DE29814563U1 - Device for the patient-dependent determination of the dosage of a medicament - Google Patents

Description

samsons &

PATENT ATTORNEYS · EUROPEAN PATENT ATTORNEYS ■ EUROPEAN TRADE MARK ATTORNEYS

OUR REF DATE

B1643001DEU00LW 13 August 1998

Bristol-Myers Squibb GmbH Volkartstrasse 83

D-80636 Munich

Device for patient-dependent determination of the dosage of a medication

The invention relates to a device for patient-dependent determination of the dosage of a drug, in particular an antineoplastic drug.

A number of different cytostatic or cytocidal substances are known for the clinical treatment of malignant tumors, such as the active ingredient carboplatin. A drug containing this active ingredient is sold under the protected trade name "Carboplat" by Bristol Arzneimittel GmbH.

Such active substances generally have side effects on the blood-forming system due to the general inhibition of regeneration of rapidly proliferating tissues that they cause, namely they limit bone marrow function in a generally reversible manner. This effect on the blood-forming system limits the dose for the use of such an active substance.

During treatment, there is generally a reduction in platelets and leukocytes, which, when administered at the highest tolerated dose, usually return to their initial values after 20 to 35 days, e.g. after an average of 28 days. If the dosage is too high, the reversibility of the restriction of bone marrow function worsens.

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In addition, renal dysfunction - usually also reversible - can occur, which can be more frequent and more severe in patients with impaired renal function before the start of therapy.

In order to keep such side effects tolerable, overdose must be avoided. With regard to the desired, largest possible antineoplastic effect,

However, underdosing should also be avoided. The effectiveness is not only determined by the initial dose, but also by how long the drug remains in the body. The dosage is therefore determined by a product of the active ingredient concentration in the serum and time. To be more precise, this quantity is the integral of the concentration function over time, or - to put it simply - the area under the concentration curve plotted over time. This quantity is called "AUC" (Area Under the Curve); its unit is e.g.

mg/ml-min.

In the case of impaired renal function, the active ingredient is excreted more slowly, so that the AUC value is higher than with normal renal function (assuming the same initial dose). In such a case, the initial dose must be reduced in order to obtain the same AUC value as with normal renal function. From a certain extent of renal dysfunction, such active ingredients are contraindicated altogether, i.e. they must no longer be administered, since the very long duration of action is likely to result in severe impairment of the hematopoietic system and renal function.

In order to be able to take renal function into account when determining the initial dose to be administered, generally knowledge of a renal function indicator is required. One such parameter is, for example, the creatinine concentration in serum. Creatinine is a

Metabolic product formed in muscle tissue, the production and excretion of which are relatively constant. In the so-called steady state (i.e. when the rate of formation and elimination are the same), serum creatinine is a measure of kidney function. It can be determined relatively easily with sufficient accuracy by blood analysis.

However, serum creatinine is not a very accurate indicator of actual kidney function. Kidney function decreases with age without this being reflected in a corresponding increase in serum creatinine. The reason for this is that creatinine production also decreases to approximately the same extent. The measured serum creatinine value must therefore be corrected depending on the patient's age in order to represent a more accurate value of kidney function.

In addition, other variables such as the patient's gender and body surface area should be taken into account in order to accurately determine kidney function from the measured serum creatinine. The body surface area can be calculated from height and body weight using known formulas.

From the first kidney function indicator - serum creatinine - a second kidney function indicator can be derived under the steady state assumption and taking the above-mentioned values into account, which represents a more precise indicator of kidney function. This is, for example, creatinine clearance.

Normal values for serum creatinine are approximately between 0.6 and 1.3 mg/dl. Creatinine clearance for men with an average body surface area between the ages of 20 and 29 is 70 to 110 ml/min. If the values are between 30 and 60 ml/min, caution is advised when using an active substance such as carboplatin; if a creatinine is

If the clearance is less than 30 ml/min, the active ingredient is contraindicated and should no longer be used.

