Population pharmacokinetic-guided dosing method and system for intravenous anti-pd-1 / pd-l1

Abstract

This invention provides a population pharmacokinetic-guided method and system for administering intravenously administered anti-PD-1 / PD-L1 antibodies. Based on a population pharmacokinetic model, the standard exposure level for a typical patient under a reference dosing regimen is obtained. Based on the standard exposure level, several exposure threshold ranges are set. The dosage intervals for simulated patients at each weight level corresponding to each exposure threshold range are obtained. Based on existing marketed specifications and several dispensing strategies, several combinations of specifications and dispensing strategies are enumerated for each exposure threshold range, and the corresponding dosing regimens for each specification and dispensing strategy combination under each exposure threshold range are obtained. A comprehensive evaluation result is obtained, and based on the comprehensive evaluation result, a target exposure threshold range, target specification, dispensing strategy combination, and its corresponding target dosing regimen are selected. This improves the accuracy of exposure control and reduces drug waste, thereby lowering treatment costs.

Description

Technical Field

[0001] This invention relates to the field of drug delivery information processing technology, and in particular to a population pharmacokinetic-guided method and system for intravenous administration of anti-PD-1 / PD-L1 drugs. Background Technology

[0002] As a significant breakthrough in tumor immunotherapy, PD-1 / PD-L1 inhibitors have seen widespread application of population pharmacokinetic modeling and simulation techniques in the optimization of dosing regimens. By constructing population pharmacokinetic models to identify key covariates, and by simulating and predicting drug exposure levels under different dosing regimens based on the models, individualized dosing can be guided.

[0003] Existing technologies include studies on optimizing dosing regimens for anti-PD-1 / PD-L1 drugs using the PopPK model. However, existing technologies still have the following shortcomings: First, the bottle-splitting strategy is usually fixed in a way that uses 1 / 2 bottles, which limits the room for dose adjustment and the potential for cost savings; second, the exposure threshold range is not included as an adjustable parameter system in the optimization, making it difficult to achieve precise exposure control. Summary of the Invention

[0004] This invention provides a population pharmacokinetic-guided method and system for intravenous administration of anti-PD-1 / PD-L1 drugs, which significantly improves the accuracy of exposure control while reducing drug waste and costs.

[0005] According to a first aspect of the present invention, the present invention provides a population pharmacokinetic-guided method for intravenous administration of anti-PD-1 / PD-L1 drugs, comprising: Obtain the population pharmacokinetic model corresponding to the target drug; Based on the population pharmacokinetic model, the standard exposure of a typical patient under the reference dosing regimen is obtained. The reference dosing regimen is characterized by the reference dosing dose and reference dosing interval used when the target drug was marketed. The standard exposure is characterized by the drug exposure of the typical patient under steady state according to the reference dosing regimen. Based on the standard exposure level, several different exposure threshold ranges are set; Based on real-world weight distribution, a simulated patient cohort is constructed, which includes simulated patients at several different weight levels. Based on the population pharmacokinetic model, the dosage ranges for simulated patients at each weight level corresponding to each of the exposure threshold ranges are obtained; Based on existing marketed specifications and several bottle-splitting strategies, several combinations of specifications and bottle-splitting strategies are enumerated under each exposure threshold range, and the dosing regimens corresponding to each combination of specifications and bottle-splitting strategies under each exposure threshold range are obtained. The dosing regimens include the achievable dosing dose and reference dosing interval within the dosing dose range corresponding to each weight level. The dosing dose is the achievable dosing dose within the dosing dose range corresponding to each weight level, and the achievable dosing dose is determined by the combination of marketed specifications and bottle-splitting strategies. A comprehensive evaluation of each dosing regimen is conducted to obtain the comprehensive evaluation results. Based on the comprehensive evaluation results, the target exposure threshold range, target product specifications, and bottle splitting strategy combination and their corresponding target dosing regimen are selected.

[0006] Optionally, the exposure threshold ranges from 80% to 120% of the standard exposure, or from 90% to 110% of the standard exposure.

[0007] Optionally, the bottle splitting strategy includes splitting into 1 / 2 bottles, 1 / 3 bottles, or 1 / 4 bottles.

[0008] Optionally, a comprehensive evaluation of each dosing regimen is performed to obtain the comprehensive evaluation results. Based on the comprehensive evaluation results, the target exposure threshold range, target product specifications, and bottle-dipping strategy combination and their corresponding target dosing regimen are selected, including: Obtain the corresponding drug exposure for each dosing regimen, wherein the drug exposure is characterized by at least one of the area under the blood drug concentration-time curve, peak concentration, or trough concentration. Based on the geometric mean of each dosing regimen and the geometric mean of the standard exposure, the geometric mean ratio of each drug exposure is obtained, whereby the geometric mean ratio is the ratio of the geometric mean of the drug exposure to the geometric mean of the standard exposure. Dosing regimens with geometric mean ratios all within the pharmacokinetic standard range were selected as the target dosing regimens; Obtain the exposure threshold range corresponding to the target dosing regimen and the corresponding combination of product specifications and bottle-filling strategies, which are respectively used as the target exposure threshold range and the target product specifications and bottle-filling strategy combination.

