JP2008273858A - Glycopeptide-based antibiotic preparation comprising vancomycin hydrochloride as active ingredient for treating cardiac insufficiency patient having normal renal function or renal dysfunction - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a glycopeptide-based antibiotic preparation comprising vancomycin hydrochloride as an active ingredient, which corrects the deviation of predictive values of doses and administration intervals calculated according to the degree of renal dysfunction from actual measurement values and properly treats a patient. <P>SOLUTION: The glycopeptide-based antibiotic preparation comprising vancomycin hydrochloride as an active ingredient for treating a cardiac insufficiency patient having a normal renal function or a renal dysfunction comprises initially administering a dose Y1 (mg/kg) calculated from a specific numerical expression to a cardiac insufficiency patient having creatinine clearance Ccr of ≥50 (mL/minute), weight X (kg) and a normal renal function or a renal dysfunction and then administering a dose Y2 (mg/kg) calculated from a specific numerical expression to the patient at an administration interval Z (hour) calculated from a specific numerical expression. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a glycopeptide antibiotic preparation containing vancomycin hydrochloride as an active ingredient for treating a heart failure patient having normal renal function or impaired renal function.

  Vancomycin hydrochloride is a glycopebutide antibiotic and acts bactericidally by inhibiting the cell wall synthesis of bacteria. Therefore, multi-drug-resistant methicillin-resistant Staphylococcus aureus (hereinafter referred to as “MRSA”) and penicillin. It is known to be an effective drug against resistant pneumococci (PenIcIllIn-ResIst Streptococcus Pneumoniae, hereinafter referred to as “PRSP”), and is widely used for the treatment of infectious indications caused by these bacteria.

There are two types of vancomycin hydrochloride, vancomycin hydrochloride for internal use and vancomycin hydrochloride for intravenous drip infusion. Vancomycin hydrochloride is a renal excretion-type drug, and since the effective blood concentration range is close to the poisoning range, administration to patients with renal dysfunction requires adjustment of the dosage and administration interval according to the degree of renal dysfunction. is there. Creatinine clearance calculated from the serum creatinine using the Cockcroft-Gault equation (see, for example, Non-Patent Document 1) is usually used as an index for renal function evaluation, and is a guideline for correcting the dose. However, depending on the degree of renal dysfunction, it is necessary to adjust the dose and administration interval from different pharmacokinetic parameters (for example, Non-Patent Documents 3 and 4). reference).
Cockcroft DW et al. , Nephron, 16, 31 (1976) MoellerIng R et al. , Ann. Intern. Med. , 94, 343 (1981) Emperor Takenaka et al., Chemotherapy, 41, 1079 (1993) Matzke GR et al. , AntImIcrob, Agents Chemother, 25 (4), 433 (1984).

  However, there is a case where a significant deviation may occur between the predicted value of the dose or administration interval calculated according to the degree of renal dysfunction and the actual measurement value, and this causes a problem that appropriate treatment cannot be performed. It was happening.

  Therefore, the object of the present invention is to correct the deviation between the predicted value and the actually measured value of the dose and the administration interval calculated according to the degree of renal dysfunction, and to enable appropriate treatment. The object is to provide a glycopeptide antibiotic preparation containing vancomycin as an active ingredient.

  In view of the problems of the prior art, the present inventor has found that the cause is a cardiac dysfunction as a result of extensive research on the cause of the deviation between the predicted value and the actual measurement value. The present invention has been completed.

から算出された投与量Ｙ１（ｍｇ／回）を初回に投与し、次いで数式（ＩＩ）

から算出された投与量Ｙ２（ｍｇ／回）を、数式（ＩＩＩ）

から算出された投与間隔Ｚ（時間）で投与することを特徴とする、前記正常な腎機能又は腎機能障害を持つ心不全患者を治療するための、塩酸バンコマイシンを有効成分とするグリコペプチド系抗生物質製剤である。 (1) That is, the present invention relates to a heart failure patient with normal renal function or renal dysfunction having a creatinine clearance Ccr of 50 (mL / min) or more and a body weight of X (kg).

First dose Y1 (mg / dose) calculated from the formula (II)

The dose Y2 (mg / time) calculated from the formula (III)

A glycopeptide antibiotic comprising vancomycin hydrochloride as an active ingredient for treating a heart failure patient having normal renal function or renal dysfunction, characterized by being administered at an administration interval Z (time) calculated from It is a formulation.

