Therapeutic agent for intractable lymphangiopathy and intractable vascular disease

Abstract

Provided is an effective agent for the treatment of intractable lymphangiopathy and intractable vascular disease. A therapeutic agent for intractable lymphatic diseases and intractable vascular diseases, which contains sirolimus as an active ingredient, and which is administered orally or via a tube at an administration amount that is determined on the basis of parameters associated with the in-vivo dynamics of sirolimus in a patient suffering from the diseases and the body weight and month age of the patient.

Description

Technical Field

[0001] The present invention relates to a drug for improving the symptoms of refractory lymphatic disease and refractory vascular disease. Specifically, it relates to an oral drug containing sirolimus and effective for improving the symptoms of refractory lymphatic disease and refractory vascular disease in children including infants and adults and for treating these diseases. Background Art

[0002] Refractory lymphatic disease and refractory vascular disease are a group of diseases that mainly cause abnormal formation of blood vessels or lymphatic vessels throughout the body during childhood. These diseases are often difficult to cure because they cause unilateral hypertrophy of the limbs, pain, ulcers, functional disorders, organ disorders and other symptoms.

[0003] As refractory lymphatic diseases and refractory vascular diseases, there are known kaposiform hemangioendothelioma, plexiform angioma, lymphangioma, lymphangiomatosis (Lymphanghiomatosis, Generalized lymphatic anomaly), Gorham's disease, venous malformation, blue rubber bleb nevus syndrome, mixed vascular malformation and Klippel-Trenaunay-Weber syndrome, etc., which are sometimes also called refractory vascular tumors, vascular malformations or refractory vascular abnormalities. These diseases not only have the cases of severe illness leading to death, but also have the cases of pain and abnormal appearance, which have a great impact on the patient's QOL (Quality of Life). Therefore, it is extremely important to establish treatment methods for these diseases.

[0004] Currently, standard treatments for refractory lymphatic and refractory vascular diseases have not been established, and there are no drugs that are effective for these diseases. In addition, in current clinical settings, for cases where surgery, radiotherapy, etc. are difficult or ineffective, steroids, interferon, propranolol, etc. are sometimes used for drug treatment, but the effects of drugs currently used for this disease are limited, so it is difficult to say that effectiveness and safety have been established. In addition, propranolol is effective for infantile hemangioma.

[0005] On the other hand, in recent years, the results of non-clinical studies using sirolimus, a metabolite of the actinomycete Streptomyces hygroscopicus isolated from the soil of Easter Island, have shown that the compound is effective against vascular tumors and vascular malformations (Non-Patent Documents 1 to 5). In addition, the results of clinical studies have also shown that sirolimus can improve various symptoms of this disease (Non-Patent Documents 6 and 7).

[0006] Prior art literature

[0007] Non-patent literature

[0008] Non-patent document 1: Huber S, Bruns CJ, Schmid G, et al. Inhibition of themammalian target of rapamycin impedes lymphangiogenesis. Kidney Int 2007; 71: 771-777.

[0009] Non-patent document 2: Kobayashi S, Kishimoto T, Kamata S, et al. Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis. Cancer Sci. 2007 May; 98(5): 726-33.

[0010] Non-patent document 3: Boscolo E, Coma S, Luks VL, et al. AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation. Angiogenesis. 2015Apr; 18(2): 151-62.

[0011] Non-patent document 4: Boscolo E, Limaye N, Huang L, et al. Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects. J Clin Invest. 2015; 125: 3491-604.

[0012] Non-patent document 5: Limaye N, Kangas J, Mendola A, et al. Somatic Activating PIK3CA Mutations Cause Venous Malformation. Am J Hum Genet. 2015 Dec 3; 97(6): 914-21.

[0013] Non-patent literature 6: Adrienne M. Hammill, et al. Sirolimus for the Treatment of Complicated Vascular Anomalies in Children, Pediatr Blood Cancer, 2011, 57, 1018-24.

[0014] Non-patent literature 7: Ozeki M, Nozawa A, Yasue S, Endo S, Asada R, Hashimoto H, Fukao T. The impact of sirolimus therapy on lesion size, clinical symptoms, and quality of life of patients with lymphatic anomalies. Orphanet J Rare Dis. 2019 Jun 13; 14(1): 141. Summary of the invention

[0015] Problem that the invention aims to solve

[0016] For refractory lymphatic disease and refractory vascular disease (hereinafter referred to as "the disease"), no therapeutic agent with fully proven effect has been found. At present, sirolimus is the most anticipated candidate drug, but when used for the treatment of the disease, it is hoped that an effective and safe usage and dosage will be used. This is especially important when used for children including infants. The present application is completed in view of this situation, and its purpose is to provide a safe and effective agent for the treatment of refractory lymphatic disease and refractory vascular disease.

[0017] Means used to solve problems

[0018] That is, the present invention provides the following embodiments.

[0019] Implementation 1:

[0020] A therapeutic agent for refractory lymphatic disease and refractory vascular disease, comprising sirolimus as an active ingredient, wherein the initial dosage is determined based on a parameter associated with the in vivo dynamics of sirolimus and the patient's weight and age, and the agent is administered orally or intravenously.

[0021] Implementation 2:

[0022] In the therapeutic agent described in Embodiment 1,

[0023] The initial dosage is calculated as follows:

[0024] Using patient information including at least age and weight and administration information including at least the dosage and timing of administration of the drug,

[0025] Calculating the parameters corresponding to the patient information by calculating the parameter calculation formula applied to the blood concentration calculation formula representing the blood concentration of sirolimus based on the two-compartment model in case of repeated administration,

[0026] Applying the parameter and the medication information to the blood concentration calculation formula to obtain a curve representing the transition of the blood sirolimus concentration, and applying the target value of the blood sirolimus concentration to the curve representing the transition of the blood sirolimus concentration to obtain the initial medication dose;

[0027] Among them, the patient's monthly age used to determine the parameters at each time point is the patient's monthly age at each time point calculated based on the date of birth, and the patient's weight used to determine the parameters at each time point is the estimated weight of the patient at each time point inferred based on the patient's past weight changes.

[0028] Implementation 3:

[0029] A therapeutic agent for refractory lymphatic disease and refractory vascular disease, comprising sirolimus as an active ingredient, wherein:

[0030] The starting dose is given orally or via tube administration according to the weight and age of the patient with the disease or condition:

[0031] (1) For patients weighing more than 30 kg, 1.4 mg / day of sirolimus is recommended.

[0032] (2) For patients weighing less than 30 kg,

[0033] If the child is less than 3 months old, use sirolimus at 0.02 mg / kg / day.

[0034] If the child is over 3 months old and less than 6 months old, use sirolimus at 0.04 mg / kg / day.

[0035] If the child is over 6 months old and less than 12 months old, use sirolimus at 0.06 mg / kg / day.

[0036] If the child is over 12 months old, sirolimus 0.08 mg / kg / day is used.

[0037] However, the upper limit of the starting dose is 1.4 mg / day of sirolimus per patient.

[0038] Implementation 4:

[0039] The therapeutic agent according to any one of Embodiments 1 to 3 is characterized in that the blood trough level of sirolimus in the patient is adjusted to 5 ng / mL or more and 15 ng / mL or less by increasing or decreasing the dosage based on the measured value of the blood concentration of sirolimus when the same dosage is repeatedly administered for a predetermined period of time.

