JP2008273859A - Antiarrhythmic comprising cibenzoline succinate as active ingredient for treating cardiac insufficiency patient having renal dysfunction - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an antiarrhythmic comprising cibenzoline succinate 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 antiarrhythmic comprising cibenzoline succinate as an active ingredient for treating a cardiac insufficiency patient having a renal dysfunction has a dose Y (mg/day) that controls a trough value of serum concentration of cardiac insufficiency patient having a creatinine clearance of X (mL/minute) and a renal dysfunction at 250 ng/mL and is represented by the numerical expression (I) shown below. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a therapeutic agent for arrhythmia comprising cibenzoline succinate as an active ingredient for treating a heart failure patient having renal dysfunction.

  Cibenzoline succinate belongs to the Vaughan Williams classification class Ia group and is one of the drugs widely used for tachyarrhythmia, and disappearance from the body is partially metabolized, It is a renal excretion type drug that is excreted unchanged from the kidney (see, for example, Non-Patent Documents 1 and 2).

  Cibenzoline succinate includes cibenzoline succinate tablets for internal use and vancomycin hydrochloride injection for injection. Their usage and dosage are set with reference to company inserts and past original papers. As mentioned above, cibenzoline succinate is a renal excretion-type drug, so the effective serum concentration range is close to the poisoning range. Adjustment of dosing interval is necessary.

  According to the package insert, the half-life of drug elimination may be extended depending on the degree of nephropathy in patients with renal impairment and renal dysfunction (for example, see Non-patent Documents 3 and 4), and the dosage and dosage are adjusted. The necessity is shown (for example, refer nonpatent literature 5). In addition, it is also known that the actual clinical use amount is different from the dose described in the package insert (for example, see Non-Patent Document 6), and the patient's serum concentration increases and the occurrence of side effects cannot be avoided. There were some problems.

Therefore, the inventor of the present application is responsible for factors other than renal function, that is, cardiac function, which are caused by a difference between a predicted value and an actually measured value of the dose and administration interval calculated according to the degree of renal dysfunction. Focusing on a certain point, the possibility of correcting the deviation between the predicted value and the actually measured value was previously reported (see Non-Patent Document 7).
Niwa T et al. , Drug Metab Dispos, 28, 1128-1134 (2000) Massarella JW et al. , Br J Clin Pharmacol, 31, 481-483 (1991). Hayato Kato et al., Clinical Pharmacology, 20, 363 (1989) Toshio Oguchi et al., Medical treatment and new drugs, 25, 2277 (1988) Kazuyuki Ueno et al., Pharma Medica, 20, 155 (2002) Takada M.M. et al. , J. et al. Clin. Pharm. Ther. , 30, 5 (2005) Kotake T. et al. , Circ. J. et al. , 70, 588-592 (2006)

  However, there may still be a significant difference between the measured values and the predicted doses and dose intervals calculated according to the degree of renal dysfunction, and this causes the problem that appropriate treatment cannot be performed. Has occurred.

  Therefore, the object of the present invention is to accurately correct the deviation between the predicted value and the measured value of the dose and administration interval calculated according to the degree of renal dysfunction, and to enable further appropriate treatment. Another object of the present invention is to provide a therapeutic agent for arrhythmia containing cibenzoline succinate as an active ingredient.

  In view of the problems of the prior art, the present inventor has completed the present invention as a result of intensive studies on a method for accurately correcting the deviation between the predicted value and the actual measurement value. .

で示されることを特徴とする、前記腎機能障害を持つ心不全患者を治療するための、コハク酸シベンゾリンを有効成分とする不整脈治療剤である。 (1) That is, the present invention relates to a dose Y (mg / day) for controlling the trough value of serum concentration to 250 ng / mL in a heart failure patient with renal dysfunction whose creatinine clearance is X (mL / min). ) Is the formula (I)

An arrhythmia therapeutic agent comprising cibenzoline succinate as an active ingredient for treating the heart failure patient having the renal dysfunction described above.

  (2) The arrhythmia therapeutic agent according to (1), wherein the dose Y is 35 mg / day to 250 mg / day.

  (3) The present invention also provides the therapeutic agent for arrhythmia according to (1), wherein the dose Y is 50 mg / day to 250 mg / day.