  (2) In the present invention, the initial dose of 20.0 mg / kg to 41.7 mg / kg is administered to a heart failure patient with renal dysfunction having a creatinine clearance of 50 mL / min or more and less than 70 mL / min, A treatment for heart failure patients with renal dysfunction, wherein 14.3 mg / kg to 29.8 mg / kg is administered as a maintenance dose at intervals of 21.5 to 28.0 hours Therefore, it is a glycopeptide antibiotic preparation containing vancomycin hydrochloride as an active ingredient.

  (3) Further, the present invention is characterized in that the initial dose is 25.4 mg / kg to 36.3 mg / kg, and the maintenance dose is 18.2 mg / kg to 25.9 mg / kg. The glycopeptide antibiotic preparation according to (2).

  (4) In addition, the present invention administers 20.0 mg / kg to 41.7 mg / kg as a first dose to a heart failure patient having normal renal function with a creatinine clearance of 70 mL / min or more, and then a maintenance dose. Vancomycin hydrochloride for treating heart failure patients with normal renal function, characterized in that 14.3 mg / kg to 29.8 mg / kg at a time is administered at intervals of 21.5 hours or less Is a glycopeptide antibiotic preparation containing as an active ingredient.

  (5) Further, the present invention is characterized in that the initial dose is 25.4 mg / kg to 36.3 mg / kg, and the maintenance dose is 18.2 mg / kg to 25.9 mg / kg. The glycopeptide antibiotic preparation according to (4).

  (6) Moreover, this invention is a glycopeptide antibiotic preparation as described in any one of (1)-(5) characterized by being an injection.

  (7) The glycopeptide antibiotic preparation according to (6), wherein the injection is an intravenous injection or an intravenous infusion.

  (8) In addition, the present invention is a therapeutic agent for infectious diseases caused by methicillin-resistant Staphylococcus aureus or penicillin-resistant pneumococci sensitive to vancomycin hydrochloride, any one of (1) to (7) 2. The glycopeptide antibiotic preparation according to item 1.

  (9) The present invention also relates to the infection caused by methicillin-resistant Staphylococcus aureus that is sensitive to vancomycin hydrochloride, such as sepsis, infective endocarditis, trauma, burns, and superficial secondary infection of surgical wounds, The glycopeptide antibiotic preparation according to (8), characterized in that it is at least one selected from the group consisting of osteomyelitis, pneumonia, lung abscess, empyema, peritonitis and purulent meningitis. is there.

  (10) Further, the present invention is characterized in that the infection caused by penicillin-resistant pneumococci sensitive to vancomycin hydrochloride is at least one of sepsis, pneumonia or purulent meningitis. The glycopeptide antibiotic preparation according to 8).

  According to the present invention, it is possible to calculate an appropriate dose and administration interval according to creatinine clearance for a heart failure patient having normal renal function or renal dysfunction. Therefore, it is possible to produce a glycopeptide antibiotic preparation that enables appropriate treatment for patients with normal renal function or heart failure, resulting from methicillin-resistant Staphylococcus aureus and penicillin-resistant pneumococci It can be used as a therapeutic agent for infectious diseases.

Hereinafter, embodiments of the present invention will be described by taking the patient group shown in Table 1 as an example. Note that the present embodiment is not limited to this, and it is needless to say that various modifications can be made without departing from the scope of the present invention.

  First, for the patient groups shown in Table 1, (A) physical examination, (B) X-ray, echocardiography or pulmonary congestion by radionuclide ventricular angiography, peripheral edema, left ventricular dilation or dysfunction associated with dysfunction symptoms A history survey of intolerance or respiratory failure was conducted, and patient groups were classified according to the presence or absence of heart failure using the results of examination (A) and survey (B). Accordingly, as shown in Table 1, patients with normal renal function or renal dysfunction were divided into 76 heart failure patients (including 57 males and 19 females) and 40 non-heart failure patients (including 32 males). And 8 women).

Next, the pharmacokinetic parameters shown in Table 2 were calculated for the heart failure patient group in Table 1. In addition, as each pharmacokinetic parameter value in Table 2, the average value of the heart failure patient group in Table 1 is described.

  First, a predetermined amount of vancomycin hydrochloride is administered by intravenous infusion for a predetermined time, and then a necessary amount of blood is collected from the subject patient by a known method, and the maximum blood concentration (the blood concentration 1 hour after administration) Cmax, μg / mL, hereinafter referred to as “peak value”) and minimum blood concentration (CmIn, μg / mL, hereinafter referred to as “trough value”) were measured.

