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WO2001052828A2 - Prevention, au moyen de glutamine, de la diarrhee tardive induite par l'irinotecan - Google Patents

Prevention, au moyen de glutamine, de la diarrhee tardive induite par l'irinotecan Download PDF

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Publication number
WO2001052828A2
WO2001052828A2 PCT/US2001/001270 US0101270W WO0152828A2 WO 2001052828 A2 WO2001052828 A2 WO 2001052828A2 US 0101270 W US0101270 W US 0101270W WO 0152828 A2 WO0152828 A2 WO 0152828A2
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WO
WIPO (PCT)
Prior art keywords
glutamine
irinotecan
onset
diarrhea
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2001/001270
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English (en)
Other versions
WO2001052828A3 (fr
Inventor
Diane Savarese
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Massachusetts Amherst
Original Assignee
University of Massachusetts Amherst
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Filing date
Publication date
Application filed by University of Massachusetts Amherst filed Critical University of Massachusetts Amherst
Priority to AU2001229478A priority Critical patent/AU2001229478A1/en
Publication of WO2001052828A2 publication Critical patent/WO2001052828A2/fr
Publication of WO2001052828A3 publication Critical patent/WO2001052828A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • TECHNICAL FIELD This invention relates to oncology and gastroenterology, and more particularly to chemotherapy involving irinotecan.
  • Irinotecan hydrochloride (CPT-11; Camptosar ®, Pharmacia & Upjohn) is a chemotherapeutic agent that displays activity against a broad spectrum of malignancies, including carcinomas of the colon, stomach, and lung.
  • Irinotecan is approved by the United States Food & Drug Administration (FDA) for treatment of metastatic colorectal cancer and is an important drug for the management of that disease (Rothenberg, et al., J Clin. Onclol. 14:1128-1135 (1996); Rougier et al., J Clin. Oncol. 15:251-260 (1997); Rothenberg et al, Seminars in Oncology 26:632-639 (1999)).
  • Diarrhea is a common side effect of irinotecan therapy. Frequently the diarrhea is of sufficient severity to necessitate limitation of irinotecan dosage to sub- optimal levels.
  • Irinotecan-associated diarrhea is classified into two types, i.e., early and delayed-onset (late). These two types of irinotecan-associated diarrhea are treated differently. Early diarrhea, typically observed within 24 hours after irinotecan infusion, is cholinergically mediated, short-lasting and can be prevented by atropine administration (Saliba et al., J. Clin. Oncol. 16:2745-2751 (1998)). Delayed-onset, irinotecan-induced diarrhea is multifactorial, with contributions from dysmotility and secretory factors as well as a direct toxic effect of the drug or a metabolite known as SN38 on the intestinal mucosa (Saliba et al.
  • loperamide and other opiates are useful for treating delayed-onset, irinotecan-induced diarrhea, this side effect still limits irinotecan dosage in many patients.
  • a means of preventing, or an improved means of treating, delayed-onset, irinotecan-induced diarrhea would allow the anti-tumor potential of irinotecan to be utilized more fully.
  • compositions include L-glutamine formulated for use to prevent or inhibit delayed-onset, irinotecan-induced diarrhea in patients.
  • the methods include administering to a mammal, e.g., a human patient, a therapeutically effective amount of irinotecan, and administering an effective amount of glutamine prior to the onset of late-onset diarrhea induced by the ininotecan.
  • the glutamine is administered enterally, e.g., orally.
  • the glutamine is administered in a dosage of 10 to 150 grams per day. More preferably, the dosage is 20 to 60 grams per day, e.g., approximately 40 or 50 grams per day. In some embodiments, the glutamine dosage is approximately 30 grams per day.
  • the daily dosage is administered in 2 to 12 individual doses. In some embodiments, the daily glutamine dosage is three oral doses of approximately 10 grams each.
  • the glutamine dosage is administered on days including days 1 and 2, with day 1 being the day on which the irinotecan is administered.
  • the glutamine dosage is administered on days including days 1, 2 and 3, with day 1 being the day on which the irinotecan is administered.
  • the glutamine can be administered in a formulation, e.g., as a component in a composition containing vitamin A, vitamin C, vitamin E, or selenium, or a combination of any two or more thereof.
  • the invention also provides a method of preventing or reducing development of delayed-onset, irinotecan-induced diarrhea.
  • the method includes identifying a mammal, e.g., a human patient, at risk for delayed-onset, irinotecan-induced diarrhea, and administering to the patient an effective amount of glutamine prior to the onset of delayed-onset diarrhea induced by the irinotecan.
  • the invention also provides a method of treating existing, delayed-onset, irinotecan-induced diarrhea.
  • the method includes administering an effective amount of glutamine to a mammal, e.g., a human patient, displaying signs of delayed-onset, irinotecan-induced diarrhea.
  • irinotecan means irinotecan and pharmaceutically acceptable salts and metabolites thereof.
  • glutamine means L-glutamine or DL-glutamine, excluding glutamine residues incorporated into proteins.
  • irinotecan as a chemotherapeutic agent is known in the art. See, e.g., Pazdur, Oncology 12 (Suppl. 6):13-21 (1998); Hecht et al., Oncology 12 (Suppl. 6):72-78 (1998).
  • Administration of irinotecan in the present invention can be carried out in accordance with established clinical practice, for example in the treatment of metastatic colorectal cancer. In some cases, however, the invention enables a clinician to prescribe an irinotecan dosage higher than in the prior art because of glutamine's alleviation of irinotecan-induced diarrhea. Using the present disclosure, such adjustment of irinotecan dosage can be accomplished by one of ordinary skill in the art, without undue experimentation.
  • Glutamine (Gin; glutamic acid 5-amide) can be synthesized chemically or isolated from natural sources. Because the glutamine molecule contains a chiral center, it is optically active. Therefore, glutamine obtained by conventional chemical synthesis is a racemic mixture (DL-glutamine). When DL-glutamine is used, dosage should be adjusted to account for any difference in activity between the D and L isomers. In preferred embodiments of the invention, L-glutamine is used. L- glutamine is commercially available as a pure compound. Traditional diets taken by mouth normally contain less than 10 grams of glutamine per day (Hall et al., Br. J. Surg., 83:305-312, 1996). Supplemental glutamine can be administered enterally or parenterally.
  • glutamine administration is enteral, with the total daily dosage being divided into separate doses administered over the course of the day. This promotes contact with the epithelial lining of the gut.