A device from "Bristol Laboratories" is known for determining the dosage of an antineoplastic drug (here "Carboplat" with the active ingredient carboplatin) on a patient-dependent basis. This device has a pair of slide scales for male and female patients with the values "serum creatinine" and "patient age" and another pair of slide scales with the values "creatinine clearance" and "patient's body surface area". The movable scales are arranged on a common slide, so they are coupled in terms of movement. To determine the creatinine clearance from the serum creatinine, the measured value of the serum creatinine is adjusted to the patient's age using the movable slide. The creatinine clearance on the patient's body surface is then read off the latter pair of slide scales, whereby the position of the slide must not be changed in the meantime.

This known device has further pairs of slide scales, which are used on the one hand to calculate the body surface area and on the other hand to determine the absolute dose of the drug to be administered. Two pairs of slide scales are used to calculate the body surface area: the patient's body weight is set using a first pair, and the body surface area for the patient's given height is read using a second pair. This read value is required for the subsequent determination of the creatinine clearance. The other pairs of slide scales each belong to a specific AUC target value; they are used to set the creatinine clearance and to read the absolute dose to be administered at the respective target AUC. These pairs of scales are used after the creatinine clearance has been determined.

This well-known device is very simple and clearly structured and has proven itself; its use has made it possible to practically avoid incorrect dosing.

The present invention aims to further improve the known device in terms of application safety.

This object is achieved by a device for patient-dependent determination of the dosage of a drug, in particular an antineoplastic drug, which has a damaging effect if the AUC is too high, which is why the dosage is determined depending on the kidney function, wherein the device has at least one pair of slide scales for setting or reading a kidney function indicator variable, wherein the pair of slide scales does not show those values of the kidney function indicator variable at which the drug must not be administered due to insufficient kidney function; in addition or alternatively, a corresponding warning is applied to the pair of slide scales in the value range of the kidney function indicator variable at which the drug must not be administered due to insufficient kidney function (claim 1).

The absence of scale values and/or the presence of a warning in the range of values for low renal function - in addition to information on package inserts, in the literature, etc. - provide additional security against administering the drug despite contraindications.

Advantageous embodiments are specified in the subclaims. Claims 2 to 4 express that the kidney function indicator variable - called "first kidney function indicator variable" - is the serum concentration of a metabolic product which, for example, decreases with the patient's age in a similar way to the kidney function.

which is particularly serum creatinine.

Claims 5 to 8 relate to another kidney function indicator variable, which is called a "second kidney function indicator variable". According to claims 5 and 6, this is the clearance of a metabolic product, in particular creatinine clearance. In particular, the second kidney function indicator variable is made of

Î the first kidney function indicator value measured on the patient as well as one or more other values, such as patient age, patient weight, patient body surface area and patient sex. The determination of the second kidney function indicator value is preferably carried out using the pair of slide scales or several pairs of slide scales with movement-coupled scales (claim 7). The device is preferably designed in such a way that the movement-coupled scales only need to be set to one position to determine the second kidney function indicator value from these values and the value to be determined can then be read without further displacement of the scales (claim 8).

According to claims 9 and 10, the device can be used to determine further quantities in connection with the drug dosage using one or more pairs of slide scales, whereby in the case of several pairs these have scales that are coupled in terms of movement. According to claim 9, the quantity that can be determined is the patient's body surface area, which is to be determined in a first step and is required, for example, as an input quantity for the determination of the second kidney function indicator quantity from the first in the second step. Input quantities for determining the body surface area are the patient's body weight and height. According to claim 10, in a third and final step, using one or more pairs of slide scales, the kidney function indicator quantity and a value specified by the doctor are calculated.

The absolute dose to be administered to the patient can be determined from the AUC target dosage specified. The previously determined second renal function indicator is considered as an input variable.
5

According to claim 11, the movable scales of the slide scale pairs are arranged together on a slide.

It should be noted that within the scope of the present invention description, a single scale mark is also considered a "scale"; accordingly, a scale with many scale marks and a single reference scale mark assigned to it is also considered a "slider scale pair".

Further explanations can be found in the introductory part of this description (pages 1 to 5 above). To avoid repetition, it is expressly stated that all information provided there also relates to the invention and not just to the state of the art.