Next, a 1-compartment model analysis was performed using these blood concentrations. Here, the compartment model analysis is a method of analyzing each organ of a living body as a single box, and the case where the whole living body can be analyzed in a single box is referred to as a 1-compartment model. In this example, the blood drug concentration Cp (μg / mL) per unit time is represented by the formula (IV), the initial dose (mg / kg) is x0, and the hypothesis representing the degree of in vivo drug distribution. The apparent distribution volume (Vc, L / kg), which is the volume of the drug, is represented by Vd, and the disappearance rate constant, which is a proportional constant representing the degree of drug disappearance per unit time, is represented by k.

In this embodiment, from the linear regression using the above peak value and trough value, the regression coefficient (slope of formula (IV)) is obtained, the disappearance rate constant is calculated, and then each patient's value is calculated using formula (V). The elimination half-life (t1 / 2, time) was calculated.

Next, the apparent volume of distribution was calculated from the formula (VI) using the initial dose, peak value, and trough value.

Further, vancomycin clearance (Cv, L / hour / kg) was calculated from the formula (VII) using the above disappearance rate constant and apparent distribution volume.

Next, the serum creatinine concentration S (mg / dL) was measured by a known method for the heart failure patient group in Table 1, and the body weight X (kg) was further measured. These measured values and the age A of the heart failure group (Years) was used to calculate creatinine clearance Ccr (mL / min). Here, creatinine clearance is the efficiency with which creatinine is excreted in urine, and is used as an index of renal function. In general, the creatinine clearance can be estimated without storing urine, and is calculated from the Cockcroft-Gault equation represented by the equation (VIII).

  When the male serum creatinine concentration is less than 0.8 mg / dL, the value is 0.8. When the female serum creatinine concentration is less than 0.6 mg / dL, the value is 0.6. The measured serum creatinine concentration value is used as it is, and in the case of women, the calculated creatinine clearance value is multiplied by 0.85. In the case of an obese person having a BMI (Body Mass Index) of 25 or more, a creatinine clearance value is calculated using an ideal weight obtained by multiplying BMI by 22, that is, a value obtained by multiplying BMI22 by the square of height (m). .

  In this example, 162 blood concentrations in the heart failure group shown in Table 1 were measured, and creatinine clearance was calculated therefrom. In Table 2, the target patient groups were classified by the degree of renal function, that is, the creatinine clearance value.

  Next, using the calculated pharmacokinetic parameters, comparative analysis of elimination half-life and vancomycin clearance according to renal function of the heart failure group and the non-heart failure group in Table 1 was performed. Since creatinine clearance is an index of renal function, this is compared with other pharmacokinetic parameters to determine whether it fluctuates due to the presence or absence of heart failure.

  In this example, creatinine clearance and elimination half-life (logarithmic value) or vancomycin clearance were distributed, and their correlation was examined. The correlation diagram is shown in FIG. 1 and FIG. As a result, it was found that the heart failure group had a longer drug disappearance time and smaller vancomycin clearance than the non-heart failure group. Therefore, it was suggested that elimination half-life and vancomycin clearance fluctuate due to the presence or absence of heart failure.

  Therefore, for the purpose of verification, the presence or absence of heart failure and the elimination half-life (logarithmic value) were analyzed by covariance analysis, and the relationship between these parameters was shown in FIG. Thus, for patients with renal dysfunction with creatine clearance of 50 mL / min or higher, the presence or absence of heart failure was found to be a significant factor involved in the vancomycin hydrochloride concentration disappearance rate.

The vancomycin clearance is a value obtained by multiplying the apparent volume of distribution by the disappearance rate constant as shown in the formula (VII). When verification was performed in the same manner as described above, the presence or absence of heart failure was significantly related to vancomycin clearance. It turned out to be a factor. But,
The analysis of creatinine clearance and apparent distribution volume, and the relationship between the two parameters was examined. The results are shown in FIG. 4. As a result, the apparent distribution volume does not depend on creatinine clearance. Since the dose does not depend on renal function, it was found that the dose could be calculated uniformly per body weight. Therefore, the formula (VI) suggested that the dose of vancomycin hydrochloride can be calculated by multiplying the apparent distribution volume by the difference between the peak value and the trough value.

Here, the effective range of the peak value and the trough value is generally in a range of 25 μg / mL to 40 μg / mL so that the peak value does not exceed 60 μg / mL, and the trough value does not exceed 20 μg / mL. It is recommended to control the dose of vancomycin hydrochloride so that it falls within the range of 5 μg / mL to 15 μg / mL. Therefore, the average value obtained by dividing the dose of vancomycin of each patient by the difference between the peak value and the trough value to the average value (35 μg / mL) of the effective range of the peak value is 0.881 L / kg converted to per body weight. It was suggested that the initial dose Y1 (mg / dose) can be expressed by the formula (I) by multiplying by X (kg).

