EP1003516A1 - Administration de composes camptotheciniques de cancerotherapie avec reduction de leurs effets secondaires - Google Patents

Administration de composes camptotheciniques de cancerotherapie avec reduction de leurs effets secondaires

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Publication number
EP1003516A1
EP1003516A1 EP99935334A EP99935334A EP1003516A1 EP 1003516 A1 EP1003516 A1 EP 1003516A1 EP 99935334 A EP99935334 A EP 99935334A EP 99935334 A EP99935334 A EP 99935334A EP 1003516 A1 EP1003516 A1 EP 1003516A1
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Prior art keywords
cpt
camptothecin
administering
alkaline
uptake
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German (de)
English (en)
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EP1003516A4 (fr
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Bernard Bouscarel
Kunihiko Kobayashi
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George Washington University
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George Washington University
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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to camptothecin compounds, in particular, irinotecan hydrochloride composition formulations, and methods of administering camptothecin compounds such as irinotecan hydrochloride for the treatment of cancer and AIDS, with reduced side effects.
  • Camptothecin is a quinoline-based alkaloid found in the barks of the Chinese Camptotheca tree and the Asian nothapodytes tree. It is a close chemical relative to a inocamptothecin, CPT-11 (irinotecan) , DX-8951F and topotecan. These compounds are useful in treating breast cancers, ovarian cancer, colon cancer, malignant melanoma, small cell lung cancer, thyroid cancers, lymphomas and leukemias. These compounds are also used for the treatment of AIDS.
  • Irinotecan hydrochloride (CPT-11) (4S) -4, ll-diethyl-4- hydroxy-9- [ (4-piperidinopiperidino) carbonyloxy] -lH-pyrano [3 ' ,4 • :6,7] indolizino[l,2-b]quinoline-3,14(4h,12H)dione hydrochloride, has a novel mechanism of antitumor activity, namely the inhibition of DNA topoisomerase I.
  • Topoisomer-ases are the enzymes which wind and unwind the DNA that makes up the chromosomes.
  • camptothecin compounds keep the chromosomes wound tight so that they cannot make proteins. Because cancer cells grow at a much faster rate than normal cells, they are more vulnerable to topoisomerase inhibition than normal cells.
  • CPT-11 has shown effective antitumor activity clinically (2, 3), and, recently, a survival benefit by CPT-11 was shown in colorectal cancer. However, it has major toxicities of leukopenia and diarrhea in clinical practice. The clinical use of CPT-11 at higher dosages was associated with an unexpected and significant incidence of diarrhea (4, 6, 7, 12) , and diarrhea is now recognized as a dose-limiting toxicity of this drug (4-7) . Although many pharmacokinetic analyses, which have shown a great interpatient variability, have been made to predict the incidence of diarrhea, there are somewhat conflicting results (8-11) .
  • CPT-11 and its metabolites, SN-38 and SN-38-Glu were detected in not only human plasma but also human bile.
  • SN-38 has strong cytotoxicity
  • SN-38-Glu is a deactivated, glucuronidated form of SN-38
  • CPT-11 has much less cytotoxicity compared to SN-38.
  • These compounds have an -hydroxy-3-lactone ring, which undergoes reversible hydrolysis at a rate that depends mainly on pH (15, 16, 17) . At more than physiological pH, the lactone form is unstable and the equilibrium favors hydrolysis to open the lactone ring and yield the carboxylate form. Under acidic conditions, the reverse reaction, with formation of the lactone, is favored.
  • CPT-11 and SN-38-Glu are hydrolyzed by carboxylesterase of mainly liver origin to the active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38) .
  • Some of SN-38 undergoes subsequent conjugation by the hepatic enzyme, UDP-glucuronyltransferase, to SN-38 ⁇ -glucuronide (SN- 38-Glu) , and is excreted into bile along with the other components, CPT-11 and SN-38 (13, 14).
  • the three compounds are believed to be reabsorbed by intestinal cells to enter the enterohepatic circulation.
  • CPT-11, SN-38 and SN38-Glu have an -hydroxy-3-lactone ring, which undergoes reversible hydrolysis at a rate which is mainly pH-dependent (Fassberg et al., 1992).
  • camptothecin derivatives The structure of several camptothecin derivatives are known .
  • camptothecin CPT
  • CPT camptothecin
  • derivatives thereof of the closed lactone ring form are administered intramuscularly or orally. In such cases, it was possible to obtain total remissions of a vast spectrum of human cancers without the toxicity observed previously with CPT Na+.
  • the derivatives of CPT used were 9- Amino-20(S) -Camptothecin (9AC) . 9-Nitro-20 (S) -Camptothecin (9N0 2 ) .
  • the patent recommends that pH levels of below 7 be used to allow the lactone form of camptothecin to predominate.
  • the patent suggests the administration of the compounds with a pharmaceutically acceptable acid.
  • U.S. Patent No. 5,447,936 describes that the HECPT form of the drug is more effective in inhibiting topoisomerase-I in an acidic environment, than in cells having higher intracellular pH levels.
  • the patent describes the administration of the drug with an acid which is an organic carboxylic acid such as citric acid.