[0040] Implementation 5:

[0041] In the therapeutic agent according to any one of Embodiments 1 to 3, the dosage is increased or decreased based on clinical symptoms when the same dosage is repeatedly administered for a predetermined period of time.

[0042] Implementation 6:

[0043] In the therapeutic agent described in any one of Embodiments 1 to 5, the refractory lymphatic disease and refractory vascular disease are selected from Kaposi's hemangioendothelioma, plexiform angioma, lymphangioma, lymphangiomatosis, Gorham's disease, venous malformation, blue rubber bleb nevus syndrome, mixed vascular malformation and Creutzfeldt-Verbene syndrome.

[0044] Implementation 7:

[0045] In the therapeutic agent described in any one of Embodiments 1 to 6, the therapeutic agent is a granule.

[0046] Implementation 8:

[0047] A method for treating refractory lymphatic disease and refractory vascular disease, comprising the following steps:

[0048] (a) determining the initial dosage of sirolimus based on parameters associated with the in vivo dynamics of sirolimus and the patient's weight and age; and

[0049] (b) administering the pharmaceutical composition comprising sirolimus orally or by tube administration.

[0050] Implementation 9:

[0051] A method for treating refractory lymphatic disease and refractory vascular disease, wherein:

[0052] The pharmaceutical composition comprising sirolimus is administered orally or via tube administration at a starting dose as shown below:

[0053] (1) For patients weighing more than 30 kg, 1.4 mg / day of sirolimus is recommended.

[0054] (2) For patients weighing less than 30 kg,

[0055] If the child is less than 3 months old, use sirolimus at 0.02 mg / kg / day.

[0056] If the child is over 3 months old and less than 6 months old, use sirolimus at 0.04 mg / kg / day.

[0057] If the child is over 6 months old and less than 12 months old, use sirolimus at 0.06 mg / kg / day.

[0058] If the child is over 12 months old, sirolimus 0.08 mg / kg / day is used.

[0059] However, the upper limit of the starting dose is 1.4 mg / day of sirolimus per patient.

[0060] Implementation 10:

[0061] A use of sirolimus for preparing medicines for treating refractory lymphatic diseases and refractory vascular diseases, characterized in that:

[0062] The initial dose of sirolimus is determined based on parameters associated with the in vivo dynamics of sirolimus and the weight and age of the patient, and sirolimus is administered orally or intravenously.

[0063] Effects of the Invention

[0064] According to the present invention, an effective and minimum dose of sirolimus can be administered for treating refractory lymphatic diseases and refractory vascular diseases or improving symptoms, and as a result, the burden on patients (especially children including infants) can be reduced and QOL can be achieved while safely improving the treatment or symptoms of refractory lymphatic diseases and refractory vascular diseases. DETAILED DESCRIPTION

[0065] Hereinafter, the therapeutic agent for refractory lymphatic disease and refractory vascular disease of the present invention will be described in detail.

[0066] In the present invention, refractory lymphatic diseases are a general term for refractory diseases caused by abnormalities in lymphatic vessels, and examples thereof include lymphangioma (lymphatic malformation), lymphangiomatosis, Gorham's disease, and lymphangiectasia.

[0067] In the present invention, refractory vascular disease is a general term for refractory diseases caused by abnormal blood vessels, and examples thereof include hemangioendothelioma, tufted angioma, venous malformation, blue rubber bleb nevus syndrome, mixed vascular malformation, and Creutzfeldt-Verbene syndrome.

[0068] Although refractory lymphatic disease and refractory vascular disease are different in disease name, they are both diseases caused by abnormal formation of blood vessels or lymphatic vessels, and are published as a treatment guideline (Guidelines for the diagnosis and treatment of hemangiomas, vascular malformations, and lymphatic malformations 2017). Therefore, in the present invention, these diseases are collectively referred to as "refractory lymphatic disease and refractory vascular disease" as treatment targets.

[0069] In the present invention, the treatment targets, namely, refractory lymphatic diseases and refractory vascular diseases, also include mixed types of lymphatic diseases and vascular diseases, which are concepts that can also be called so-called vascular tumors and vascular malformations or vascular abnormalities.

[0070] The therapeutic agent of the present invention is a therapeutic agent for one or more diseases or symptoms selected from refractory lymphatic disease, refractory vascular disease and symptoms associated with these diseases, containing sirolimus as an active ingredient, and is administered orally or intravenously with a dose determined based on a parameter associated with the in vivo dynamics of sirolimus and the weight and age of the patient as the initial dosage.

[0071] Specifically, the therapeutic agent of the present invention is a therapeutic agent for refractory lymphatic diseases and refractory vascular diseases containing sirolimus as an active ingredient, characterized in that administration is initiated by oral or intravenous administration at a dosage determined based on parameters related to the in vivo dynamics of sirolimus (blood hemoglobin concentration, dosage form (difference between tablets and granules), storage state of blood concentration quantification specimens (difference between frozen storage and refrigerated storage), presence or absence of concomitant medication (particularly CYP3A4 inducers or inhibitors)) and the patient's weight and age.

[0072] In a preferred embodiment of the present invention, the initial dosage can be calculated based on a theoretical formula that represents the dynamics of the patient's body after sirolimus administration. Specifically, the dosage of sirolimus in patients with the target disease and the measured value of the blood concentration are applied to a theoretical formula such as a two-compartment model to calculate each inherent parameter, and based on the theoretical formula completed using the parameters, the dosage suitable for the patient can be calculated. More specifically, the dosage suitable for the patient can be calculated according to the following method for estimating the blood concentration of sirolimus.

[0073] Method for estimating sirolimus blood concentration

[0074] In a preferred embodiment, the initial dose of sirolimus in the present invention can be determined using a blood sirolimus concentration estimation system for estimating the blood sirolimus concentration.

[0075] In a preferred embodiment, the blood sirolimus concentration estimating system used for estimating the blood sirolimus concentration in the present invention has the following configuration.

[0076] That is, a system for estimating the change of the blood sirolimus concentration of a patient who has been repeatedly administered a drug containing sirolimus as an active ingredient, comprising: a patient information input unit for receiving input of patient information including at least age and weight; a drug administration information input unit for receiving input of drug administration information including at least the dosage and timing of administration of the drug; a storage unit for storing a blood concentration calculation formula and a parameter calculation formula, the blood concentration calculation formula representing the blood concentration of sirolimus based on a two-compartment model when the drug is repeatedly administered, and the parameter calculation formula calculating parameters applicable to the blood concentration calculation formula; a parameter calculation unit for calculating parameters corresponding to the patient information using the parameter calculation formula read from the storage unit; and an inference curve calculation unit for applying the parameters and the drug administration information to the blood concentration calculation formula to obtain a curve representing the change of the blood sirolimus concentration; the age of the patient in months used to determine the parameters at each time point is the age of the patient at each time point calculated based on the date of birth, and the weight of the patient used to determine the parameters at each time point is the estimated weight of the patient at each time point inferred based on the change of the patient's past weight change.