In addition, as a dose for increasing from the average value of the effective range of the trough value (10 μg / mL) to the average value of the effective range of the peak value (35 μg / mL), the difference between the effective range of the peak value and the trough value ( 25 μg / mL), and the average value obtained by dividing the vancomycin dose of each patient by the difference between the peak value and the trough value in the same manner as the initial dose is 0.881 L / kg of body weight X (kg) The maintenance dose Y2 (mg / dose) could be expressed by the formula (II).

  Similar to the creatinine clearance value, in the case of an obese person having a BMI (Body Mass Index) of 25 or more, an ideal weight with a BMI of 22, that is, a value obtained by multiplying the BMI 22 by the square of the height (m), The initial dose and maintenance dose are calculated.

  As described above, since the maintenance dose is a dose for increasing from the average value of the effective range of the trough value to the average value of the effective range of the peak value, the administration interval between the initial dose and the maintenance dose It was suggested that the time required to decrease from the average value of the effective range of the peak value (35 μg / mL) to the average value of the effective range of the trough value (10 μg / mL) was required. .

Further, as described above, the elimination half-life is a significant factor related to the elimination rate of vancomycin hydrochloride concentration, and therefore, the administration interval of each patient calculated from the creatinine clearance, the slope of formula (IV), and formula (V) Correlation analysis with Z (time) was performed, and the results are shown in Table 3 and FIG. From these, it was found that the power type showed the highest correlation. Therefore, it was suggested that the administration interval of vancomycin hydrochloride depends on renal function.

  As described above, in the present embodiment, the dose Y1, the dose Y2, and the dose interval Z could be determined from the formulas (I) to (III) using the measured body weight of the target patient and the calculated creatinine clearance. .

  Therefore, the dosage of the glycopeptide antibiotic preparation of the present invention is usually 20.0 mg / kg to 41.7 mg / kg, preferably 25, as the initial dosage in terms of the dosage of vancomycin hydrochloride for adults. .4 mg / kg to 36.3 mg / kg, followed by maintenance doses of 14.3 mg / kg to 29.8 mg / kg, preferably 18.2 mg / kg to 25.9 mg / kg, It can be administered parenterally at intervals of 21.5 hours to 28 hours when the creatinine clearance is 50 mL / min or more and less than 70 mL / min, and 21.5 hours or less when the creatinine clearance is 70 mL / min or more. all right.

  In addition, the difference between heart failure patients and non-heart failure patients was not clarified by the test this time, but the initial dose was 20.0 mg for heart failure patients with renal dysfunction with creatinine clearance of 30 mL / min or more and less than 50 mL / min. / Kg to 41.7 mg / kg, followed by maintenance doses of 14.3 mg / kg to 29.8 mg / kg at intervals of 27.0 hours to 41.0 hours with a creatinine clearance of 15 mL / 10.0 mg / kg to 41.7 mg / kg as the initial dose and then 14.3 mg / kg to 29 as the maintenance dose for heart failure patients with renal dysfunction greater than or equal to 30 mL / min .8 mg / kg at an interval of 40.0 to 68.6 hours with cardiac dysfunction with creatinine clearance less than 15 mL / min The patient is administered 20.0 mg / kg to 41.7 mg / kg as the initial dose, and then 14.3 mg / kg to 29.8 mg / kg as the maintenance dose at intervals of 68.5 hours or more. Thus, the glycopeptide antibiotic preparation of the present invention can be administered to treat heart failure patients having normal renal function or renal dysfunction.

  The exact dose may be determined by a doctor's diagnosis according to the patient, the type of disease, the degree of symptoms, the patient's age, sex difference, difference in sensitivity to drugs, and the like.

  The glycopeptide antibiotic preparation of the present invention can be administered to a patient by parenteral or the like. Specifically, it can be administered as a non-solid preparation such as an injection (including an injection for infusion), and in the case of producing a liquid preparation such as an injection, the pH adjusting agent is added to vancomycin hydrochloride as necessary. , Suspending agents, solubilizers, stabilizers, tonicity agents, antioxidants, preservatives, and the like can be added to produce them by conventional methods. The non-solid preparation can be made into a lyophilized product as necessary, and the injection can be administered intravenously, etc. The administration method is intravenous injection, intravenous infusion, etc. Etc. Examples of the pH adjusting agent include hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, and the suspending agent includes methyl cellulose, polysorbate 80, hydroxyethyl cellulose, Arabic Rubber, tragacanth powder, sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate, etc., and solubilizing agents include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, etc. Examples of the stabilizer include sodium sulfite, sodium metasulfite, and ether. Examples of the isotonic agent include sodium chloride and glucose. Examples of the preservative include methyl paraoxybenzoate and paraoxy. Ikikosan ethyl, sorbic acid, phenol, cresol, chlorocresol and the like.

