WO2001049299A2

WO2001049299A2 - Prevention of ironotecan induced diarrhea with activated carbon

Info

Publication number: WO2001049299A2
Application number: PCT/CA2000/001544
Authority: WO
Inventors: Malcolm J. Moore; Michael Michael
Original assignee: Moore Malcolm J; Michael Michael
Priority date: 2000-01-06
Filing date: 2000-12-21
Publication date: 2001-07-12
Also published as: AU2335601A; WO2001049299A3; AR026791A1; PE20010990A1; CA2295429A1

Abstract

Irinotecan is an anti-cancer drug whose use sometimes causes diarrhea in patients. The invention provides a method of preventing or mitigating the diarrhea by administration of carbon to patients in need thereof.

Description

Treatment or Prevention of Diarrhea

The present invention relates to prevention of diarrhea caused by administration to a patient of irinotecan or a pharmaceutically acceptable salt of irinotecan.

Background of the Invention

Irinotecan and its preparation are known, for instance, from United States Patent No. 4,604,463. Irinotecan has the chemical name [1 , 4 ' -Bipiperidine] -1 ' -carboxylic acid(S)- 4, ll-diethyl-3,4, 12, 14 - tetrahydro-4 -hydroxy-3 , 14-dioxo-lH- pyrano [3 ' , 4 ' : 6, 7] indolizino [1, 2-b] quinolin-9-yl ester; and has the following structure

Irinotecan, in the form of its hydrochloride , is available commercially as Camptosar* Injection from Pharmacia and Upjohn. Irinotecan hydrochloride trihydrate is a pale yellow to yellow crystalline powder, with the empirical formula

^C33^H38^N4°6 '^HC1 ' ^3H2° ^{and a} molecular weight of 677-.19.

Irinotecan hydrochloride was clinically investigated as CPT-11. Irinotecan hydrochloride has shown activity against a variety of tumour types, particularly refractory colorectal tumours, and it is used for the treatment of various forms of cancer. Its primary use is in the treatment of colon cancer, particularly advanced colon cancer. It is also of interest for treatment of other cancers, however, and mention is made of cancers of the lung, the stomach and the pancreas.

Irinotecan is usually administered in one of two

treatment regimens. In one regimen, a dose of 125mg/m2 of irinotecan is given i.v. over a 90 minute period each week for four weeks. After a lapse of two weeks this is repeated, so that the patient receives irinotecan in four weeks out of every

six. In the other treatment regimen a dose of 350 mg/m² is given i.v. over 90 minutes, every third week. Thus, the one regimen operates with a six week cycle and the other regimen on a three week cycle.

It is found that administration of irinotecan causes diarrhea in some patients. The occurrence of diarrhea is unpredictable, but in a significant number of cases the diarrhea is severe. In some cases the effect of the diarrhea on the general health of the patient is so severe that the treatment with irinotecan has to be terminated.

Diarrhea often develops as a side-effect disorder during the clinical treatment with chemotherapeutic agents, whose typical symptom is characterized by the frequent defecation of liquid or liquid-like stools. This adverse effect is prevalently associated with, e.g., the use of 5-fluorouracil , cisplatin and CPT-11. In particular, late diarrhea due to the administration of CPT-11 can be prolonged, may lead to dehydration and electrolyte imbalance and can be, in some cases, so serious that CPT-11 administration should be interrupted and dose may need to be reduced.

So far, no definite and efficacious means for prevention and/or treatment of CPT-11-induced diarrhea have been currently identified. Thus, there is a need to develop an agent for preventing and/or treating diarrhea, particularly late diarrhea, caused by CPT-11 administration, which has good safety and efficacy.

Summary of the Invention

It has now been discovered that diarrhea can be avoided or alleviated if carbon is also administered to a patient who is receiving irinotecan.

Accordingly, in one aspect of the invention there is provided a method of avoiding or alleviating irinotecan- induced diarrhea in a patient in need thereof, which method comprises administering carbon to the patient.

In another aspect the invention provides the use of carbon for avoiding or alleviating irinotecan- induced diarrhea. Description of the Preferred Embodiments In the present specification, the term "irinotecan" includes not only the free base but also pharmaceutically acceptable salts of irinotecan, for example the hydrochloride salt .

In accordance with the invention, a patient who is receiving irinotecan or a pharmaceutically acceptable salt of irinotecan is also given carbon. The irinotecan can be given m the unsalified form, or in the form of a pharmaceutically acceptable salt. Mention is made of irinotecan hydrochloride (CPT-11) especially irinotecan hydrochloride trihydrate The carbon is suitably in activated form, and activated charcoal m a form suitable for administration to humans is available.