[0009] Optionally, the pharmacokinetic standard range is 0.80~1.25.

[0010] Optionally, a comprehensive evaluation of each dosing regimen is performed to obtain the comprehensive evaluation results. Based on the comprehensive evaluation results, the target exposure threshold range, target product specifications, and bottle-dipping strategy combination and their corresponding target dosing regimen are selected, including: Obtain cost parameters, which include the unit price of each marketed product, labor costs, total equipment depreciation and maintenance costs, waste disposal and consumable costs; Based on the cost parameters, the total cost corresponding to each dosing regimen is obtained; The exposure threshold range and the combination of product specifications and bottle splitting strategy corresponding to the dosing regimen with the lowest total cost are obtained as the target exposure threshold range and the target product specifications and bottle splitting strategy combination. The target exposure threshold range and the dosing regimen corresponding to the combination of the target product specification and the bottle splitting strategy are obtained as the target dosing regimen.

[0011] Optionally, a comprehensive evaluation of each dosing regimen is performed to obtain the comprehensive evaluation results. Based on the comprehensive evaluation results, the target exposure threshold range, target product specifications, and bottle-dipping strategy combination and their corresponding target dosing regimen are selected, including: Obtain the drug exposure distribution of simulated patients at different weight levels for each dosing regimen. The drug exposure distribution is characterized by at least one of the following: box plot of area under the blood drug concentration-time curve, box plot of peak concentration, or box plot of trough concentration. Based on obtaining the drug exposure distribution of simulated patients at different weight levels for each dosing regimen, the exposure deviation between the median drug exposure of simulated patients at different weight levels for each dosing regimen and the standard exposure is obtained, and the exposure deviation is the absolute deviation. The exposure threshold range with the smallest exposure deviation for simulated patients at each weight level, along with the product specification and bottle-division strategy, are respectively taken as the target exposure threshold range and the target product specification and bottle-division strategy. The target dosing regimen is defined as the dosing regimen corresponding to the target exposure threshold range and the target product specification and bottling strategy.

[0012] According to a second aspect of the present invention, the present invention also provides a population pharmacokinetic-guided intravenous administration system for anti-PD-1 / PD-L1, for realizing the population pharmacokinetic-guided intravenous administration method for anti-PD-1 / PD-L1 as described above, comprising: The model acquisition module acquires the population pharmacokinetic model corresponding to the target drug; The standard exposure acquisition module, based on the population pharmacokinetic model, acquires the standard exposure of typical patients under the reference dosing regimen. The reference dosing regimen is characterized by the reference dosing dose and reference dosing interval used when the target drug was marketed. The standard exposure is characterized by the drug exposure of the typical patients under steady state according to the reference dosing regimen. The exposure threshold range determination module sets several different exposure threshold ranges based on the standard exposure amount; The simulated patient setting module constructs a simulated patient queue based on real-world weight distribution. The simulated patient queue includes several simulated patients at different weight levels. The dosage interval acquisition module, based on the population pharmacokinetic model, acquires the dosage intervals of simulated patients at each weight level corresponding to each of the exposure threshold ranges; The dosing regimen acquisition module, based on existing marketed specifications and several bottle-splitting strategies, enumerates several combinations of specifications and bottle-splitting strategies under each exposure threshold range, and obtains the dosing regimen corresponding to each combination of specifications and bottle-splitting strategies under each exposure threshold range. The dosing regimen includes the achievable dosing dose and reference dosing interval within the dosing dose range corresponding to each weight level. The dosing dose is the achievable dosing dose within the dosing dose range corresponding to each weight level, and the achievable dosing dose is determined by the combination of marketed specifications and bottle-splitting strategies. The target dosing regimen determination module performs a comprehensive evaluation of each dosing regimen, obtains the comprehensive evaluation results, and selects the target exposure threshold range, target product specifications, and bottle splitting strategy combination and their corresponding target dosing regimen based on the comprehensive evaluation results.

[0013] Compared with the prior art, the technical solution of the embodiments of the present invention has the following beneficial effects: The population pharmacokinetic-guided intravenous administration method and system for anti-PD-1 / PD-L1 drugs of this invention integrates bottle-dipping strategies and exposure threshold ranges as key design variables into the population pharmacokinetic-guided dosing regimen optimization method. By enumerating various combinations of bottle-dipping strategies and different exposure threshold ranges, and combining existing marketed specifications to screen the actual dosage for simulated patients at different weight levels, this invention fully utilizes the dosage adjustment space provided by precise bottle-dipping, reducing drug waste and treatment costs. Furthermore, this invention also ensures that the dosing regimen not only controls the patient's exposure within a preset acceptable range but is also feasible in clinical practice by reverse-engineering the dosage range and combining it with the product specifications and bottle-dipping strategies to enumerate practically feasible dosages. This achieves a balance between precise exposure control and clinical feasibility. Attached Figure Description

[0014] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0015] Figure 1 This is a schematic flowchart of a population pharmacokinetic-guided intravenous administration method for anti-PD-1 / PD-L1 provided in an embodiment of the present invention; Figures 2a-2i Box plots comparing drug exposure distributions of several dosing regimens provided in an embodiment of the present invention with a reference dosing regimen when applied to simulated patients at various weight levels; Figure 3 This is a schematic diagram of a population pharmacokinetic-guided intravenous anti-PD-1 / PD-L1 drug delivery system provided in an embodiment of the present invention. Detailed Implementation

[0016] As described in the background section, this invention improves the precision of exposure control while reducing drug waste to lower treatment costs.