[0077] According to this structure, the age and weight at the time point of estimating the blood sirolimus concentration can be applied to the parameter calculation formula to calculate the parameters, and the blood sirolimus concentration can be appropriately obtained. In particular, since the weight of infants and young children varies greatly according to their age, it is difficult to predict the clearance rate. Therefore, by estimating the change of blood sirolimus concentration, an appropriate medication plan can be made.

[0078] The blood sirolimus concentration estimation system further includes a dosage form information input unit for receiving input of information related to the dosage form of the drug, and the parameter calculation unit can determine the parameters based on the information related to the dosage form. According to this structure, the dosage form of the sirolimus preparation can also be considered as a variable factor to determine the parameters of the blood concentration calculation formula, and the blood sirolimus concentration transition can be estimated. In addition, the parameter calculation unit can determine the parameters based on drug concentration assay information.

[0079] The blood sirolimus concentration estimation system further has a concomitant medication information input unit for receiving input of information related to the concomitant medication, and the parameter calculation unit can determine the parameters based on the information related to the concomitant medication. According to this structure, the concomitant medication can also be considered as a variable factor to determine the parameters of the blood concentration calculation formula, and the blood sirolimus concentration transition can be estimated. Here, the concomitant medication that becomes the input object in the concomitant medication information input unit can be a CYP3A4 inhibitor or a CYP3A4 inducer, or other drugs that affect the clearance rate of sirolimus or complications such as liver damage.

[0080] The blood sirolimus concentration estimation system comprises: a measured value input unit for receiving an input of a measured value of the blood concentration of the drug at at least one arbitrary time point of the patient; and a parameter correction unit for performing a posteriori estimation of the parameter based on Bayesian inference using the measured value; and the estimated curve calculation unit can also use the a posteriori estimated parameter to obtain a curve representing the blood concentration transition. According to this structure, the blood sirolimus concentration transition inherent to the patient can be estimated.

[0081] The blood sirolimus concentration estimation system may further include a recommended dosage calculation unit that calculates the recommended dosage of the drug by applying the target value of the blood sirolimus concentration to a curve representing the transition of the blood concentration. According to this structure, the recommended dosage for controlling the transition of the blood sirolimus concentration to the target value can be calculated. In addition, the target value can be set according to the trough value.

[0082] In a preferred embodiment, the method for estimating the blood sirolimus concentration used in the present invention is a method for estimating the change in the blood sirolimus concentration of a patient who has been repeatedly administered a drug containing sirolimus as an active ingredient, comprising the following steps: accepting input of patient information including at least age and weight; accepting input of medication information including at least the dosage and timing of the medication; reading a blood concentration calculation formula and a parameter calculation formula from a storage unit, the blood concentration calculation formula representing the blood concentration of sirolimus based on a two-compartment model when the medication is repeatedly administered, the parameter calculation formula calculating parameters applicable to the blood concentration calculation formula; using the parameter calculation formula read from the storage unit to calculate parameters corresponding to the patient information; and applying the parameters and the medication information to the blood concentration calculation formula to obtain a curve representing the change in the blood sirolimus concentration; the age of the patient used to determine the parameters at each time point is the age of the patient at each time point calculated based on the date of birth, and the weight of the patient used to determine the parameters at each time point is the estimated weight of the patient at each time point estimated based on the change in the patient's past weight. The blood sirolimus concentration estimation method may have various structures of the blood sirolimus concentration estimation system described above. For example, the presence or absence of a CYP3A4 inhibitor or CYP3A4 inducer, dosage form information of sirolimus preparations, and drug concentration assay information may be used to determine the parameters at each time point.

[0083] Hereinafter, the configuration and operation of the blood sirolimus concentration estimation system used for determining the initial dosage in the present invention will be described.

[0084] Figure 1 1 is a diagram showing the structure of a blood sirolimus concentration estimation system 1 in a preferred embodiment. The blood sirolimus concentration estimation system 1 includes: an input unit 10 for receiving input of various data; a calculation unit 11 for estimating the transition of the blood sirolimus concentration based on the input data; a storage unit 12 for storing data used for calculation; and an output unit 13 for outputting an estimated curve of the estimated transition of the blood sirolimus concentration or a recommended dosage of a drug.

[0085] The input unit 10 receives input of patient information including the patient's date of birth or weight, medication information related to the dosage and timing of the medication, information on the dosage form (tablet / granule / crushed) of the medication, and information on concomitant medication. In this embodiment, information on CYP3A4 inhibitors or CYP3A4 inducers is received as concomitant medications. Here, the information on concomitant medications may be the rate of change of a pharmacodynamic parameter (particularly CL / F (clearance / dose), but not limited thereto) when the concomitant medication is taken together with the medication. In addition, the input unit 10 receives input of data on the actual value of the sirolimus concentration in the patient's blood and data on the target value.

[0086] The storage unit 12 stores pre-constructed PK (pharmacokinetics) model information. Specifically, a calculation formula for the blood concentration of sirolimus, the active ingredient, when the drug is repeatedly administered, a parameter calculation formula for calculating the parameters corresponding to the patient information, and an estimated value of the pre-constructed drug dynamic parameter are stored. The blood concentration calculation formula is a formula that represents the blood concentration of sirolimus based on a two-compartment model. The parameters corresponding to the patient information are parameters used in the blood concentration calculation formula, and are standard parameters for inferring the blood sirolimus concentration of patients with the same patient information (also referred to as "patient background"). In this manual, it is referred to as a "standard PK parameter."

[0087] In an embodiment of the blood sirolimus concentration estimation system, the blood concentration calculation formula is represented by the following formula (1).

[0088] [Formula 1]

[0089]

[0090] Among them, k a is the absorption rate constant (h-1), Cl / F is the clearance rate (L / h), V1 / F is the volume of the first compartment (L), V2 / F is the volume of the second compartment (L), and Q / F is the intercompartmental clearance rate (L). The values ​​of these parameters are related to the patient's weight and age, the dosage form of the drug administered, and the presence or absence of concurrent CYP3A4 inhibitors or CYP3A4 inducers. In addition, D i It is the dosage of the drug.

[0091] Each parameter of the blood concentration calculation formula is represented by a function with the patient's weight and age, the dosage form of the drug, etc. as variables. This function is equivalent to a parameter calculation formula for calculating the parameters corresponding to the patient. This parameter calculation formula is obtained in advance by a population pharmacokinetic analysis using a nonlinear mixed effect model.

[0092] The calculation formula for obtaining the parameter corresponding to the patient is described in detail. In one example, the absorption rate constant k a The calculation formula of is expressed by the following formula (2).

[0093] [Formula 2]

[0094] k a =TVk a ×[4.26 if Granule formulation] …(2)

[0095] In formula (2), TVk a is the absorption rate constant k aThe typical value (TypicalValue) is obtained in advance by population pharmacokinetic analysis. In this embodiment, TVK a The point estimate is 0.235 (h-1), the relative error is 1.17%, and the width of the 95% confidence interval is 0.229-0.240. In addition, "Granule formulation" means granules. Formula (2) shows that when the drug is a granule, TVk a Multiply by 4.26.

[0096] The calculation formula of the clearance rate Cl / F is represented by the following formula (3).

