe the changes in the number of bacteria in the central chamber at different times, correspond the changes in the number of bacteria to the concentration of antibiotics, and record and study the bactericidal effect of antibiotics when simulating changes in concentration in vivo.
[0040] In S2, the antimicrobial drug simulation requirements include: using clinically obtained drug concentration data or drug concentration data calculated by pharmacokinetic methods as drug target concentration data in the central chamber, adding two different antimicrobial drugs to two dosing tanks respectively, or adding two different antimicrobial drugs to two dosing tanks at the same time.
[0041] In S3, the drug concentration change simulation requirements include: using clinically obtained drug concentration data or drug concentration data calculated by pharmacokinetic methods as the drug target concentration data in the central chamber, and continuously infusing into the central chamber from two dosing tanks at the same time, but replacing the culture medium in one of the dosing tanks with a drug-free culture medium to simulate the continuous increase in the concentration of a single drug of the two drugs and the beginning of elimination of the other drug concentration, or, replacing the culture medium in both dosing tanks with a drug-free culture medium to simulate the simultaneous elimination of the two drugs in the body after reaching peak concentrations.
[0042] To simulate the process of drug concentration increase, assume that only the concentration change process of a single drug A or B in the central chamber is simulated. At this time, the dosing tank only has one drug A or B, and the concentration is C. A or C B , the second drug delivery tank is discarded, and the flow rate from the drug delivery tank 1 to the central chamber is F A or F B If we simulate the concentration change process of two drugs A and B in the central chamber, where both the dosing tank 1 and the dosing tank 2 contain two drugs A and B, then the concentrations are The flow rates of R1 and R2 pumped into the central chamber are F1 and F2 respectively. The volume of liquid in the central chamber is V C At the beginning of the experiment, a fixed Vc is set using the following formula: F1 and F2 simulate the expected concentration changes of the drug in the body.
[0043] (a) If Figure 3 As shown, in S2, when the medication tank contains two antibacterial drugs, the drug with the fastest rising speed of drug concentration is drug A, and the other is drug B. When the drug target concentration meets In the case of, the design flow rate is: F2>0, F1>0.
[0044] Wherein, F1 is the flow rate of dosing tank 1; F2 is the flow rate of dosing tank 2; is the concentration of drug A at the current moment; is the concentration of drug B at the current moment; is the concentration of drug A at the previous moment; is the concentration of drug B at the previous moment; Δt is the time interval between moments i-1 and i; F B is the flow rate of drug B from the dosing tank to the central chamber when only a single drug is infused, and F B =F1+F2; V C is the volume of the central chamber; C B The concentration of drug B in the administration tank when only a single drug is infused; The concentration of drug A in the dosing tank 1 when only a single drug is infused; The concentration of drug A in dosing tank 2 when only a single drug is infused.
[0045] (ii) Figure 4 As shown, in S3, when the medication tank contains two antibacterial drugs, the drug A whose concentration continues to rise is the drug A, and the drug B that begins to disappear is the drug B. When the drug target concentration meets In the case of, the design flow rate 2 is:
[0046] Wherein, F1 is the flow rate of dosing tank 1; F2 is the flow rate of dosing tank 2; is the concentration of drug A at the current moment; is the concentration of drug B at the current moment; is the concentration of drug A at the previous moment; is the concentration of drug B at the previous moment; Δt is the time interval between moments i-1 and i; F B is the flow rate of drug B from the dosing tank to the central chamber when only a single drug is infused, and F B =F1+F2; V C is the volume of the central chamber; C B The concentration of drug B in the administration tank when only a single drug is infused; The concentration of drug A in the dosing tank 1 when only a single drug is infused; The concentration of drug A in dosing tank 2 when only a single drug is infused.
[0047] (III) Figure 5 As shown in the figure, it simulates the process of drug concentration elimination (decline). In the single drug simulation, a blank tank is usually set to pump into the central chamber, that is, C A , C B The concentrations are all 0. Then in S3, when the drug administration tanks are all replaced with medium without drug, when the drug target concentration meets In the case of, the design flow rate 2 is: F2>0, F1>0.