[0017] In view of this, the present invention proposes a population pharmacokinetic-guided intravenous administration method for anti-PD-1 / PD-L1 drugs, which obtains a population pharmacokinetic model corresponding to the target drug; based on the population pharmacokinetic model, the standard exposure of typical patients under a reference dosing regimen is obtained, where the reference dosing regimen is characterized by the reference dosage and reference dosing interval used when the target drug was marketed, and the standard exposure is characterized by the steady-state drug exposure of typical patients according to the reference dosing regimen; based on the standard exposure, several different exposure threshold ranges are set; based on real-world weight distribution, a simulated patient cohort is constructed, which includes simulated patients at several different weight levels; based on the population pharmacokinetic model, the model of each weight level corresponding to each exposure threshold range is obtained. The invention proposes a dosage range for the patient; based on existing marketed drug specifications and several bottle-dispensing strategies, it enumerates several combinations of drug specifications and bottle-dispensing strategies within each exposure threshold range, and obtains the corresponding dosing regimen for each combination of drug specifications and bottle-dispensing strategies within each exposure threshold range. The dosing regimen includes the achievable dosage and reference dosing interval within the dosage range corresponding to each weight level. The achievable dosage is determined by the combination of marketed drug specifications and bottle-dispensing strategies. A comprehensive evaluation of each dosing regimen is performed to obtain the comprehensive evaluation results. Based on the comprehensive evaluation results, the target exposure threshold range, target drug specifications, and bottle-dispensing strategy combinations and their corresponding target dosing regimens are selected. Therefore, this invention improves the accuracy of exposure control and reduces drug waste, thereby lowering treatment costs.

[0018] The terms “first,” “second,” “third,” “fourth,” etc. (if present) in the specification, claims, and accompanying drawings of this invention are used to distinguish similar objects and are not necessarily used to describe a particular order or sequence. It should be understood that such data can be interchanged where appropriate so that embodiments of the invention described herein can be implemented in orders other than those illustrated or described herein. Furthermore, the terms “comprising” and “having,” and any variations thereof, are intended to cover a non-exclusive inclusion; for example, a process, method, system, product, or apparatus that comprises a series of steps or units is not necessarily limited to those steps or units explicitly listed, but may include other steps or units not explicitly listed or inherent to such processes, methods, products, or apparatus.

[0019] The technical solution of the present invention will be described in detail below with reference to specific embodiments. These specific embodiments can be combined with each other, and the same or similar concepts or processes may not be described again in some embodiments.

[0020] Please refer to Figure 1 Embodiments of the present invention provide a population pharmacokinetic-guided intravenous administration method for anti-PD-1 / PD-L1 drugs, which may include: S100: Obtain the population pharmacokinetic model corresponding to the target drug.

[0021] For example, the target drug can be any one of tislelizumab, adebelimumab, segulimumab, or toripalimab. Of course, the present invention is not limited to this, and the target drug can be any intravenous anti-PD-1 / PD-L1 drug.

[0022] In this embodiment, the population pharmacokinetic model is obtained by acquiring the antitumor monoclonal antibody population pharmacokinetic model from FDA review documents or peer-reviewed literature, and reconstructing the model and model parameters based on a nonlinear mixed-effects model (NONMEM).

[0023] In this embodiment, different target drugs are used with corresponding population pharmacokinetic models.

[0024] S200: Based on the population pharmacokinetic model, obtain the standard exposure of a typical patient under the reference dosing regimen, wherein the reference dosing regimen is characterized by the reference dosing dose and reference dosing interval used when the target drug was marketed, and the standard exposure is characterized by the drug exposure of the typical patient under steady state according to the reference dosing regimen.

[0025] In this embodiment, drug exposure can be measured using the area under the blood drug concentration-time curve (AUC) and peak concentration (Tc). ) and trough concentration ( The standard is based on this.

[0026] In this embodiment, the reference dosage and reference dosing interval can be obtained from the drug instructions, FDA review reports, EMA public evaluation reports, or published clinical trial literature.

[0027] In this embodiment, the AUC of the standard exposure can be calculated by the ratio of the reference dose to the clearance rate of a typical patient. The clearance rate of a typical patient can be calculated using a population pharmacokinetic model.

[0028] In this embodiment, the standard exposure is the median of drug exposures simulated in 1000 typical patients using a reference dosing regimen.

[0029] The typical patient characterization is based on patient covariates.

[0030] In this embodiment, covariates may also include: albumin level, tumor size, tumor type, anti-drug antibody, age, and sex. For continuous covariates (e.g., weight), the median can be used as the covariate value for a typical patient. For non-continuous covariates (e.g., sex), a reference level that does not affect pharmacokinetic parameters can be used as the covariate value for a typical patient.