[0097] [Formula 3]

[0098]

[0099] In formula (3), TVCl is the typical value of the clearance Cl / F, which is obtained in advance by population pharmacokinetic analysis. In this embodiment, the point estimate of TVCl is 6.44 (L / h), the relative error is 6.04%, and the width of the 95% confidence interval is 5.72-7.25. In addition, WT is the patient's weight. PMA (Post menstrual age) is the age after the last menstrual period (pregnancy + postnatal age), which corresponds to the patient's age. e ηCL Indicates inter-individual variation. When there is no actual measured value for a patient, ηCL is 0 and inter-individual variation is 1. "Clinical trials assay" refers to frozen blood samples. For frozen blood samples, multiply by 1.92. For refrigerated blood samples, multiply by 1. "CYP3A4 foldchange" is a coefficient determined by the combined medication when there is a combined medication. For the coefficient, refer to Fig. 9 Provide explanation.

[0100] The calculation formula for the volume V1 / F of the first chamber is expressed by the following formula (4).

[0101] [Formula 4]

[0102]

[0103] In formula (4), TVV1 is the typical value of the volume of the first chamber V1 / F, which is obtained in advance by population pharmacokinetic analysis. In the embodiment, the point estimate of TVV1 is 176 (L), the relative error is 2.43%, and the width of the 95% confidence interval is 168-185. In addition, WT is the weight of the patient. ηV1 indicates inter-individual variation. In the absence of actual measured values ​​for patients, ηV1 is 0 and inter-individual variation is 1. In addition, it is sometimes difficult to infer the random effect of patients on V1 based on the available information, but in this case, for all patients, inter-individual variation can also be set to 1 relative to V1.

[0104] The calculation formula for the volume V2 / F of the second chamber is expressed by the following formula (5).

[0105] [Formula 5]

[0106]

[0107] In formula (5), TVV2 is the typical value of the volume of the second chamber V2 / F, which is obtained in advance by population pharmacokinetic analysis. In this embodiment, the point estimate of TVV2 is 281 (L), the relative error is 13%, and the width of the 95% confidence interval is 218-362. In addition, WT is the weight of the patient.

[0108] The calculation formula of the interventricular clearance rate Q / F is expressed by the following formula (6).

[0109] [Formula 6]

[0110]

[0111] In this formula, TVQ is the typical value of the interventricular clearance rate Q / F, which is obtained in advance by population pharmacokinetic analysis. In this embodiment, the point estimate of TVQ is 33.6 (L), the relative error is 4.07%, and the width of the 95% confidence interval is 31.0-36.3. In addition, WT is the weight of the patient.

[0112] The calculation unit 11 includes a parameter calculation unit 20, a parameter correction unit 21, an estimated curve calculation unit 22, a recommended dosage calculation unit 23, and a report generation unit 24. These functions are realized by the calculation unit 11 executing a program for estimating the blood sirolimus concentration.

[0113] The parameter calculation unit 20 has a function of calculating a standard PK parameter (absorption rate constant k a , clearance Cl / F, volume of the first chamber V1 / F, volume of the second chamber V2 / F, and inter-chamber clearance Q / F). The parameter calculation unit 20 calculates the standard PK parameters corresponding to the patient information using the date of birth and weight data of the patient input from the input unit 10. The details of the processing will be described later.

[0114] The parameter correction unit 21 has a function of updating the standard PK parameter afterward using the actual measured value of the patient's blood sirolimus concentration.a , Cl / F, V1 / F, V2 / F, Q / F) have variances randomly. The patient's actual measured values ​​are used to reduce the variance and obtain the patient-specific PK parameters. In this manual, they are referred to as "patient PK parameters". As an example, the clearance rate Cl / F is used as an example for explanation. The TVCl of the final model of Cl / F and its variance are used as the conjugate prior distribution, and the patient's actual measured values ​​and their variances are used as the likelihood, and the conjugate posterior distribution is obtained according to Bayes' theorem. Specifically, the conjugate posterior distribution is obtained by multiplying the conjugate prior distribution by the likelihood. The central value TVCl of the updated distribution obtained in this way is i Become the patient's unique TVCl.

[0115] The estimated curve calculation unit 22 has a function of calculating the standard PK parameters calculated by the parameter calculation unit 20 or the patient PK parameters corrected and obtained by the parameter correction unit 21 and the medication information D. i A function to obtain a curve showing the transition of the blood concentration of sirolimus accompanying drug administration by applying the blood concentration calculation formula (formula (1)). The curve showing the transition of the blood concentration obtained using the standard PK parameters is a standard concentration transition curve for a patient of the same age and weight as the patient, whereas the curve showing the transition of the blood concentration obtained using the patient PK parameters is a patient-specific blood concentration transition curve reflecting the patient data.

[0116] Figure 2 The patient's age is 7 years old (body surface area 1.0 to less than 1.5 m 2 ) is a graph showing a standard transition curve of blood sirolimus concentration when a 2 mg tablet is administered once a day to a patient. Figure 2 The change in blood sirolimus concentration is estimated with a 90% prediction interval as shown in medium gray. That is, the blood sirolimus concentration of patients of the same age and weight falls within the range shown in gray with a 90% probability. Figure 2 In FIG. 8 , the curve indicated by the bold line shows the transition of the blood sirolimus concentration obtained by using the point estimation of TypicalValue as the standard PK parameter.

[0117] The recommended dosage calculation unit 23 calculates the recommended dosage of the drug containing sirolimus as the active ingredient by applying the target value of the blood sirolimus concentration to the curve representing the transition of the blood concentration. The report preparation unit 24 has the function of preparing a report on the transition of the blood sirolimus concentration. The output unit 13 has the function of outputting the calculation result of the blood sirolimus concentration transition, the recommended dosage of the drug, and the report.

[0118] Figure 3This is a flowchart showing the operation of the blood sirolimus concentration inference system 1. The blood sirolimus concentration inference system 1 receives input of patient information, medication information, dosage form information, concomitant medication information of CYP3A4 inhibitors or CYP3A4 inducers, and drug concentration test information (S10). The patient information is the patient's date of birth and weight data, and the medication information is data on the dosage of the drug (for example, 1 mg, 2 mg, etc.) and the timing of medication (once a day, twice a day, etc.). The dosage form information is information showing whether the drug administered to the patient is a granule or tablet. The concomitant medication information of the CYP3A4 inhibitor or CYP3A4 inducer may be the rate of change of the drug dynamic parameter when the concomitant medication is taken together with the present drug. For this rate of change, use Fig. 9 This will be described later. The drug concentration test information is information indicating whether the blood sample is stored frozen or refrigerated. In the future, if the parameters that affect the blood concentration calculation formula (for example, the amount of hemoglobin, etc.) are clarified, new parameters can also be input as patient information.

[0119] In addition, the blood sirolimus concentration estimation system 1 receives an input of a target value of the blood sirolimus concentration (S11). In the present embodiment, the target value is a trough value of the blood sirolimus concentration. Next, the blood sirolimus concentration estimation system 1 calculates a standard PK parameter based on the input patient information, medication information, and dosage form information (S12).