  • enteral administration of glutamine can be by alternative means, for example by feeding tube.
  • glutamine powder is practically tasteless.
  • glutamine powder can be mixed with food or a beverage, or dissolved in water and flushed into a feeding tube.
  • Such glutamine mixed with food or dissolved in liquid can be in the form of pure glutamine.
  • glutamine for use in this invention can be formulated as an active ingredient in any pharmaceutically acceptable composition.
  • Other components in a glutamine-containing composition can be of various types, including inert fillers, nutritional supplements, therapeutic agents, flavorings, food colorings, and preservatives.
  • Such compositions can be prepared by any of the methods known in the art. Useful methods and compositions are described, for example, in Remington s ' Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980).
  • a convenient glutamine formulation suitable for use in the present invention is available commercially under the name "Glutamine Enriched Antioxidant Formula” (Cambridge Nutraceuticals, Cambridge, MA). This formulation is sold in individual packets, each containing: 10 grams of L-glutamine, 10 grams of protein, 6,500 IU of vitamin A (as beta carotene), 200 mg of vitamin C (as ascorbic acid), 100 IU of vitamin E (as dl-alpha-tocopherol), and 50 meg of selenium (as selenomethionine) .
  • Oral glutamine supplementation was administered to 5 cancer patients being treated with irinotecan.
  • This treatment alleviated delayed onset, irinotecan-induced diarrhea.
  • This alleviation allowed full doses of irinotecan to be administered in subsequent chemotherapy.
  • the first patient a 65-year-old man with 5-fluorouracil-refractory metastatic colon cancer, developed grade 4 diarrhea (as assessed according to National Cancer Institute Common Toxicity Criteria) requiring hospital admission for hydration and bowel rest 4 days after receiving the second week of his first cycle of irinotecan administered at 125 mg/m /week.
  • Intensive loperamide treatment failed to control this patient's diarrhea.
  • a two-week break was instituted, and he was retreated for the second cycle of chemotherapy with 100 mg/m 2 /week resulting in grade 1 diarrhea only for the 4 weeks of therapy.
  • the second patient a 56-year-old woman with metastatic and locally recurrent rectal cancer, had an ileostomy with baseline daily firm stool output of ⁇ 500 cc/day. She received weekly irinotecan 125 mg/m 2 /week after failing to respond to treatment with 5-fluorouracil. After the second week of therapy she was admitted to the hospital with grade 3 vomiting, grade 4 diarrhea, and >1500 cc per day of watery stool per ileostomy despite taking up to 20 loperamide tablets (2 mg each) every 24 hours. She was intravenously rehydrated, and a new cycle of chemotherapy was instituted 2 weeks later at 100 mg/m 2 /week. This still resulted in grade 3 diarrhea, with >1500 cc/day watery stool output via ileostomy.
  • Glutamine at a dosage of 10 Gm given orally three times per day was begun the night before she received her next weekly dose of irinotecan at 100 mg/m 2 /week. The patient continued taking 10 grams of glutamine every 8 hours for 6 additional doses after receiving each week's therapy. She continued to receive therapy at a dose of 100 mg/m /week with no watery ileostomy output.
  • the following is a protocol for a larger study of the use of glutamine to alleviate late-onset diarrhea associated with irinotecan therapy.
  • the objectives of the study include obtaining further data on the effectiveness of glutamine in the prevention of late-onset, irinotecan-induced diarrhea; obtaining further information on the ability of glutamine to allow dose re-escalation of irinotecan to standard doses; obtaining further information on potential side effects of glutamine administration in the context of irinotecan therapy; and obtaining further information on the efficacy of irinotecan in therapy of metastatic colorectal cancer in patients receiving oral glutamine, including response rate and time to progression
  • Eligibility criteria for participation in the study will be: documented malignancy for which irinotecan therapy is being used, either weekly, or every 3 weeks; late diarrhea related to irinotecan, beginning more than 24 hours after receiving irinotecan, and grade 2 in severity; no chronic diarrhea illness (more than 4 stools per day for >4 weeks); medical and psychiatric condition sufficient to tolerate therapy; and no concurrent radiation to the abdomen. Patients deemed eligible will have their most recent dose level of irinotecan recorded, and must have recovered from irinotecan toxicity to grade 1 diarrhea. The therapy of that episode of diarrhea must have concluded.
  • Table 1 Patients Receiving Weekly Therapy
  • Each 10-gram glutamine dose will be in the form of Glutamine Enriched Antioxidant Formula (Cambridge Nutraceuticals, Boston MA). Each dose of glutamine will be mixed in cold, non-acidic liquid and drunk quickly. The glutamine will be administered orally, in 10-gram doses, 3 times per day for 2 or 3 days following each dose irinotecan.
  • Subsequent irinotecan dose re-escalation for patients receiving weekly therapy will be as follows. Patients will receive two weekly courses at the dose level indicated above. Patients then will undergo dose re-escalation as indicated below, as long as the patient has not experienced greater than grade 1 diarrhea. Table 3: For Patients Receiving Weekly Therapy
  • dose may be re-escalated again to a maximum of 125mg/m2/week.
  • dose may be re-escalated again, if no greater than grade 1 diarrhea occurs, to a maximum of 350 mg/m 2 every 3 weeks.
  • Patients will be followed in the study for as long as they continue to receive irinotecan. Patients will be assessed for diarrhea and any other toxic side effects weekly while they continue to receive irinotecan, or every 3 weeks if they are receiving therapy on an every 3-week basis. If patients have recurrence of > grade 2 diarrhea despite the use of oral glutamine supplements, they will be removed from protocol therapy, and further management will be at the discretion of the treating physician.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des procédés et des compositions permettant d'inhiber la diarrhée tardive induite par l'irinotécan. Les procédés comprennent l'administration de quantités efficaces de glutamine, associée à l'irinotécan. Dans des exemples décrits, la glutamine par voie orale est efficace pour inhiber la diarrhée quand elle est administrée en doses de 10 grammes trois fois par jour pendant deux ou trois jours, après l'administration d'irinotécan.
PCT/US2001/001270 2000-01-18 2001-01-12 Prevention, au moyen de glutamine, de la diarrhee tardive induite par l'irinotecan Ceased WO2001052828A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001229478A AU2001229478A1 (en) 2000-01-18 2001-01-12 Glutamine prevention of delayed-onset irinotecan-induced diarrhea