[0031] In this embodiment, the median level of the covariates is determined based on the distribution of covariates in the model building population (i.e., the clinical trial subject population used to establish the population pharmacokinetic model).

[0032] In this embodiment, the standard exposure can be calculated based on the population pharmacokinetic model established in step S100.

[0033] S300: Based on the standard exposure level, set several different exposure threshold ranges.

[0034] In this embodiment, the exposure threshold range can be 80% to 120% of the standard exposure amount, or it can be 90% to 110% of the standard exposure amount. Of course, the present invention is not limited to this, and this embodiment can also use 80% to 125% of the standard exposure amount.

[0035] This invention achieves a systematic balance and unification between exposure control precision and clinical operability for the first time by setting the exposure threshold range to 80%~120% of the standard exposure and 90%~110% of the standard exposure, with two different constraint intensities.

[0036] The exposure threshold range of 80% to 120% of the standard exposure is set with reference to the exposure comparability and equivalence threshold (80% to 125% of the standard exposure) stipulated by the Center for Drug Evaluation (CDE) of the National Medical Products Administration. This provides a moderate constraint space for dose optimization and achieves greater cost savings potential while ensuring compliance with regulatory review expectations. The narrowed exposure threshold range of 90% to 110% of the standard exposure strictly limits exposure variability, keeping the exposure level of the adjusted dosing regimen highly controlled near the standard exposure, significantly improving the accuracy of exposure control. This is particularly suitable for drugs with a narrow therapeutic window or a steep exposure-response relationship.

[0037] The parallel setting of two exposure threshold ranges enables the present invention to systematically compare the comprehensive performance of dosing regimens under different constraint intensities in terms of exposure comparability, cost-effectiveness, and clinical operability through multi-strategy combination enumeration. This provides a quantitative basis for clinical decision-making and achieves flexible adaptation of "wide threshold to ensure cost and narrow threshold to ensure accuracy," overcoming the limitations of regimen selection caused by the single exposure target and fixed constraint intensity in the prior art.

[0038] S400: Based on real-world weight distribution, a simulated patient cohort is constructed, which includes simulated patients at several different weight levels.

[0039] As an implementation case, in order to optimize the dosing strategy by taking into account both exposure target achievement and clinical feasibility, this embodiment constructs a simulated patient cohort covering a weight range of 30kg to 160kg to fully reflect extreme weight scenarios that may occur in clinical practice. The weight intervals of the weight levels in the simulated patient cohort can be selected according to the specific exposure threshold range and the combination of product specifications and bottle splitting strategies.

[0040] As an example, the present invention can divide the simulated patient cohort into weight levels with different weight intervals, and set 10 simulated patients in each weight level.

[0041] S500: Based on the population pharmacokinetic model, obtain the dosage range of simulated patients at each weight level corresponding to each of the exposure threshold ranges.

[0042] S600: Based on existing marketed specifications and several bottle-splitting strategies, enumerate several combinations of specifications and bottle-splitting strategies under each exposure threshold range, and obtain the dosing regimen corresponding to each combination of specifications and bottle-splitting strategies under each exposure threshold range. The dosing regimen includes the achievable dosing dose and reference dosing interval within the dosing dose range corresponding to each weight level. The dosing dose is the achievable dosing dose within the dosing dose range corresponding to each weight level, and the achievable dosing dose is determined by the combination of marketed specifications and bottle-splitting strategies.

[0043] As an example, the bottle-dividing strategy may include 1 / 2 bottle, 1 / 3 bottle, or 1 / 4 bottle.

[0044] In this embodiment, the 1 / 2 bottle is the simplest to operate and has high clinical fit, the 1 / 3 bottle balances precision and operability, and the 1 / 4 bottle offers the best exposure control accuracy. By designing multiple bottle-division strategies, various dosing regimens can be screened, providing a basis for subsequently selecting the optimal target dosing regimen.

[0045] In this embodiment, when a new specification of the target drug is added, the new specification can be incorporated into the marketed specifications, and a dosing regimen matching the new specification can be generated. Therefore, this embodiment can respond promptly to changes in the specification of the target drug.

[0046] In this embodiment, the actual dosage can be selected as the smallest achievable dosage enumerated from the corresponding dosage range.

[0047] S700: Perform a comprehensive evaluation of each dosing regimen, obtain the comprehensive evaluation results, and select the target exposure threshold range, target product specifications, and bottle splitting strategy combination and their corresponding target dosing regimen based on the comprehensive evaluation results.

[0048] In this embodiment, the target exposure threshold range is selected from several different exposure threshold ranges, and the target product specification and bottle-splitting strategy combination is selected from several product specification and bottle-splitting strategy combinations.

[0049] As an optional embodiment, S700 involves performing a comprehensive evaluation of each dosing regimen, obtaining a comprehensive evaluation result, and selecting the target exposure threshold range, target product specification, and bottle-dipping strategy combination and its corresponding target dosing regimen based on the comprehensive evaluation result. This may include: S731: Obtain the corresponding drug exposure for each dosing regimen, wherein the drug exposure is characterized by at least one of the area under the blood drug concentration-time curve, peak concentration, or trough concentration.