The invention will now be explained in more detail using embodiments and the accompanying drawings.

In the drawing show:

Fig. 1 the front of a device for determining dosage in a setting for determining the body surface area depending on 0 body weight and height,-

Fig. 2 a representation according to Fig. 1, but in a setting for determining creatinine clearance depending on age and body surface area of a patient with adequate kidney

function;

Fig. 3 is a representation according to Fig. 2, but in a setting for a patient with insufficient kidney function;

Fig. 4 the back of the device according to Figures 1 to 3 in a setting for determining the absolute dose depending on the creatinine clearance.

&iacgr;&ogr; The dosage determination device 1 according to Figures 1 to 4 consists of a slide cover 2 and a slide 3 that can be moved in a direction r therein. The slide cover 2 has a plurality of scale windows 4 on the front and back, which allow a view of the slide 3 arranged in the cover 2. They can be formed, for example, by the slide cover being made of transparent plastic, which is printed outside the windows 4 and is therefore not made transparent, and is unprinted - and therefore transparent - in the area of the windows 4. Each of the scale windows 4 has at least one pair of slide scales 5 with a fixed scale 6 and a movable scale 7. The fixed scales 6 are printed on the slide cover 2; the movable scales 7 are printed on the slide 3.

The existing scale windows 4 can be divided into three groups, namely the group of windows 4.1 for determining the body surface area, the group of windows 4.2 for determining the creatinine clearance and the group of windows 4.3 for determining the absolute dose. The windows of groups 4.1 and 4.2 are located on the front of the dosage determination device 1, the windows of group 4.3 are located on the back.

The group of windows 4.1 for determining the body surface area includes a body weight setting window 4.1.1 and a body surface area reading window 4.1.2. The body weight setting window 4.1.1 has a slider scale

len pair 5.1.1, which is formed by a fixed scale 6.1.1 and a movable scale 7.1.1. The fixed scale 6.1.1 consists of a single scale line with the inscription "kg", the movable scale 7.1.1 is a labelled scale with divisions of ten and an intermediate scale with divisions of one or two. The body surface area reading window 4.1.2 has a body height-body surface area slide scale pair 5.1.2, which is formed by a fixed body height scale 6.1.2 and

Î a movable body surface scale 7.1.2 is formed. The body height scale 6.1.2 is a labelled cm scale in tens with an intermediate scale in twos. The body surface scale 7.1.2 is a labelled m ² scale in 0.1 divisions with an intermediate scale in 0.02 divisions. The scales of the group of windows 4.1 are designed and - as far as the movable scales 7.1.1 and 7.1.2 are concerned - arranged relative to one another on the slide 3 in such a way that after setting the body weight of a patient in the body weight setting window 4.1.1, with the slide 3 not moved in the meantime in the body surface reading window 4.1.2, the body surface of the patient can be read off at the scale line corresponding to his body height.

The group of windows 4.2 for calculating creatinine clearance comprises a serum creatinine setting window 4.2.1 and a creatinine clearance reading window 4.2.2. The serum creatinine setting window 4.2.1 has two age-serum creatinine slider scale pairs 5.2.1.1 and 0 5.2.1.2, the first of which is intended for men and the second for women. Each of these two slider scale pairs 5.2.1.1, 5.2.1.2 has a fixed age scale 6.2.1.1 (men) and 6.2.1.2 (women) in labeled ten-year divisions with five-year intermediate divisions as well as a movable serum creatinine scale 7.2.1.1, 7.2.1.2 in labeled 0.5 mg/dl divisions with 0.1 mg/dl intermediate divisions. The creatinine clearance reading window 4.2.2 has a body surface creatinine clearance slider scale pair 5.2.2. The-

This is formed by a fixed body surface area scale 6.2.2 with a labelled 0.2 m ² graduation with an intermediate 0.1 m scale and a movable creatinine clearance scale 7.2.2 with a labelled 20 ml/min. scale with an intermediate 0.2 ml/min. scale. The scales of group 4.2 for determining creatinine clearance are designed and, as far as the movable scales are concerned, arranged relative to one another in such a way that when the serum creatinine value measured in the patient is set to the corresponding

&iacgr;&ogr; Gender and age of the patient using one of the slider scale pairs 5.2.1.1, 5.2.1.2 without subsequently moving the slider 3, the creatinine clearance can be read by reading the previously determined body surface of the patient on the slider scale pair 5.2.2.