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US48496200A 2000-01-18 2000-01-18
US09/484,962 2000-01-18

Publications (2)

Publication Number Publication Date
WO2001052828A2 true WO2001052828A2 (fr) 2001-07-26
WO2001052828A3 WO2001052828A3 (fr) 2002-04-18

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PCT/US2001/001270 Ceased WO2001052828A2 (fr) 2000-01-18 2001-01-12 Prevention, au moyen de glutamine, de la diarrhee tardive induite par l'irinotecan

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Country Link
AU (1) AU2001229478A1 (fr)
CO (1) CO5280204A1 (fr)
PE (1) PE20011042A1 (fr)
WO (1) WO2001052828A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001049299A3 (fr) * 2000-01-06 2002-02-21 Malcolm J Moore Traitement contre la diarrhee ou prevention de la diarrhee
WO2004103371A1 (fr) * 2003-05-21 2004-12-02 Pharmacia & Upjohn Company Llc Utilisation d'inhibiteurs de cftr dans le traitement de la diarrhee induite par la chimiotherapie

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5786344A (en) * 1994-07-05 1998-07-28 Arch Development Corporation Camptothecin drug combinations and methods with reduced side effects
US5646159A (en) * 1994-07-20 1997-07-08 Research Triangle Institute Water-soluble esters of camptothecin compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001049299A3 (fr) * 2000-01-06 2002-02-21 Malcolm J Moore Traitement contre la diarrhee ou prevention de la diarrhee
WO2004103371A1 (fr) * 2003-05-21 2004-12-02 Pharmacia & Upjohn Company Llc Utilisation d'inhibiteurs de cftr dans le traitement de la diarrhee induite par la chimiotherapie

Also Published As

Publication number Publication date
PE20011042A1 (es) 2001-09-26
CO5280204A1 (es) 2003-05-30
AU2001229478A1 (en) 2001-07-31
WO2001052828A3 (fr) 2002-04-18

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