[0050] S732: Based on the geometric mean of each dosing regimen and the geometric mean of the standard exposure, obtain the geometric mean ratio of each drug exposure, wherein the geometric mean ratio is characterized as the ratio of the geometric mean of the drug exposure to the geometric mean of the standard exposure.

[0051] S733: Select a dosing regimen in which the geometric mean ratio is within the pharmacokinetic standard range as the target dosing regimen.

[0052] S734: Obtain the exposure threshold range corresponding to the target dosing regimen and the corresponding combination of product specifications and bottle-filling strategies, respectively, as the target exposure threshold range and the target product specifications and bottle-filling strategy combination.

[0053] In this embodiment, the pharmacokinetic standard range is 0.80~1.25.

[0054] In this embodiment, the present invention achieves a high degree of equivalence between the dosing regimen and the reference dosing regimen by selecting the dosing regimen with the exposure level closest to the reference dosing regimen.

[0055] As an optional embodiment, S700, a comprehensive evaluation of each dosing regimen is performed to obtain the comprehensive evaluation results, and the target exposure threshold range, target product specification, and bottle-dipping strategy combination and their corresponding target dosing regimen are selected based on the comprehensive evaluation results, including: S721: Obtain cost parameters, which include the unit price of each listed product, labor costs, total equipment depreciation and maintenance costs, waste disposal and consumable costs.

[0056] The above cost parameters overcome the limitation of existing technologies that only consider drug costs.

[0057] S722: Based on the cost parameters, obtain the total cost corresponding to each dosing regimen.

[0058] S723: Obtain the exposure threshold range and product specification and bottle-dipping strategy combination corresponding to the dosing regimen with the lowest total cost, as the target exposure threshold range and target product specification and bottle-dipping strategy combination.

[0059] S724: Obtain the target exposure threshold range and the dosing regimen corresponding to the combination of the target product specification and the bottle splitting strategy as the target dosing regimen.

[0060] This invention can identify the cost-optimal dosing regimen from multiple strategy combinations while ensuring that exposure targets are met, thus achieving cost reduction.

[0061] As another optional embodiment, in S700, a comprehensive evaluation of each dosing regimen is performed to obtain the comprehensive evaluation results, and the target exposure threshold range, target product specification, and bottle-dipping strategy combination and their corresponding target dosing regimen are selected based on the comprehensive evaluation results, including: S731: Obtain the drug exposure distribution of simulated patients at different weight levels for each dosing regimen, wherein the drug exposure distribution is characterized by at least one of the following: box plot of area under the blood drug concentration-time curve, box plot of peak concentration, or box plot of trough concentration.

[0062] S732: Based on obtaining the drug exposure distribution of simulated patients at different weight levels for each dosing regimen, obtain the exposure deviation between the median drug exposure of simulated patients at different weight levels for each dosing regimen and the median standard exposure, wherein the exposure deviation is an absolute deviation.

[0063] S733: The exposure threshold range with the smallest exposure deviation for simulated patients at each weight level, along with the product specification and bottle-separation strategy, shall be respectively used as the target exposure threshold range and the target product specification and bottle-separation strategy.

[0064] S734: The target dosing regimen is the dosing regimen corresponding to the target exposure threshold range and the target product specification and bottle splitting strategy.

[0065] In this embodiment, by incorporating the accuracy of exposure as a core evaluation indicator into the comprehensive evaluation method of the dosing regimen, the accuracy of the exposure of the target dosing regimen is high, and consequently, the drug safety of the target dosing regimen is high.

[0066] As demonstrated by the above embodiments, by integrating bottle-splitting strategies and exposure threshold ranges as key design variables into the population pharmacokinetic-guided dosing regimen optimization method, and by enumerating various combinations of bottle-splitting strategies and different exposure threshold ranges, and by combining existing marketed drug specifications to screen the dosage for simulated patients at different weight levels, the method fully utilizes the dosage adjustment space provided by precise bottle splitting, reducing drug waste and treatment costs. Furthermore, this invention also ensures that the dosing regimen not only controls the patient's exposure within a preset acceptable range but is also feasible in clinical practice by reverse-engineering the dosage range and combining drug specifications and bottle-splitting strategies to enumerate practically feasible dosages. This achieves a balance between the precision of exposure control and the feasibility of clinical operation.

[0067] In one specific embodiment, tislelizumab is used as the target drug as an example to describe the above administration method: As an example, tislelizumab uses the following pharmacokinetic model: Where CL represents the clearance rate. The apparent volume of distribution in the central compartment is WT, where WT is body weight (kg), ALB is albumin concentration (g / L), TUMSZ is tumor size (mm), ADA is anti-drug antibody (positive = 1, negative = 0), TUMTP is tumor type (GC for gastric cancer, cHL for typical Hodgkin lymphoma), SEX is sex (female = 1, male = 0), and AGE is age (years). The parameters for a typical patient in this embodiment can be set as follows: body weight 65kg, male, age 60 years, albumin 41g / L, tumor size 63mm, anti-drug antibody negative, and tumor type hepatocellular carcinoma. A population pharmacokinetic model was used to simulate the drug exposure of a typical patient under the reference regimen (200 mg every three weeks), and this was taken as the target exposure, i.e., 1282.48 mg·day / L.