  Since the glycopeptide antibiotic preparation of the present invention inhibits the synthesis of bacterial cell wall peptidoglycan and further changes the permeability of bacterial cell membranes to inhibit RNA synthesis and exhibits a bactericidal antibacterial action, MRSA, PRSP, etc. Infectious diseases caused by septicemia, specifically, in the case of parenteral administration, for example, intravenous administration, infectious diseases caused by MRSA, such as sepsis, infective endocarditis, trauma, burns and surgical wounds For the prevention and treatment of septicemia, pneumonia, pyogenic meningitis, etc., which are infections caused by PRSP, such as secondary secondary infection, osteomyelitis, pneumonia, lung abscess, empyema, peritonitis, purulent meningitis, etc. be able to.

FIG. 5 is a correlation diagram in which creatinine clearance and elimination half-life (logarithmic value) are distributed. It is the correlation diagram which distributed creatinine clearance and vancomycin clearance. It is a graph which shows the result analyzed in order to investigate the relationship between the grade of heart failure and elimination half-life. It is a graph which shows the result analyzed in order to investigate the relationship between a creatinine clearance and an apparent distribution volume. It is a graph which shows the result analyzed in order to investigate the relationship between a creatinine clearance and a dosing interval.

Claims (10)

For a heart failure patient with normal renal function or dysfunction having a creatinine clearance Ccr of 50 (mL / min) or more and a body weight of X (kg), formula (I)

First dose Y1 (mg / dose) calculated from the formula (II)

The dose Y2 (mg / time) calculated from the formula (III)

A glycopeptide antibiotic comprising vancomycin hydrochloride as an active ingredient for treating a heart failure patient having normal renal function or renal dysfunction, characterized by being administered at an administration interval Z (time) calculated from Formulation.   For heart failure patients with renal dysfunction with creatinine clearance of 50 mL / min or more and less than 70 mL / min, the initial dose is 20.0 mg / kg to 41.7 mg / kg, and then the maintenance dose is 14. Vancomycin hydrochloride as an active ingredient for treating a patient with heart failure having renal dysfunction, wherein 3 mg / kg to 29.8 mg / kg is administered at intervals of 21.5 to 28.0 hours A glycopeptide antibiotic preparation.   The glyco of claim 2, wherein the initial dose is 25.4 mg / kg to 36.3 mg / kg, and the maintenance dose is 18.2 mg / kg to 25.9 mg / kg. Peptide antibiotic preparation.   For heart failure patients with normal renal function with creatinine clearance of 70 mL / min or more, the initial dose is 20.0 mg / kg to 41.7 mg / kg, and then the maintenance dose is 14.3 mg / kg per dose. A glycopeptide antibiotic containing vancomycin hydrochloride as an active ingredient for treating a heart failure patient having normal renal function, wherein ˜29.8 mg / kg is administered at intervals of 21.5 hours or less Substance formulation.   The glyco of claim 4, wherein the initial dose is 25.4 mg / kg to 36.3 mg / kg, and the maintenance dose is 18.2 mg / kg to 25.9 mg / kg. Peptide antibiotic preparation.   The glycopeptide antibiotic preparation according to any one of claims 1 to 5, which is an injection.   The glycopeptide antibiotic preparation according to claim 6, wherein the injection is an intravenous injection or an intravenous infusion.   The glycopeptide antibiotic preparation according to any one of claims 1 to 7, which is a therapeutic agent for infectious diseases caused by methicillin-resistant Staphylococcus aureus or penicillin-resistant pneumococci sensitive to vancomycin hydrochloride. .   Infectious diseases caused by methicillin-resistant Staphylococcus aureus sensitive to vancomycin hydrochloride include sepsis, infective endocarditis, trauma, burn and superficial secondary infection of surgical wound, osteomyelitis, pneumonia, lung abscess, empyema The glycopeptide antibiotic preparation according to claim 8, which is at least one selected from the group consisting of peritonitis and purulent meningitis.   The glycopeptide antibiotic according to claim 8, wherein the infection caused by penicillin-resistant pneumococci sensitive to vancomycin hydrochloride is at least one of sepsis, pneumonia, and purulent meningitis. Substance formulation.

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