The manor dose-limiting toxicity in cancer patients receiving CPT-11 therapy is a severe delayed chronic grade 3-4 diarrhea. The loss of fluids and electrolytes associated with persistent and severe diarrhea, such as late diarrhea occurring more than 24 hours after administration of CPT-11, can result m life-threatening dehydration, renal insufficiency, and electrolyte imbalances. Fluctuation m mtravascular fluids caused by severe diarrhea may result m cardiovascular morbidity The life- threatening aspects of persistent or severe diarrhea require aggressive treatment and often lead to hospitalization. Persistent and severe diarrhea can also have tremendous negative effect on the patient's quality of life, and interferes with roles and responsibilities and interpersonal relationships and promotes feelings of social isolation.

Quick resolution or, more preferably, prevention of diarrhea is important, not only to prevent hospitalization, but also to improve quality of life and to enable patients to continue chemotherapy treatment to effect a remission or cure.

A variety of strategies for the control of chemo- therapeutic-related diarrhea, particularly for the control of diarrhea induced by CPT-11, have been examined in humans and in animal models.

In humans, aggressive high-dose co-therapy with loperamide (an agent that slows intestinal motility and affects water and electrolyte movement through the bowel) has been used to reduce or control diarrhea (Rougier P, Bugat R. CPT-11 in the treatment of colorectal cancer: clinical efficacy and safety profile. Semin Oncol 1996; 23 (Suppl 3): 34-41.) Though partially successful in some cases, this agent requires administration at 2 hr intervals at the onset of diarrhea and is not used prophylactically. The present situation is such that there is not yet any established efficacious and safe agent, which is suitable in prophylaxis and/or treatment of diarrhea, especially persistent and severe diarrhea, such as late diarrhea induced by irinotecan administration to a cancer patient. It has now been unexpectedly found that carbon can be utilized in the prophylaxis and/or treatment of the diarrhea, especially persistent and severe diarrhea such as late diarrhea, related to CPT-11 administration.

Namely, the present invention is directed to a method for preventing diarrhea caused by the administration of irinotecan, comprising administering to a patient susceptible to said diarrhea a therapeutically effective amount of carbon.

The use of carbon in preventing/treating diarrhea induced by irinotecan according to the present invention has excellent prophylactic effect. Therefore, use of carbon not only permits the continuation of a cancer chemotherapy which would otherwise need to be reduced or even interrupted, but also provide a marked improvement in the patient's quality of life and reduces or avoids the risk of hospitalization .

The term "diarrhea" includes persistent and severe diarrhea, such as diarrhea which occurs more than 24 hours after irinotecan administration (late diarrhea) . Persistent and severe diarrhea can delay treatment and reduce patient compliance, and thus interfere with the completion of the full course of therapy and ultimately increase the cost of care.

In the methods according to the invention, carbon may be administered simultaneously with irinotecan, or the compounds may be administered sequentially, in any desired order.

Irinotecan is normally administered intravenously. Carbon is administered orally, for example in the form of a stirred aqueous suspension or in solid chewable form as, say, a charcoal biscuit. Ideally, for each dose of irinotecan there are given several doses of carbon, some before, some simultaneously with and some after the dose of irinotecan.

The dosage ranges for the administration of the carbon and of the irinotecan may vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art.

The dosage regimen must therefore be tailored to the particular of the patient's conditions, response and associate treatments in a manner which is conventional for any therapy, and may need to be adjusted in response to changes in conditions and/or in light of other clinical conditions.

CPT-11 is usually administered in a regimen wherein a

dose of 125 mg/m² of CPT-11 is given i.v. over a 90 minutes period once weekly for 4 weeks, followed by a 2 -week rest period. Thereafter, additional courses of treatment may be repeated every 6 weeks (4 weeks on therapy, followed by 2 weeks off therapy) . Subsequent doses may be adjusted to as high as

150 mg/m² or to as low as 50 mg/m² in 25-mg/m² to 50-mg/m², increments depending upon individual patient tolerance of treatment, as judged by the attending physician.