[0068] Taking tislelizumab as an example, its reference dosing regimen can be as follows: Reference dose: 200 mg; Reference dosing interval: once every 3 weeks (21 days).

[0069] This embodiment uses a simulated patient cohort with a weight range of 30kg to 160kg.

[0070] The current marketed specification for tislelizumab is 100 mg / vial.

[0071] Tislelizumab is administered via a 1 / 2 or 1 / 4 bottle splitting strategy.

[0072] For ease of description, the dosing regimen corresponding to the marketed product with an exposure threshold range of 80% to 120% of the standard exposure, and a combination of product specification and bottle splitting strategy of 100 mg / bottle and 1 / 2 bottle splitting strategy, is referred to as the first dosing regimen.

[0073] The dosing regimen corresponding to the marketed product with an exposure threshold range of 80% to 120% of the standard exposure, and the combination of product specification and bottle splitting strategy of 100 mg / bottle and 1 / 4 bottle splitting strategy, is referred to as the second dosing regimen.

[0074] The dosing regimen corresponding to the marketed product with an exposure threshold range of 90% to 110% of the standard exposure, and the combination of product specification and bottle splitting strategy of 100 mg / bottle and 1 / 4 bottle splitting strategy, is referred to as the third dosing regimen.

[0075] For the dosage of simulated patients at each weight class in each dosing regimen, please refer to Tables 1-3.

[0076] Table 1. Dosage for simulated patients at different weight levels under the first dosing regimen. Table 2. Dosage for simulated patients at different weight levels under the second dosing regimen. Table 3. Dosage for simulated patients at different weight levels under the third dosing regimen. Under different exposure threshold ranges, different combinations of product specifications and bottle splitting strategies, as well as different exposure threshold ranges, will simulate patient cohorts divided at different weight intervals.

[0077] As an optional implementation of this embodiment, the geometric mean ratio of drug exposure after the first administration of each of the first, second, and third administration regimens is shown in Table 4.

[0078] Table 4. Geometric mean ratio of drug exposure after first dose and at steady state for each dosing regimen Therefore, all three of the above dosing regimens can be used as target dosing regimens.

[0079] In this embodiment, the cost parameters of tislelizumab are as follows: the unit price of the drug corresponding to the marketed specification is RMB 856 / 100 mg; the labor cost is RMB 50 / hour (12 bottles are prepared per hour); the total equipment depreciation and maintenance cost is RMB 98 / week; and the waste disposal and consumable cost is RMB 5 / time.

[0080] When using the reference dosing regimen, the total cost was RMB 43,265,683.33.

[0081] Please refer to Table 7 for the total cost of each dosing regimen.

[0082] Table 7 Total Cost of Different Dosing Regimens As can be seen, the total cost of the dosing regimens obtained by this invention is lower than the total cost of the reference dosing regimens. Furthermore, the second dosing regimen has the lowest total cost.

[0083] As an optional implementation of this embodiment, in order to further reduce the total cost, the dosing regimen with the lowest total cost is adopted, that is, the dosing regimen corresponding to the standard exposure dose with a target exposure range threshold of 80% to 120% and the target product specification and bottle splitting strategy combination of 100mg / bottle and 1 / 4 bottle is used as the target dosing regimen.

[0084] As another optional implementation method of this embodiment, please refer to Figures 2a-2i .

[0085] in, Figures 2a-2iThe black horizontal line "median" represents the standard exposure level.

[0086] Figures 2a-2i The horizontal line in the orange box represents the median drug exposure under the reference dosing regimen.

[0087] Figures 2a-2i The horizontal line in the blue box represents the median drug exposure under the dosing regimen of this invention.

[0088] Figure 2a , Figure 2b and Figure 2c Box plots comparing the AUC of simulated patients at various weight classes with a standard exposure threshold of 80% to 120% and a dosing strategy of 100 mg / vial and 1 / 2 bottle, and the reference dosing regimen. Box plot comparison chart and Box plot comparison chart.

[0089] Figure 2d , Figure 2e and Figure 2f Box plots comparing the AUC of simulated patients at various weight classes with a standard exposure threshold of 80% to 120% and a dosing strategy of 100 mg / vial and 1 / 4 bottle, and the reference dosing regimen. Box plot comparison chart and Box plot comparison chart.

[0090] Figure 2g , Figure 2h and Figure 2i Box plots comparing the AUC of simulated patients at various weight classes with a standard exposure threshold of 90% to 110% and a dosing strategy of 100 mg / vial and 1 / 4 bottle, and the reference dosing regimen. Box plot comparison chart and Box plot comparison chart.

[0091] Figures 2a-2i The horizontal axis represents body weight.

[0092] Figure 2a , Figure 2d as well as Figure 2g The ordinate is AUC.

[0093] Figure 2b , Figure 2e as well as Figure 2h The ordinate is .

[0094] Figure 2c , Figure 2f as well as Figure 2i The ordinate is .