[0120] Figure 4: is a flowchart showing the calculation process of the standard PK parameters. The blood sirolimus concentration estimation system 1 calculates the age (monthly age) at the time of estimation of the blood concentration based on the patient's date of birth (S20). In addition, the weight at the time of estimation of the blood concentration is predicted based on the patient's weight data (S21). In order to predict the weight, the weight data input as patient information is preferably data indicating the transition of weight change. That is, it is preferred to have weight data at multiple times. For example, linear regression is performed on the weight data at three time points to predict the patient's weight in the next three months. As an example, 3 months (90 days) are divided into 500, and the weight at each time point is predicted. The blood sirolimus concentration estimation system 1 applies the age at the time of estimation and the predicted weight data to the parameter calculation formula to determine the standard PK parameters used at each estimation time (S22). In addition, the blood sirolimus concentration estimation system 1 can also perform linear regression of the future weight based on the input weight data as described above to obtain the weight predicted at the time of estimation, or use the final weight data after the final weight data. Whether to perform linear regression or use the final weight data can be determined based on the number of input weight data. Linear regression can be performed when weight can be inferred with high accuracy through linear regression, and the final weight data can be used when linear regression is not successful. For example, linear regression can be performed when the number of input data is more than 3 points, and the final weight data can be used when the number of input data is less than 3 points, but the threshold is not limited to 3 points, and can also be 2 points, or more than 4 points.

[0121] return Figure 3 The blood sirolimus concentration estimation system 1 determines whether the actual value of the patient's blood sirolimus concentration has been input (S13). When the patient's actual value is input ("Yes" in S13), the standard PK parameters are updated using the actual value, and the patient's PK parameters are calculated (S14). When the actual value is not input ("No" in S13), the standard PK parameters are directly used.

[0122] The blood sirolimus concentration estimation system 1 generates a blood concentration calculation formula using the standard PK parameters or patient PK parameters at the estimation time, applies the drug administration information to the blood concentration calculation formula, estimates the blood sirolimus concentration at each estimation time, and performs PK simulation (S15). The blood sirolimus concentration estimation system 1 applies the target value to the obtained blood concentration transition and calculates the recommended dosage of the drug (S16). Next, the blood sirolimus concentration estimation system 1 creates a report summarizing the blood sirolimus concentration transition, the recommended dosage, etc. (S17), and outputs the created report (S18).

[0123] Figure 5(a) is a graph showing the change in blood sirolimus concentration estimated using standard PK parameters to which patient information is applied. Figure 5 (b) is a graph showing the estimated change in blood sirolimus concentration by updating the standard PK parameters and obtaining the patient-specific PK parameters using the patient's actual measured values ​​of blood sirolimus concentration (3 o'clock on February 13, March 13, and April 13, 2021). Figure 5 (a) and Figure 5 As can be seen from (b) in FIG. 1 , the blood sirolimus concentration corrected based on the actual measured value changes at a position lower than the standard blood sirolimus concentration, and becomes a concentration change specific to the patient including the actual measured value.

[0124] Figure 5 (c) is a graph showing the change in blood sirolimus concentration when a drug corresponding to the target value is administered when 10 ng / mL is input as the target trough value. Figure 5 (b) and Figure 5 As shown in (c), the trough value increased to 10 ng / mL by changing to the recommended dosage corresponding to the target value.

[0125] Figure 6 to Figure 9 1 is a diagram showing an example of an output screen of the blood sirolimus concentration estimation system 1 according to the present embodiment. The output screen is a screen created by the report creation unit 24. Figure 6 As shown, the output screen has tabs "Individual prediction results of concentration transition", "CYP3A4 reference materials", and "Application usage guide" at the top of the screen.

[0126] Figure 6 An example of a screen when the tab "Individual prediction results of concentration transition" is selected is shown. In this tab, the individual prediction results of concentration transition predicted based on the patient information and medication information of the selected patient and the actual measured value are displayed in a graph. The vertical axis of the graph is the sirolimus concentration in the blood, and the horizontal axis is the time axis. The black dots in the graph show the actual measured values ​​of the trough values ​​of the sirolimus concentration in the patient's blood.

[0127] A slider for setting the "target valley concentration range" is provided between the label and the graph at the top of the screen. The upper and lower limits of the target valley concentration range can be set using the round button on the slider. The set upper and lower limits are displayed on the graph as dotted lines extending horizontally. Figure 6 In the example shown, the upper limit is 15 ng / mL and the lower limit is 5 ng / mL. By displaying the upper and lower limits on the graph in this way, the target trough concentration range can be understood at a glance.

[0128] exist Figure 6The lower part of the screen shows the optimal dosage of the drug based on the simulation results. It contains "dosing interval", "target trough concentration (ng / mL)", "optimal dose per dose (mg)", and "optimal daily dose (mg)". This is the dosage that is the premise for the above concentration prediction. Figure 6 In the example shown, the optimal dose per dose is 0.47 mg and the optimal daily dose is 0.94 mg for a dosing interval of BID / Q12h (twice a day) and a target trough concentration of 10 ng / mL. The optimal dose per dose is 1.08 mg and the optimal daily dose is 1.08 mg for a dosing interval of QD / Q24h (once a day) and a target trough concentration of 10 ng / mL.

[0129] Figure 7 FIG. 2 is a diagram showing another example of the screen when the tab "Individual prediction result of concentration transition" is selected. Figure 7 The screen example shown shows the 90% prediction interval of sirolimus concentration in the blood of patients with the same patient background such as age, weight, and concurrent medication information, so that it is possible to check how much the concentration transition of an individual patient differs from the average value of a group of patients with the same patient background.

[0130] Figure 8 FIG. 2 is a diagram showing another example of the screen when the tab "Individual prediction result of concentration transition" is selected. Figure 8 In the example screen shown, the absorption phase and distribution phase of the concentration curve are not displayed, only the valley concentration is displayed, and Figure 7 Similarly, the 90% prediction interval of the blood sirolimus concentration in the same patient background is shown. Since the trough concentration value is important in the dosage planning of sirolimus, it is convenient to be able to confirm the transition of the trough concentration value.

[0131] Users can choose to Figure 6 to Figure 8 In which mode do you want to display the "individual prediction results of concentration transition"? For example, in the screen for inputting patient data, there are interfaces for switching "displaying concentration transition of only trough concentration" on and off, and for switching "patient background" on and off. When both "displaying concentration transition of only trough concentration" and "patient background" are turned off, the display Figure 6 When "Display only valley concentration changes" is turned on, the screen Figure 8 When “Patient Background” is turned on, Figure 7 and Figure 8 Shown are 90% prediction intervals for blood sirolimus concentrations for the same patient background.

[0132] Fig. 9 It is shown in Figure 6 to Figure 8The figure shows an example of a screen when the tab of "CYP3A4 Reference Materials" is selected in the screen shown. In the screen of "CYP3A4 Reference Materials", when a patient takes a CYP3A4 inhibitor or a CYP3A4 inducer at the same time as sirolimus, the degree of influence of these combined drugs on the concentration of sirolimus is shown in a list. The list shows the rate of change of the drug dynamic parameters when the present drug and the CYP3A4 inhibitor or the CYP3A4 inducer are used in combination. Here, the rate of change refers to the ratio of the geometric least squares (GLS) mean, specifically, (present drug + combined drug) / (present drug alone). In the case of combined drugs recorded in the "CYP3A4 Reference Materials", the value of the rate of change of "CL / F" (clearance rate) is input as the combined drug information. Thus, the value of the clearance rate Cl / F calculated by formula (3) is appropriately corrected based on the information on the combined drug. For example, when a CYP3A4 inhibitor is used concurrently, the change ratio of CL / F is less than 1, and the inhibition of drug metabolism is reflected in the standard / patient PK parameters.