In one embodiment of the invention the patient is given charcoal in a stirred aqueous suspension, in a dose of 30 ml of the suspension containing 1000 mg of charcoal. Suitably one such dose is given to the patient the night before the patient is scheduled to receive irinotecan, three such doses are given on the day that the patient receives the irinotecan and three such doses are given on the following day. The patient therefore receives seven doses per dose of irinotecan. It has been found that this treatment avoids or alleviates diarrhea in many cases. Of course, different patients show different response to the treatment, and some departure from these amount of dose and frequency of dose may be required. The precise dose to be given to an individual patient, and the frequency, are matters to be decided by the attending physician or other medical professional.

The activated carbon can be given in other forms. For instance charcoal biscuits can be given. The preferred form for administration will vary from patient to patient and this is again a matter to be decided by the attending physician or nursing staff.

The invention extends to a commercial package containing carbon in a form suitable for oral administration, together with instructions for its use for preventing or mitigating irinotecan- induced diarrhea.

The invention further extends to a kit containing irinotecan and, separately, carbon in a form suitable for oral administration. The irinotecan and the carbon may each be present in one or more unit doses. For instance, the kit may comprise one unit dose of irinotecan and seven unit doses of carbon.

When referring to "carbon in a form suitable for oral administration'' we are referring particularly to the degree of purity of the carbon. Thus, a quantity of pure, finely divided charcoal that is intended to be made up into an aqueous suspension is considered to be "in a form suitable for oral administration" both before and after it is made up into the suspension.

The invention also relates to combining separate pharmaceutical compositions in kit form. That is, a kit is contemplated wherein two separate units are combined: a irinotecan pharmaceutical composition, optionally also containing a pharmaceutically acceptable carrier or excipient, and a unit of carbon in a form suitable for oral administration.

It is therefore a further object of the present invention to provide a kit comprising a package housing a first container containing a pharmaceutical composition comprising irinotecan and a second container containing the carbon.

The kit will preferably include^' directions for the administration of the separate components. The kit form is particularly advantageous when the separate components must be administered in different dosage forms (e.g. oral and parenteral) or are administered at different dosage intervals. The invention is further illustrated in the following examples .

A group of 28 patients (cycle 1) completed a first cycle of therapy in which each patient was treated with irinotecan hydrochloride in accordance with the first treatment regimen mentioned above, and was also treated with charcoal.

Thus, each patient was given a dose of 125 mg/m² of the irinotecan i.v. on days 1, 8, 15 and 22 of 42 day periods. The doses were given intravenously over 90 minutes. Each patient was also given orally doses of charcoal in stirred aqueous suspension. Each patient was given one dose on the day before receiving irinotecan, three doses on the day of receiving irinotecan and three doses on the day after receiving irinotecan. Each dose contained 1000 mg charcoal in a 15 ml aqueous suspension.

Of the group of 28 patients- who completed the first cycle 24 patients (cycle 2) completed a second cycle in which each patient was treated with irinotecan hydrochloride, in accordance with the first treatment regimen mentioned above, but was not treated with charcoal. Thus, each patient was given a

dose of 125 mg/m² of the irinotecan i.v. on days 1, 8, 15 and 22 of 42 day periods.

The incidence of diarrhea among the patients was noted and graded, from zero, indicating no diarrhea, to higher numbers indicating more severe diarrhea. The results are given in the following Table.

TABLE

This table indicates that on the first cycle of therapy [when charcoal was also given] the incidence of severe diarrhea was less [2/28 versus 6/24] . In support of this is the fact that these patients took less anti-diarrheal medication. In addition these patients were able to receive significantly more irinotecan because of the reduced diarrhea. This could potentially translate into a higher rate of tumor control although this was not assessed in this trial.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method of avoiding or alleviating irinotecan- induced diarrhea in a patient in need thereof ,• which method comprises administering carbon to the patient.

2. A method according to claim 1, wherein the carbon is administered in the form of an aqueous suspension of charcoal.

3. A method according to claim 1 or 2 , wherein the diarrhea is late diarrhea.

4. A method according to claim 1, 2 or 3 , wherein the irinotecan is in the hydrochloride salt form.

5. Use of carbon for avoiding or alleviating irinotecan- induced diarrhea.

6. A commercial package containing carbon in a form suitable for oral administration, together with instructions for its use for preventing or mitigating irinotecan- induced diarrhea .

7. A kit contai ing as one component, irinotecan or an irinotecan-containing composition and, as a second component, one or several doses of carbon in a form suitable for oral administration.

8. A kit comprising a package housing a first container containing a pharmaceutical composition comprising irinotecan or a pharmaceutically acceptable salt thereof and a second container containing carbon in a form suitable for administration.

9. A kit according to claim 7 or 8 , which further houses direction for the administration of the separate components.