[0095] Depend on Figures 2a-2i It can be seen that the exposure threshold range is 90% to 110% of the standard exposure. The dosing regimen corresponding to the 100 mg / bottle and the 1 / 4 bottle combination has the smallest exposure deviation.

[0096] Therefore, in order to improve the accuracy of exposure control, this embodiment uses a standard exposure of 90% to 110% of the target exposure threshold and a target product specification and bottling strategy combination of 100 mg / bottle and 1 / 4 bottle as the target dosing regimen.

[0097] In addition, please refer to Figure 3 The embodiments of the present invention also propose a population pharmacokinetic-guided intravenous administration system for anti-PD-1 / PD-L1, used to achieve the population pharmacokinetic-guided intravenous administration method for anti-PD-1 / PD-L1 as described above, which may include: Model acquisition module 100 acquires the population pharmacokinetic model corresponding to the target drug.

[0098] The standard exposure acquisition module 200 acquires the standard exposure of a typical patient under a reference dosing regimen based on the population pharmacokinetic model. The reference dosing regimen is characterized by the reference dosing dose and reference dosing interval used when the target drug was marketed. The standard exposure is characterized by the drug exposure of the typical patient under steady state according to the reference dosing regimen.

[0099] The exposure threshold range determination module 300 sets several different exposure threshold ranges based on the standard exposure amount.

[0100] The simulated patient setting module 400 constructs a simulated patient queue based on real-world weight distribution, and the simulated patient queue includes several simulated patients of different weight levels.

[0101] The dosage interval acquisition module 500 acquires the dosage interval of simulated patients at each weight level corresponding to each of the exposure threshold ranges based on the population pharmacokinetic model.

[0102] The dosing regimen acquisition module 600, based on existing marketed specifications and several bottle-splitting strategies, enumerates several combinations of specifications and bottle-splitting strategies under each exposure threshold range, and acquires the dosing regimen corresponding to each combination of specifications and bottle-splitting strategies under each exposure threshold range. The dosing regimen includes the achievable dosing dose and reference dosing interval within the dosing dose range corresponding to each weight level. The dosing dose is the achievable dosing dose within the dosing dose range corresponding to each weight level, and the achievable dosing dose is determined by the combination of marketed specifications and bottle-splitting strategies.

[0103] The target dosing regimen determination module 700 performs a comprehensive evaluation of each dosing regimen, obtains the comprehensive evaluation results, and selects the target exposure threshold range, target product specifications, and bottle splitting strategy combination and their corresponding target dosing regimens based on the comprehensive evaluation results.

[0104] In this embodiment, the model acquisition module 100, standard exposure acquisition module 200, exposure threshold range determination module 300, simulated patient setting module 400, dosing dose range acquisition module 500, dosing regimen acquisition module 600, and target dosing regimen determination module 700 are integrated into one system. This system can be deployed in a computer device and implemented in the form of an interactive web page, thereby realizing an automated closed loop from parameter input to regimen output, overcoming the fragmentation problem of existing technologies that rely on manual operation across multiple platforms.

[0105] While the present invention has been disclosed above, it is not limited thereto. Any person skilled in the art can make various modifications and alterations without departing from the spirit and scope of the invention; therefore, the scope of protection of the present invention should be determined by the scope defined in the claims.

Claims

1. A population pharmacokinetic-guided intravenous administration method for anti-PD-1 / PD-L1 drugs, characterized in that, include: Obtain the population pharmacokinetic model corresponding to the target drug; Based on the population pharmacokinetic model, the standard exposure of a typical patient under the reference dosing regimen is obtained. The reference dosing regimen is characterized by the reference dosing dose and reference dosing interval used when the target drug was marketed. The standard exposure is characterized by the drug exposure of the typical patient under steady state according to the reference dosing regimen. Based on the standard exposure level, several different exposure threshold ranges are set; Based on real-world weight distribution, a simulated patient cohort is constructed, which includes simulated patients at several different weight levels. Based on the population pharmacokinetic model, the dosage ranges for simulated patients at each weight level corresponding to each of the exposure threshold ranges are obtained; Based on existing marketed specifications and several bottle-splitting strategies, several combinations of specifications and bottle-splitting strategies are enumerated under each exposure threshold range, and the dosing regimens corresponding to each combination of specifications and bottle-splitting strategies under each exposure threshold range are obtained. The dosing regimens include the achievable dosing dose and reference dosing interval within the dosing dose range corresponding to each weight level. The dosing dose is the achievable dosing dose within the dosing dose range corresponding to each weight level, and the achievable dosing dose is determined by the combination of marketed specifications and bottle-splitting strategies. A comprehensive evaluation of each dosing regimen is conducted to obtain the comprehensive evaluation results. Based on the comprehensive evaluation results, the target exposure threshold range, target product specifications, and bottle splitting strategy combination and their corresponding target dosing regimen are selected.

2. The method of administration as described in claim 1, characterized in that, The exposure threshold ranges from 80% to 120% of the standard exposure, or from 90% to 110% of the standard exposure.

3. The method of administration according to claim 1, characterized in that, The bottle splitting strategy includes splitting the bottle into 1 / 2, 1 / 3, or 1 / 4 bottles.