[0133] The "Guide to the use of the application" tab is explained. The "Guide to the use of the application" tab displays the user manual of the blood sirolimus concentration estimation system.

[0134] The blood sirolimus concentration estimation system and the blood sirolimus concentration estimation method are described above. The blood sirolimus concentration estimation system of this embodiment can calculate the age at the estimation time and predict the weight at the estimation time, and calculate the standard PK parameters using the age and weight of the patient at the estimation time, and can appropriately estimate the starting dosage as follows.

[0135] In another embodiment of the present invention, the initial dosage is determined by:

[0136] Using patient information including at least age and weight and administration information including at least the dosage and timing of administration of the drug,

[0137] calculating the parameter corresponding to the patient information using a blood concentration calculation formula representing the blood concentration of sirolimus based on a two-compartment model in case of repeated administration and a parameter calculation formula for calculating a parameter applied to the blood concentration calculation formula,

[0138] Applying the parameter and the medication information to the blood concentration calculation formula to obtain a curve representing the transition of the blood sirolimus concentration, and applying the target value of the blood sirolimus concentration to the curve representing the transition of the blood sirolimus concentration to obtain the initial medication dose;

[0139] Here, the patient's age in months used to determine the parameters at each time point is the patient's age in months at each time point calculated based on the date of birth, and the patient's weight used to determine the parameters at each time point is the estimated weight of the patient at each time point inferred based on the patient's past weight changes.

[0140] As a preferred example, the initial dosage may be the following dosage.

[0141] That is, (1) for patients weighing more than 30 kg, 1.4 mg / day of sirolimus is used. (2) For patients weighing less than 30 kg, according to the amount per unit body weight corresponding to the age in months, when the age is less than 3 months, 0.02 mg / kg / day of sirolimus is used, when the age is more than 3 months and less than 6 months, 0.04 mg / kg / day of sirolimus is used, when the age is more than 6 months and less than 12 months, 0.06 mg / kg / day of sirolimus is used, and when the age is more than 12 months, 0.08 mg / kg / day of sirolimus is used. However, the upper limit of the starting dose is 1.4 mg / day of sirolimus per patient. That is to say, when the dosage calculated in the above manner exceeds 1.4 mg, 1.4 mg is set as the starting dosage.

[0142] It is generally believed that sirolimus inhibits tumors by inhibiting the action of mTOR (mammalian target of rapamycin) which regulates cell division, proliferation, survival, etc. The inventors have shown that by orally or intravenously administering the agent of the present invention containing sirolimus as an active ingredient at the starting dose specified in the present invention, the blood trough value of sirolimus is shown to be in the range of 5 to 15 ng / mL or a value in the vicinity thereof. Here, the blood trough value refers to the lowest blood drug concentration in a stable state when the drug is repeatedly administered. The therapeutic agent for refractory lymphatic disease and refractory vascular disease of the present invention can safely and effectively treat the disease by maintaining the blood trough value of sirolimus within such a range.

[0143] In a preferred embodiment, the therapeutic agent for refractory lymphatic disease and refractory vascular disease of the present invention can also be adjusted so that the blood trough level of sirolimus in the patient is 5 ng / mL or more and 15 ng / mL or less by increasing or decreasing the dosage based on the measured value of the blood trough level of sirolimus. Since the therapeutic agent for refractory lymphatic disease and refractory vascular disease of the present invention has such a structure, it can safely and effectively treat the disease even when the systemic clearance rate of sirolimus varies greatly.

[0144] Specifically, after administering the agent of the present invention, the blood sirolimus concentration is measured at the moment when the blood sirolimus concentration approaches a steady state, and the dose can be increased or decreased under the conditions that the dose is not changed when the blood sirolimus concentration is 5 ng / mL or more and 15 ng / mL or less, the dose is increased when it is less than 5 ng / mL, and the dose is reduced when it exceeds 15 ng / mL. Here, the measurement period of the blood sirolimus concentration can be between 6 and 14 days after the start of administration at the same dose. The increase or decrease range of the dose can be, for example, a condition that the dose is increased by 30 to 50% when the blood sirolimus concentration is less than 5 ng / mL, and a condition that the dose is reduced by 30 to 50% when it exceeds 15 ng / mL. The increase or decrease of the dosage can be selected according to the patient's condition, but in a preferred embodiment, the increase or decrease can be set to 30% for patients weighing less than 30 kg (that is, an increase of 30% when the blood sirolimus concentration is less than 5 ng / mL, and a decrease of 30% when it exceeds 15 ng / mL), and in the case of patients weighing more than 30 kg, the increase or decrease can be set to 50% (that is, an increase of 50% when the blood sirolimus concentration is less than 5 ng / mL, and a decrease of 50% when it exceeds 15 ng / mL). In addition, the repeated administration period until the blood sirolimus concentration is measured for judging the increase or decrease can be any period required for calculating the trough value. For example, it can be set to 1 week to 3 weeks. That is, it is possible to use repeated administration of the same dosage for 1 week, measure the trough value of the blood sirolimus concentration at this time, and judge the increase or decrease of the dosage.

[0145] In addition, in another preferred embodiment, the dosage of the therapeutic agent for refractory lymphatic diseases and refractory vascular diseases of the present invention can be increased or decreased based on clinical symptoms observed after repeated administration for a predetermined period. For example, after repeated administration for a predetermined period, the dosage can be increased by 30 to 50% when the expansion of the lesion site is not suppressed, and the original dosage can be continued when the lesion site is reduced, and the dosage can be reduced by 30 to 50% when significant side effects are confirmed. The increase or decrease range of the dosage can be selected according to the patient's condition, but in a preferred embodiment, the increase or decrease range can be set to 30% for patients weighing less than 30 kg (that is, increase by 30% when the expansion of the lesion site is not suppressed, and reduce by 30% when serious side effects are confirmed), and the increase or decrease range can be set to 50% for patients weighing more than 30 kg (that is, increase by 50% when the expansion of the lesion site is not suppressed, and reduce by 50% when serious side effects are confirmed).

[0146] The therapeutic agent for refractory lymphatic diseases and refractory vascular diseases of the present invention is provided in all dosage forms that can be administered orally or via tube, for example, in the form of granules, syrups (including dry syrups), tablets, or orally disintegrating tablets, and preferably in the form of granules or syrups.

[0147] The therapeutic agent for refractory lymphatic disease and refractory vascular disease of the present invention can be manufactured by a known method according to the respective dosage forms. For example, in the case of tablets, it can be manufactured by adding a binder or a lubricant to sirolimus as needed, mixing it with an excipient, and compressing it using a tablet molding machine. Alternatively, commercially available tablets with sirolimus as an active ingredient can also be purchased for use. In addition, in the case of granules, it can be manufactured by mixing a solution containing sirolimus with a binder and core particles and drying them. In more detail, it can be manufactured by the method described in Japanese Patent Laid-Open No. 2021-88507. The therapeutic agent for refractory lymphatic disease and refractory vascular disease of the present invention is preferably able to use the granules containing sirolimus disclosed in Japanese Patent Laid-Open No. 2021-88507.