[0048] Wherein, F1 is the flow rate of dosing tank 1; F2 is the flow rate of dosing tank 2; is the concentration of drug A at the current moment; is the concentration of drug B at the current moment; is the concentration of drug A at the previous moment; is the concentration of drug B at the previous moment; Δt is the time interval between moments i-1 and i; F B is the flow rate of drug B from the dosing tank to the central chamber when only a single drug is infused, and F B =F1+F2; V C is the volume of the central chamber; C B The concentration of drug B in the administration tank when only a single drug is infused; The concentration of drug A in the dosing tank 1 when only a single drug is infused; The concentration of drug A in dosing tank 2 when only a single drug is infused.
[0049] In a special case, when the drug target concentration meets In the case of
[0050] After calculation, when F2>0 but F1<0, use the obtained F2 as the common elimination phase flow rate of the two dosing tanks, and use the single variable analysis or planning solution method to obtain the optimal flow rate F after inferring the concentration, and set the design flow rates of the two dosing tanks to F. (This is similar to the in vitro pharmacokinetic / pharmacodynamic simulation of a single drug, omitted)
[0051] The formula is selected according to the antimicrobial drugs required for the experiment. If the two drugs begin to be eliminated at the same time, the entire contents of (ii) the single drug rising phase and the single drug elimination phase are ignored, and the flow rates F1 and F2 are calculated only through (i) the two-drug rising phase and (iii) the two-drug elimination phase.
Claims
1. A two-drug combined in vitro pharmacokinetic / pharmacodynamic simulation system, characterized in that: The invention comprises a central chamber with a bacterial culture medium therein and two medication tanks, wherein the medication tanks are connected to the central chamber via a fluid path provided with an infusion pump. A waste liquid pipe is connected to the bottom of the central chamber, and the waste liquid pipe is used to keep the liquid volume in the central chamber unchanged. The method for using the two-drug combined in vitro pharmacokinetic / pharmacodynamic model system comprises the following steps: S1: inoculating the study bacteria on the bacterial culture medium in the central chamber; S2: Simulating the rising drug concentration stage, adding antimicrobial drugs to the culture medium of the dosing tank according to the antimicrobial drug simulation requirements, starting the infusion pump according to the designed flow rate to make the two dosing tanks continuously infuse into the central chamber, and at the same time, the waste pipe discharges an equal amount of liquid to simulate the rising drug concentration during oral medication or intravenous infusion; S3: Simulating drug concentration elimination stage, changing the content of the medication tank according to the drug concentration change simulation requirements, keeping the infusion pump started according to the designed flow rate 2 so that the two medication tanks continue to infuse into the central chamber, and at the same time, the waste pipe discharges an equal amount of liquid; S4: Use the drug concentration data obtained clinically or calculated by pharmacokinetic methods as the concentration relationship between the two antimicrobial drugs at different times, and observe the changes in the number of bacteria in the central chamber at different times. Correspond the changes in the number of bacteria to the concentration relationship of the antimicrobial drugs, record and study the bactericidal effect of the antimicrobial drugs when simulating the concentration changes in vivo. Among them, in S2, the requirements for simulating the antimicrobial drugs include: using the drug concentration data obtained clinically or the drug concentration data calculated by the pharmacokinetic method as the target drug concentration data in the central chamber, adding two different antimicrobial drugs to the two dosing tanks respectively, or adding two different antimicrobial drugs to the two dosing tanks at the same time, wherein in S3, the requirements for simulating the change of drug concentration simulation include: using the drug concentration data obtained clinically or the drug concentration data calculated by the pharmacokinetic method as the target drug concentration data in the central chamber, the two dosing tanks continuously infuse into the central chamber at the same time, but the culture medium in one of the dosing tanks is replaced with a drug-free culture medium to simulate the continuous increase in the concentration of a single drug of the two drugs and the beginning elimination of the concentration of the other drug, or the culture medium in both dosing tanks is replaced with a drug-free culture medium to simulate the simultaneous elimination of the two drugs in the body after reaching a peak concentration.