  (4) The present invention also treats a heart failure patient with renal dysfunction, wherein 50 mg / day or less is administered to a heart failure patient with renal dysfunction having a creatinine clearance of less than 15 mL / min. Therefore, it is an arrhythmia therapeutic agent containing cybenzoline succinate as an active ingredient.

  (5) The present invention is also characterized in that 50 mg / day to 200 mg / day is administered to a heart failure patient having renal dysfunction having a creatinine clearance of 15 mL / min or more and less than 70 mL / min. It is a therapeutic agent for arrhythmia containing cibenzoline succinate as an active ingredient for treating heart failure patients with disabilities.

  (6) The present invention also treats heart failure patients with renal dysfunction characterized by administering 200 mg / day or more to heart failure patients with renal dysfunction having a creatinine clearance of 70 mL / min or more. Therefore, it is an arrhythmia therapeutic agent containing cybenzoline succinate as an active ingredient.

  (7) The present invention is also a therapeutic agent for arrhythmia according to any one of (1) to (6), which is an oral preparation.

  (8) Furthermore, the present invention is the therapeutic agent for arrhythmia according to any one of (1) to (7), which is a therapeutic agent for tachyarrhythmia.

  ADVANTAGE OF THE INVENTION According to this invention, the dosage which can control a serum concentration to an appropriate value according to creatinine clearance with respect to a heart failure patient with renal dysfunction can be calculated. Therefore, it is possible to produce an arrhythmia therapeutic agent that makes it possible to appropriately treat a heart failure patient with renal dysfunction, and it can be used as a therapeutic agent for arrhythmia, particularly tachyarrhythmia.

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). Thus, as shown in Table 1, there were 88 heart failure patients (including 50 men and 38 women) and 278 non-heart failure patients (including 181 men and 97 women). It was possible to sort it.

Next, the serum creatinine concentration S (mg / dL) was calculated by a known method for the heart failure groups shown in Table 1, and the body weight W (kg) was measured. These measured values and the age A of the heart failure group (Years old) was used to calculate creatinine clearance X (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 equation (II).

  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 embodiment, as shown in Table 1, 134 serum concentrations in the heart failure group were measured, and creatinine clearance was calculated therefrom.

  Next, from the creatinine clearance X, the dose of cibenzoline succinate calculated by the conventional method, and the trough value of the serum concentration, the predicted dose Yα (proportionalally calculated so that the target serum concentration is 250 ng / mL) mg / day) and regression analysis was performed. Here, the effective therapeutic serum concentration range of cibenzoline succinate is 200 ng / mL to 800 ng / mL, and the elimination half-life is known to be about an average of about 5 hours if renal function is normal. . Generally, in clinical practice, when monitoring the blood drug concentration for the purpose of setting an appropriate dose for each patient, there are many cases where one trough value is used. In the present invention, since it is intended for heart failure patients with renal dysfunction, the effective therapeutic serum concentration range for proper administration of cibenzoline succinate as a trough value is considered to be 150 ng / mL to 350 ng / mL, The median value of 250 ng / mL was set as the target value.

The regression equation and correlation coefficient r obtained by regression analysis are shown in Table 2, and the correlation diagram in which the creatinine clearance X and the expected dose Yα of the heart failure group shown in Table 1 are distributed is shown in FIG.

As shown in Table 2 and FIG. 1, comparing the correlation coefficient between the linear regression equation and the logarithmic regression equation, it can be said that the logarithmic type has a higher correlation. Therefore, the creatinine clearance X and the expected dose Yα It was suggested that is in the relationship of Formula (III).

Next, correlation analysis was performed using the expected dose, creatinine clearance, and trough value, and each parameter was evaluated. The results are shown in Table 3.

  As shown in Table 3, since the significance probability is clearly 5% or less, it was suggested that the expected dose and creatinine clearance are significant factors for the trough value.

Next, using the expected dose Yα derived from the formula (III) and the estimated serum concentration Zα calculated proportionally from the dose of cibenzoline succinate and the trough value of the serum concentration calculated by the conventional method, The validity of the correlation analysis results was verified. FIG. 2 is a correlation diagram in which the predicted dose Yα calculated using each parameter of the heart failure group shown in Table 1 and the predicted serum concentration Zα are distributed, and the results of verifying the predicted dose Yα from the scatter diagram are shown. It is shown in Table 4.