[0148] The therapeutic agent for refractory lymphatic disease and refractory vascular disease of the present invention contains about 0.01% to about 20% by weight of sirolimus based on the total composition, preferably about 0.05% to about 10% by weight of sirolimus based on the total composition, and more preferably about 0.1% to about 5% by weight of sirolimus based on the total composition.

[0149] The therapeutic agent for refractory lymphatic diseases and refractory vascular diseases of the present invention thus obtained can be adjusted in dosage according to the initial dosage, for example, when it is in the form of a tablet.

[0150] In one embodiment of the present invention, the target refractory lymphatic disease and refractory vascular disease of the present invention is a disease selected from Kaposi's hemangioendothelioma, plexiform angioma, lymphangioma, lymphangiomatosis, Gorham's disease, venous malformation, blue rubber bleb nevus syndrome, mixed vascular malformation and Creutzfeldt-Verbene syndrome.

[0151] Therefore, the therapeutic agent for refractory lymphatic diseases and refractory vascular diseases of the present invention can be used for the treatment of diseases selected from Kaposi's hemangioendothelioma, plexiform angioma, lymphangioma, lymphangiomatosis, Gorham's disease, venous malformation, blue rubber bleb nevus syndrome, mixed vascular malformation and Creutzfeldt-Verbene syndrome.

[0152] The therapeutic agent for refractory lymphatic disease and refractory vascular disease of the present invention sets the initial dosage according to the patient's age or weight, and can safely and effectively treat refractory lymphatic disease and refractory vascular disease through less frequent blood monitoring.

[0153] On the other hand, when the therapeutic agent for refractory lymphatic diseases and refractory vascular diseases of the present invention is used to treat the above-mentioned various diseases, the dose of sirolimus can be increased or decreased based on the clinical symptoms of the disease observed after repeated administration for a predetermined period of time.

[0154] In the present invention, when a combined drug is used, the administration method of sirolimus and the combined drug is not particularly limited, and either sequential administration or simultaneous administration may be used.

[0155] In the present invention, even when a CYP3A4 inducer or inhibitor is used as a concomitant drug, the initial dose of sirolimus can be determined according to the method for estimating the blood concentration of sirolimus in consideration of the use of the concomitant drug.

[0156] Furthermore, the therapeutic agent for refractory lymphatic diseases and refractory vascular diseases of the present invention can be combined with surgery, nutritional therapy, or radiotherapy known to those skilled in the art.

[0157] Furthermore, when the therapeutic agent for refractory lymphatic diseases and refractory vascular diseases of the present invention is used for treatment together with the above-mentioned concomitant agent, or when combined with nutritional therapy or radiotherapy, the dosage of sirolimus can be increased or decreased based on clinical symptoms observed after repeated administration for a predetermined period of time.

[0158] [Example]

[0159] The following specific implementations are given to illustrate the present invention, but it should be understood that the present invention is not limited to this implementation, and those skilled in the art can perform various changes and modifications therein without departing from the scope or spirit of the present invention as defined in the appended claims.

[0160] (Manufacture of sirolimus granules)

[0161] 1.0 g of tocopherol (DL-ALPHA-Tocopherol manufactured by BASF Japan Co., Ltd.) was added to 100 g of sirolimus ethanol solution (1% by mass) and dissolved. The solution was added to 298.0 g of mannitol while stirring in a mixer. The mixture was transferred to a fluidized bed dryer and dried at an air supply temperature of 70° C. until the loss on drying was less than 0.4%. The obtained solid was sieved with a sieve having a mesh size of 1 mm to prepare sirolimus granules.

[0162] Example 1 (Administration to patients and confirmation of blood concentration)

[0163] Sirolimus granules were repeatedly administered to 5 patients at an initial dose that matched their body weight and age (in months) for a specified period. Blood was collected 6 to 10 days after the first administration and immediately before the second and subsequent administrations, and the sirolimus concentration was quantified using LC-MS (Liquid Chromatograph-Mass Spectrometer) under the following conditions and used as blood trough data. Administration was continued while adjusting the dosage according to the blood trough value. The results are shown in Tables 2 to 6 together with the names of the diseases suffered by the patients. As shown in the table, the therapeutic effect was confirmed in all patients by administering the therapeutic agent of the present invention.

[0164] ·LC conditions

[0165] Column: ZORBAX (registered trademark) XDB-CN (inner diameter 2.1 mm, length 50 mm) (Agilent Technologies, Inc.)

[0166] Column temperature: 50°C

[0167] Mobile phase: 0.1% acetic acid aqueous solution and 0.1% acetic acid acetonitrile solution were mixed in the ratio listed in Table 1

[0168] Flow rate: 0.45mL / min

[0169] [Table 1]

[0170] Gradient Program

[0171] Time (min) 0.1% acetic acid aqueous solution 0.1% acetic acid in acetonitrile 0 48 52 8 48 52 8.5 0 100 10 0 100 10.5 80 20

[0172] MS / MS conditions

[0173] Measurement mode: Positive ESI

[0174] Gas temperature: 350℃

[0175] Gas flow rate: 10L / min

[0176] Sprayer pressure: 50psi

[0177] Capillary voltage: 4000V

[0178] [Table 2]

[0179] Case 1: Krashen-Trevor-Weiss syndrome

[0180]

[0181] [Table 3]

[0182] Case 2: Creutzfeldt-Willi syndrome

[0183]

[0184] [Table 4]

[0185] Case 3: Lymphangioma

[0186]

[0187] [Table 5]

[0188] Case 4 Lymphangiomatosis

[0189]

[0190] The treatment effect in time series No. 4, "normalization of FDP (Fibrin Degradation Products), normalization of D-dimer, and increase in fibrinogen", indicates that the blood coagulation abnormalities (increased FDP, increased D-dimer, and decreased fibrinogen) in lymphangiomatosis have been improved.

[0191] [Table 6]

[0192] Case 5: Vascular tumor with Kasabach-Merritt phenomenon

[0193]

[0194] Example 2 (confirmed by simulation based on population pharmacokinetic analysis)

[0195] Population pharmacokinetic (PPK) analysis was performed using a nonlinear mixed effects model based on the trough concentration of sirolimus in whole blood of patients with refractory angio-lymphatic diseases, lymphangioleiomyomatosis, etc. who were orally administered sirolimus and healthy adults (number of cases: 215, male: female = 77: 138, average age: 21.3 years). As variable factors affecting the pharmacodynamics of sirolimus, body weight, age in months, blood hemoglobin concentration, dosage form of sirolimus preparation (tablets, granules), storage status of blood concentration quantification specimens during transportation (refrigerated storage, frozen storage), and the presence or absence of concomitant medication (especially CYP3A4 inducers or inhibitors) were determined. According to the above-mentioned method for estimating the blood concentration of sirolimus, the exposure of sirolimus was described by a two-compartment model with a primary absorption process incorporating weight correction based on allometric growth law and maturity correction.