In order to rule out administration of the drug to patients with insufficient renal function, the creatinine clearance scale 7.2.2 ends at the lower limit above which administration is contraindicated (here: 30 ml/min). In addition, a warning indicating the contraindication is included on this scale in the contraindication area below the limit. It reads, for example: "Do not use Carboplat® if the value is < 30 ml/min!".

The above-mentioned lower limit of creatinine clearance corresponds to an upper limit in serum creatinine, which is, however, less precise. The reason for this is the additional dependence of serum creatinine on variables such as age, gender, body surface area, etc., as already explained above. Above this limit, a limit can be found in serum creatinine which represents the beginning of the contraindication range in the vast majority of cases. This value is, for example, 2.0 mg/dl. As an additional safety measure against administration despite contraindication, the serum creatinine scales 7.2.1.1, 7.2.1.2 end at this upper limit.

value; the area above does not contain any scale marks or similar.

The group of windows 4.3 for determining the absolute dose comprises a creatinine clearance setting window 5.3.1 and several absolute dose reading windows 4.3.2. The creatinine clearance setting window 4.3.1 has a pair of slide scales 5.3.1, the fixed scale 6.3.1 of which has the form of a single scale mark and the movable scale 7.3.1 of which is a creatinine clearance scale in labeled 10 ml/min. divisions with 5 ml/min. intermediate scales. For each target AUC from 2 to 11 mg/ml in steps of 1 mg/ml, an absolute dose reading window 4.3.2 is provided, each with a pair of slide scales 5.3.2. The fixed scale 6.3.2 has the form of a single scale mark. The movable scale 7.3.2 is an absolute dose scale in labeled 100 mg/ml divisions or 50 mg/ml divisions in 2 5 or 10 mg/ml divisions. The scales of group 4.3 are designed and - as far as the movable scales 7.3.1 and 7.3.2 are concerned - arranged relative to each other in such a way that after setting the creatinine clearance determined in the previous step in window 4.3.1, the absolute dose corresponding to the respective target AUC can be read in each of the windows 4.3.2 while avoiding movement of the slider 3.

As a further measure to avoid administration to patients with poor renal function, the creatinine clearance scale 7.3.1 of the creatinine clearance setting window 5.3.1 ends at the lower limit (here 30 ml/min.). Below this limit, there are no scale marks or anything else.

The following examples explain how the absolute dose to be administered to a patient is determined using device 1. The input variables of the determination process, i.e. body weight, body surface area, serum creatinine, age and gender,

must be determined for each patient through measurements, blood analysis and, if necessary, questioning. The other input variable, the target AUC, is determined by the doctor depending on the specific illness present, any previous treatments, any combination with other agents, etc.

As a first example, let us assume a patient with the following values of these variables:

Body weight: 60 kg

Height: 170 cm

Age: 70 years

Serum creatinine: 1.4 mg/dl

Target AUC: 8 mg/ml-min.

In a second example, the patient has a serum creatinine of 2.0 ml/dL with otherwise unchanged values.

First example:

In a first step, which is illustrated in Fig. 1, the body weight (60 kg) is set using the slider scale pair 5.1.1. Without moving the slider 3 in the meantime, the patient's body surface area is then read off the slider scale pair 5.1.2 at the patient's height (170 cm); the value thus obtained is 1.7 m ² . This value is recorded for later use, e.g. noted in a work document.

In a second step, which is illustrated in Fig. 2, the measured serum creatinine value of the patient (1.4 mg/dl) is set on the slider scale pair 4.2.1.1 intended for males at the patient's age (70 years). Without moving the slider 2 in the meantime, the patient's creatinine clearance is then read on the slider scale pair 4.2.2 at the body surface area determined in the first step (1.7 m ² ); the value thus obtained is 41 ml/min.