4. The method of administration according to claim 1, characterized in that, A comprehensive evaluation of each dosing regimen is conducted to obtain the comprehensive evaluation results. Based on the comprehensive evaluation results, the target exposure threshold range, target product specifications, and bottle splitting strategy combinations and their corresponding target dosing regimens are selected, including: Obtain the corresponding drug exposure for each dosing regimen, wherein the drug exposure is characterized by at least one of the area under the blood drug concentration-time curve, peak concentration, or trough concentration. Based on the geometric mean of each dosing regimen and the geometric mean of the standard exposure, the geometric mean ratio of each drug exposure is obtained, whereby the geometric mean ratio is the ratio of the geometric mean of the drug exposure to the geometric mean of the standard exposure. Dosing regimens with geometric mean ratios all within the pharmacokinetic standard range were selected as the target dosing regimens; Obtain the exposure threshold range corresponding to the target dosing regimen and the corresponding combination of product specifications and bottle-filling strategies, which are respectively used as the target exposure threshold range and the target product specifications and bottle-filling strategy combination.

5. The method of administration according to claim 4, characterized in that, The pharmacokinetic standard range is 0.80~1.

25.

6. The method of administration according to claim 1, characterized in that, A comprehensive evaluation of each dosing regimen is conducted to obtain the comprehensive evaluation results. Based on the comprehensive evaluation results, the target exposure threshold range, target product specifications, and bottle splitting strategy combinations and their corresponding target dosing regimens are selected, including: Obtain cost parameters, which include the unit price of each marketed product, labor costs, total equipment depreciation and maintenance costs, waste disposal and consumable costs; Based on the cost parameters, the total cost corresponding to each dosing regimen is obtained; The exposure threshold range and the combination of product specifications and bottle splitting strategy corresponding to the dosing regimen with the lowest total cost are obtained as the target exposure threshold range and the target product specifications and bottle splitting strategy combination. The target exposure threshold range and the dosing regimen corresponding to the combination of the target product specification and the bottle splitting strategy are obtained as the target dosing regimen.

7. The method of administration according to claim 1, characterized in that, A comprehensive evaluation of each dosing regimen is conducted to obtain the comprehensive evaluation results. Based on the comprehensive evaluation results, the target exposure threshold range, target product specifications, and bottle splitting strategy combinations and their corresponding target dosing regimens are selected, including: Obtain the drug exposure distribution of simulated patients at different weight levels for each dosing regimen. The drug exposure distribution is characterized by at least one of the following: box plot of area under the blood drug concentration-time curve, box plot of peak concentration, or box plot of trough concentration. Based on obtaining the drug exposure distribution of simulated patients at different weight levels for each dosing regimen, the exposure deviation between the median drug exposure of simulated patients at different weight levels for each dosing regimen and the standard exposure is obtained, and the exposure deviation is the absolute deviation. The exposure threshold range with the smallest exposure deviation for simulated patients at each weight level, along with the product specification and bottle-division strategy, are respectively taken as the target exposure threshold range and the target product specification and bottle-division strategy. The target dosing regimen is defined as the dosing regimen corresponding to the target exposure threshold range and the target product specification and bottling strategy.

8. A population pharmacokinetic-guided intravenous drug delivery system for anti-PD-1 / PD-L1, characterized in that, A method for administering intravenously anti-PD-1 / PD-L1 drugs via population pharmacokinetic guidance as described in any one of claims 1-7, comprising: The model acquisition module acquires the population pharmacokinetic model corresponding to the target drug; The standard exposure acquisition module, based on the population pharmacokinetic model, acquires the standard exposure of typical patients under the reference dosing regimen. The reference dosing regimen is characterized by the reference dosing dose and reference dosing interval used when the target drug was marketed. The standard exposure is characterized by the drug exposure of the typical patients under steady state according to the reference dosing regimen. The exposure threshold range determination module sets several different exposure threshold ranges based on the standard exposure amount; The simulated patient setting module constructs a simulated patient queue based on real-world weight distribution. The simulated patient queue includes several simulated patients at different weight levels. The dosage interval acquisition module, based on the population pharmacokinetic model, acquires the dosage intervals of simulated patients at each weight level corresponding to each of the exposure threshold ranges; The dosing regimen acquisition module, based on existing marketed specifications and several bottle-splitting strategies, enumerates several combinations of specifications and bottle-splitting strategies under each exposure threshold range, and obtains the dosing regimen corresponding to each combination of specifications and bottle-splitting strategies under each exposure threshold range. The dosing regimen includes the achievable dosing dose and reference dosing interval within the dosing dose range corresponding to each weight level. The dosing dose is the achievable dosing dose within the dosing dose range corresponding to each weight level, and the achievable dosing dose is determined by the combination of marketed specifications and bottle-splitting strategies. The target dosing regimen determination module performs a comprehensive evaluation of each dosing regimen, obtains the comprehensive evaluation results, and selects the target exposure threshold range, target product specifications, and bottle splitting strategy combination and their corresponding target dosing regimen based on the comprehensive evaluation results.

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