[0196] The model was used to generate virtual patients of "0 to <3 months old", "3 to <6 months old", "6 to <12 months old", and "12 months old to <10 years old". The pharmacokinetic simulation was performed when 0.02 mg, 0.04 mg, 0.06 mg, and 0.08 mg per unit body weight (maximum 1.4 mg / person) of sirolimus granules 0.2% preparation were administered once a day. The results were presented in Fig.10 and Fig.11 In Fig.11 In each graph, the dotted line shows the target sirolimus trough concentration (5 to 15 ng / mL). In addition, the solid line is the average value of sirolimus concentration in whole blood, and its bottom line shows the average sirolimus trough concentration. Fig.11 The gray area in the figure shows the 90th percentile. As can be seen from the figure, for the virtual patients of "0 to <3 months of age", "3 to <6 months of age", "6 to <12 months of age", and "12 months of age to <10 years old", it was confirmed that the average value of the trough concentration of sirolimus in whole blood was included in the range of the target trough concentration of sirolimus in whole blood (5 to 15 ng / mL) in the steady state. In addition, based on the results of this simulation, it is inferred that for the virtual patients of "0 to <3 months of age", "3 to <6 months of age", "6 to <12 months of age", and "12 months of age to <10 years old", 82.2%, 82.8%, 76.1% and 74.2% of the patients respectively maintained the target trough concentration of sirolimus in whole blood (5 to 15 ng / mL) in the steady state. Fig.10 ).

[0197] Industrial Applicability

[0198] According to the present invention, an effective and minimum dose of sirolimus can be administered for treating refractory lymphatic diseases and refractory vascular diseases or improving symptoms, and as a result, the burden on patients (especially children including infants) can be reduced and QOL can be achieved while safely improving the treatment or symptoms of refractory lymphatic diseases and refractory vascular diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0199] Figure 1 It is a diagram showing the structure of the blood sirolimus concentration estimation system.

[0200] Figure 2 This is a graph showing the transition of sirolimus concentration in standard blood. The solid line is the desired transition (posterior probability maximum value MAP), and the shaded area shows the 90% prediction interval. The line parallel to the x-axis shows the treatment area of ​​the valley value.

[0201] Figure 3 This is a diagram showing a flowchart representing the operation of the blood sirolimus concentration estimation device.

[0202] Figure 4 is a flow chart illustrating the patient parameter determination process.

[0203] Figure 5 Among them, (a) is a diagram showing an example of obtaining the change of blood sirolimus concentration based on patient information. (b) is a diagram showing an example of post hoc inference of the change of blood sirolimus concentration obtained based on patient information using the patient's actual measured value by Bayesian inference method. It becomes a change inherent to the patient. (c) is a diagram showing the change of blood sirolimus concentration when a drug with a recommended dosage corresponding to a target value of blood sirolimus concentration is administered.

[0204] Figure 6 This is a diagram showing an example of an output screen of the blood sirolimus concentration estimation system. It is only a graph showing the transition of MAP.

[0205] Figure 7 This is a diagram showing an example of an output screen of the blood sirolimus concentration estimation system. This is a diagram showing MAP and 90% prediction interval.

[0206] Figure 8 This is a diagram showing an example of an output screen of the blood sirolimus concentration estimation system. This is a diagram showing only the trough value MAP and the 90% prediction interval.

[0207] Fig. 9 This is a diagram showing an example of a screen of "CYP3A4 Reference Materials". It shows the change rate of the pharmacodynamic parameter when a CYP3A4 inhibitor is used in combination. The information used in this application is the numerical information of CL / F.

[0208] Fig.10 is a summary of parameters for simulation of sirolimus concentration in whole blood based on PPK analysis.

[0209] Fig.11 The figure shows the simulation of sirolimus concentration in whole blood based on PPK analysis. Respectively, 0m-<3m: 0 to <3 months of age, 3m-<6m: 3 to <6 months of age, 6m-<12m: 6 to <12 months of age, 12m-<10y: 12 months of age to <10 years of age. The horizontal dotted line shows the target sirolimus trough concentration. The solid line is the average whole blood sirolimus concentration, and its bottom edge shows the average trough concentration. The gray area shows the 90th percentile.

[0210] Description of Reference Numerals

[0211] 1: Blood sirolimus concentration estimation system,

[0212] 10: Input section,

[0213] 11: Operation unit,

[0214] 12: Storage Department,

[0215] 13: Output section,

[0216] 20: Parameter calculation unit,

[0217] 21: Parameter correction unit,

[0218] 22: Inference curve calculation unit,

[0219] 23: Recommended dosage calculation unit,

[0220] 24: Report production department.

Claims

1. A therapeutic agent for refractory lymphatic disease and refractory vascular disease, comprising sirolimus as an active ingredient, characterized in that: The initial dosage is determined based on parameters related to the in vivo dynamics of sirolimus and the patient's body weight and age, and the administration is performed orally or intravenously.

2. The therapeutic agent according to claim 1, characterized in that The initial dosage is calculated as follows: Using patient information including at least age and weight and administration information including at least the dosage and timing of administration of the drug, Calculating the parameters corresponding to the patient information by calculating the parameter calculation formula applied to the blood concentration calculation formula representing the blood concentration of sirolimus based on the two-compartment model in case of repeated administration, Applying the parameter and the medication information to the blood concentration calculation formula to obtain a curve representing the transition of the blood sirolimus concentration, and applying the target value of the blood sirolimus concentration to the curve representing the transition of the blood sirolimus concentration to obtain the initial medication dose; Among them, the patient's monthly age used to determine the parameters at each time point is the patient's age at each time point calculated based on the date of birth, and the patient's weight used to determine the parameters at each time point is the estimated weight of the patient at each time point inferred based on the patient's past weight changes.

3. A therapeutic agent for refractory lymphatic disease and refractory vascular disease, comprising sirolimus as an active ingredient, characterized in that: The starting dose is given orally or via tube administration according to the weight and age of the patient with the disease or condition: (1) For patients weighing more than 30 kg, 1.4 mg / day of sirolimus is recommended. (2) For patients weighing less than 30 kg, If the child is less than 3 months old, use sirolimus at 0.02 mg / kg / day. If the child is over 3 months old and under 6 months old, use sirolimus at 0.04 mg / kg / day. If the child is over 6 months old and less than 12 months old, use sirolimus at 0.06 mg / kg / day. If the child is over 12 months old, use sirolimus at 0.08 mg / kg / day. However, the upper limit of the starting dose is 1.4 mg / day of sirolimus per patient.

4. The therapeutic agent according to any one of claims 1 to 3, characterized in that The dosage is increased or decreased based on the measured value of the blood concentration of sirolimus when the same dosage is repeatedly administered for a predetermined period of time, so that the blood trough level of sirolimus in the patient is adjusted to 5 ng / mL or more and 15 ng / mL or less.

5. The therapeutic agent according to any one of claims 1 to 3, characterized in that The dosage is increased or decreased based on clinical symptoms when the same dosage is repeatedly administered for a predetermined period of time.

6. The therapeutic agent according to any one of claims 1 to 5, characterized in that The refractory lymphatic disease and refractory vascular disease are selected from the group consisting of kaposiform hemangioendothelioma, plexiform angioma, lymphangioma, lymphangiomatosis, Gorham's disease, venous malformation, blue rubber bleb nevus syndrome, mixed vascular malformation and Creutzfeldt-Verbene syndrome.

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