2. The two-drug combined in vitro pharmacokinetic / pharmacodynamic simulation system according to claim 1, characterized in that: The central chamber is arranged on the magnetic stirrer, and a stirring rod matched with the magnetic stirrer is arranged inside the central chamber.
3. The two-drug combined in vitro pharmacokinetic / pharmacodynamic simulation system according to claim 1, characterized in that: A sampler is arranged on the central chamber.
4. The two-drug combined in vitro pharmacokinetic / pharmacodynamic simulation system according to claim 1, characterized in that: In S2, when the medication tank contains two antibacterial drugs, the drug with the fastest rising speed of drug concentration is drug A, and the other is drug B. When the drug target concentration meets In the case of (F2>0, F1>0), the design flow rate is: Wherein, F1 is the flow rate of dosing tank 1; F2 is the flow rate of dosing tank 2; is the concentration of drug A at the current moment; is the concentration of drug B at the current moment; is the concentration of drug A at the previous moment; is the concentration of drug B at the previous moment; Δt is the time interval between moments i-1 and i; F B is the flow rate of drug B from the dosing tank to the central chamber when only a single drug is infused, and F B =F1+F2; V C is the volume of the central chamber; C B The concentration of drug B in the administration tank when only a single drug is infused; The concentration of drug A in the dosing tank 1 when only a single drug is infused; The concentration of drug A in dosing tank 2 when only a single drug is infused.
5. The two-drug combined in vitro pharmacokinetic / pharmacodynamic simulation system according to claim 1, characterized in that: In S3, when the dosing tank contains two antibacterial drugs, the drug A whose concentration continues to rise is the drug A, and the drug B that begins to disappear is the drug B. When the drug target concentration meets In the case of (F2>0, F1>0), the design flow rate 2 is: Wherein, F1 is the flow rate of dosing tank 1; F2 is the flow rate of dosing tank 2; is the concentration of drug A at the current moment; is the concentration of drug B at the current moment; is the concentration of drug A at the previous moment; is the concentration of drug B at the previous moment; Δt is the time interval between moments i-1 and i; F B is the flow rate of drug B from the dosing tank to the central chamber when only a single drug is infused, and F B =F1+F2; V C is the volume of the central chamber; C B The concentration of drug B in the administration tank when only a single drug is infused; The concentration of drug A in the dosing tank 1 when only a single drug is infused; The concentration of drug A in dosing tank 2 when only a single drug is infused.
6. The two-drug combined in vitro pharmacokinetic / pharmacodynamic simulation system according to claim 1, characterized in that: In S3, when the drug administration tanks are all replaced with medium without drug, when the drug target concentration meets In the case of (F2>0, F1>0), the design flow rate 2 is: Wherein, F1 is the flow rate of dosing tank 1; F2 is the flow rate of dosing tank 2; is the concentration of drug A at the current moment; is the concentration of drug B at the current moment; is the concentration of drug A at the previous moment; is the concentration of drug B at the previous moment; Δt is the time interval between moments i-1 and i; F B is the flow rate of drug B from the dosing tank to the central chamber when only a single drug is infused, and F B =F1+F2; V C is the volume of the central chamber; C B The concentration of drug B in the administration tank when only a single drug is infused; The concentration of drug A in the dosing tank 1 when only a single drug is infused; The concentration of drug A in dosing tank 2 when only a single drug is infused.
7. The two-drug combined in vitro pharmacokinetic / pharmacodynamic simulation system according to claim 6, characterized in that: Drug target concentrations may not be met In the case of After calculation, it is found that F2>0, but F1<0, according to Use the obtained F B After inferring the concentration, use univariate analysis or planning solution to obtain the optimal flow rate F, and set the design flow rates of the two dosing tanks to F as the common elimination phase flow rate of the two drugs.