This value is again saved for use in the next step.

In the third step, which is illustrated in Fig. 4, the slider scale pair 5.3.1 is set to the previously determined creatinine clearance value (41 ml/min.). Then - without moving the slider 3 in the meantime - the window valid for the target AUC (here 4.3.2.4.) is selected and the absolute dose to be administered (here 525 mg) is read off the associated slider scale pair (here 5.3.2.4).

Second example:

The determination of creatinine clearance in the second example with higher serum creatinine (2 mg/dl) is illustrated in Fig. 3. The first step is the same as that of the first example. In the second step, it is just possible to set the slider scale pair 5.2.1.1 to the serum creatinine value measured in the patient, since this value corresponds to the upper limit and is therefore not yet outside the serum creatinine value range covered by scale 7.2.1.1. (Note: A slightly higher measured serum creatinine value (approximately 2.1 ml/dl) would no longer be within the value range, so that a dose determination with device 1 would no longer be possible.) With the setting to 2.0 ml/dl, the reading for creatinine clearance on the slider scale pair 5.2.1. is below 30 ml/min, and thus outside the value range of scale 7.2.2. The note placed here expressly warns the user against using the medication with the low creatinine clearance value. The user will therefore stop determining the dosage at this point. An additional safeguard against administration despite contraindications is that the scale 7.3.1 used in the following step also ends below the limit of 30 ml/min (Fig. 4). This means that a corresponding dose can be taken despite the warning.

subsequent adjustment of slider 3 and thus any execution of the third step is excluded.

Overall, the device according to the invention allows a simple and precise determination of the absolute dose to be administered while at the same time providing a high level of security against incorrect dosing and administration of the medication despite contraindications.

Claims (11)

Protection claims 1. Device (1) for patient-dependent determination of the dosage of a drug, in particular an antineoplastic drug, which has a damaging effect if the AUC is too high - i.e. too large an area under the time-concentration curve in the body - which is why the dosage is determined depending on the kidney function, wherein the device (1) has at least one pair of slide scales (5.2, 5.3) for setting or reading a kidney function indicator value, and wherein the pair of slide scales (5.2, 5.3) does not display those values of the kidney function indicator value at which the medication must not be administered due to insufficient kidney function, and/or wherein a corresponding warning is provided on the slider scale pair (5.2) in the value range of the renal function indicator variable at which the medication must not be administered due to insufficient renal function. 2. Device according to claim 1, wherein the renal function indicator variable - called "first renal function indicator variable" - is the serum concentration of a metabolite. 3. Device according to claim 2, wherein the production of the metabolite decreases with patient age in a similar manner to renal function. 4. The device of claim 3, wherein the serum concentration measure is serum creatinine. 5. Device according to one of claims 1 to 4, in which the or another of the renal function indicator variables - "second renal function indicator variable ß" - the clearance of a metabolite. 6. The device of claim 5, wherein the second renal function indicator is the patient’s creatinine clearance. 7. Device according to one of the preceding claims, insofar as it is dependent on claims 2 and 5, γ in which with the aid of the slider scale pair (5.2) or several slider scale pairs (5.2) with movement-coupled scales (7.2) depending on the value of the first kidney function variable found in the patient and one or more of the following variables: patient age, patient weight, patient body surface area and patient gender, a value for the second kidney function indicator variable can be determined. 8. Device according to claim 7, which is designed in such a way that the movement-coupled scales (7.2) for determining the second kidney function indicator variable from the variables mentioned in claim 7 only need to be set in one position. 9. Device according to one of the preceding claims, which also has one or more pairs of slide scales (5.1), with the aid of which the body surface area of the patient can be determined from the body weight and height of the patient. 10. Device according to one of the preceding claims, which also has one or more pairs of slide scales (5.3), with the aid of which the absolute dose to be administered to the patient can be determined from the kidney function indicator variable - in particular the determined second kidney function indicator variable - and a target dosage. 11. Device according to claims 7 and 9 and/or 10, in which the movable scales (7) of the slide scale pairs (5) are arranged together on a slide (3).