  As shown in FIG. 2 and Table 4, since the ratio of the expected serum concentration in the range of 150 ng / mL to 400 ng / mL (arrow in FIG. 2) is less than 70%, the above correlation analysis result was secured.

Therefore, from the above results, the therapeutic agent for arrhythmia of the present invention whose dosage can be calculated using the formula (I) is controlled to 250 ng / mL, which is the trough value of the target serum concentration, and arrhythmia, particularly tachycardia. Table 5 shows the results of summarizing the calculated dose Y, trough value, and average value of predicted dose Yα.

  As shown in Table 5, for adults, 35 mg to 250 mg, preferably 50 mg to 250 mg, or 50 mg / day when the creatinine clearance is less than 15 mL / min. It was found that 50 mg / day to 200 mg / day can be administered orally when the creatinine clearance is 15 mL / min or more and less than 70 mL / min, and 200 mg / day or more can be administered when the creatinine clearance is 70 mL / min or more.

  The above-mentioned cibenzoline succinate may be administered once or several times a day, and more accurately depending on the patient, the type of disease, the degree of symptoms, the patient's age, sex difference, drug sensitivity difference, etc. The appropriate dosage may be determined by a physician's diagnosis.

  The therapeutic agent for arrhythmia of the present invention can be administered to a patient orally. Specifically, after adding excipients, binders, disintegrants, lubricants, colorants, flavoring agents, antioxidants, etc. to cibenzoline succinate, tablets, coated tablets, It can be administered as a solid preparation such as an agent, granule, powder, powder, troche, capsule and the like. Examples of excipients include lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide, and the like, and binders include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, Hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin, pectin, etc. are listed. Disintegrants include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, and the like. Examples of the colorant include pharmaceuticals. The flavoring agent may be cocoa powder, mint brain, aromatic acid, mint oil, Borneolum, cinnamon powder, etc., and the antioxidant may be ascorbine. Any material that is permitted to be added to pharmaceuticals such as acid and α-tocopherol may be used. The above solid preparation may be appropriately coated with sugar coating, gelatin coating, and the like as necessary.

  Since the therapeutic agent for arrhythmia of the present invention can calculate a dose capable of controlling the serum concentration to an appropriate value according to creatinine clearance for heart failure patients with renal dysfunction, other therapeutic agents for arrhythmia are treated. It can be used for the prevention and treatment of tachyarrhythmia when it is not possible or is not effective with other therapeutic agents for arrhythmia.

FIG. 6 is a correlation diagram in which creatinine clearance X and expected dose Yα are distributed. FIG. 5 is a correlation diagram in which an expected dose Yα and an expected serum concentration Zα are distributed.

Claims (8)

The dose Y (mg / day) for controlling the trough value of serum concentration to 250 ng / mL in a heart failure patient with renal dysfunction whose creatinine clearance is X (mL / min) is expressed by the formula (I)

A therapeutic agent for arrhythmia comprising cibenzoline succinate as an active ingredient for treating a heart failure patient having the renal dysfunction described above.   The arrhythmia therapeutic agent according to claim 1, wherein the dose Y is 35 mg / day to 250 mg / day.   The arrhythmia therapeutic agent according to claim 1, wherein the dose Y is 50 mg / day to 250 mg / day.   Effective for treatment of heart failure patients with renal dysfunction, characterized by administering 50 mg / day or less to heart failure patients with renal dysfunction with a creatinine clearance of less than 15 mL / min, effective cibenzoline succinate Arrhythmia therapeutic agent as a component.   To treat a heart failure patient having renal dysfunction, wherein 50 mg / day to 200 mg / day is administered to a heart failure patient having a renal dysfunction having a creatinine clearance of 15 mL / min or more and less than 70 mL / min. An antiarrhythmic agent comprising cibenzoline succinate as an active ingredient.   Effective for treatment of heart failure patients with renal dysfunction, characterized by administering 200 mg / day or more to heart failure patients with renal dysfunction with creatinine clearance of 70 mL / min or more, effective cibenzoline succinate Arrhythmia therapeutic agent as a component.   The therapeutic agent for arrhythmia according to any one of claims 1 to 6, wherein the therapeutic agent is an oral agent.   The therapeutic agent for arrhythmia according to any one of claims 1 to 7, which is a therapeutic agent for tachyarrhythmia.

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