  • U.S. Patent No. 5,225,404 describes the administration of a camptothecin compound with water-based solvents for water- soluble compounds such as normal saline or phosphate buffered saline solutions.
  • the patent indicates that signs of diarrhea and cystitis were prevented and no overall toxicity was obtained.
  • U.S. Patent No. 5,637,770 describes the creation of a hexacyclic compound obtained by the addition of a water- soluble ring to camptothecin, which had superior characteristics to camptothecin.
  • U.S. Patent No. 5,633,016 describes a combination cancer therapy including administering an effective amount of topotecan with cisplatin.
  • U.S. Patent No. 5,633,260 discloses a 7-11-substituted camptothecin derivative.
  • the patent also describes that maintaining an acidic pH (3 to 4) in the formulation is important to reduce the slow conversion of 11,7-HECPT lactones with the E-ring-hydrolyzed carboxylate which occurs at physiological pH.
  • This patent prescribes regulated dosages to eliminate toxicity of the compound.
  • U.S. Patent No. 5,652,244 describes a method of treating human carcinoma with camptothecin derivatives.
  • U.S. Patent No. 5,658,920 describes a hexacyclic compound derivative of camptothecin.
  • U.S. Patent No. 5,597,829 discloses that CPT is excreted unchanged by the kidneys, although a large percentage of the drug administered cannot be accounted for in the urine.
  • the patent suggests that enhanced renal excretion of the carboxylate form of CPT occurs when exposed to a pH lower than 5. Therefore, it is recommended the administration of the drug to assure an acidic pH value by administering the compound with organic carboxylic acids.
  • U.S. Patent No. 5,674,874 describes the pharmacologic conversion of CPT 11 to HECPT.
  • the patent describes administration of the compound in sufficient quantities to maintain the pH of the formulation from about 2 to about 6 with the administration of a pharmaceutically acceptable acid.
  • Cancer Investigation, Volume 14, Supplement 1, No. 31, describes the use of irinotecan (CPT 11) to treat colon cancer and non-small cellular lung cancer.
  • the publication confirms the incidence of grade 4 diarrhea associated with administration of CPT 11 dropped from 17% to 5% following adoption of an aggressive loperimide therapy.
  • Camptosar Patient Management Guidelines suggest avoiding the diarrhea side effect of camptosar by administering loperimides and gatorade.
  • the present invention overcomes one of the major side effects, diarrhea, associated with administration of camptothecin compounds, in particular irinotecan hydrochloride. This is one of the major deficiencies in the prior art in delivering irinotecan hydrochloride for the treatment of tumors.
  • the present invention overcomes the diarrhea side effect associated with the administration of irinotecan hydrochloride and its related compounds.
  • the present invention provide for methods of administering camptothecin compounds which are cleared through the liver, preferably irinotecan hydrochloride and its derivatives.
  • the invention provides a method of inhibiting a diarrhea side effect of camptothecin compounds cleared by the liver, including but not limited to, irinotecan hydrochloride (CPT- 11) , SN38-Glu, and SN-38 comprising administering irinotecan hydrochloride while the intestinal lumen is maintained an alkaline pH.
  • the invention also provides a method of treating cancer comprising administering camptothecin compounds such as irinotecan hydrochloride while maintaining the intestinal lumen at an alkaline pH.
  • the cancer is selected from, but not limited to, breast cancer, ovarian cancer, colon cancer, malignant melanoma, small .cell lung cancer, thyroid cancers, lympho as and leukemias.
  • the invention provides a method of treating AIDS comprising administering irinotecan hydrochloride while maintaining the intestinal lumen at an alkaline pH .
  • the invention advantageously provides a method of administering a camptothecin compound such as irinotecan hydrochloride (CPT-11) intravenously comprising prior to or simultaneously administering said camptothecin compound, orally administering a bicarbonate and alkaline H 2 0.
  • a camptothecin compound such as irinotecan hydrochloride (CPT-11)
  • the invention provides a method of administering a camptothecin compound such as irinotecan hydrochloride (CPT- 11) intravenously comprising prior to or simultaneously administering said camptothecin compound, orally administering a composition comprising borbic acid.
  • a camptothecin compound such as irinotecan hydrochloride (CPT- 11) intravenously comprising prior to or simultaneously administering said camptothecin compound, orally administering a composition comprising borbic acid.
  • the invention also provides for a method of administering a camptothecin compound comprising prior to or simultaneously administering said camptothecin compound, orally administering a composition comprising urso-deoxycholic acid.
  • compositions, kits, and methods are described as including or comprising specific components, it is contemplated by the inventors that compositions of the present invention also consist essentially of or consist of the recited components.
  • Figure 1 shows structures of CPT-11, SN-38 and SN-38- glucuronide (SN-38-GLU) : Lactone forms of CPT-11 and SN-38 are non-ion charged, and carboxylate forms of CPT-11 and SN-38 are anions. Not only carboxylate form of SN-38-Glu but also its lactone form, which possesses an additional carboxyl group in its glucuronide moiety, is an anion. The reversible conversion between lactone and carboxylate forms is pH driven.
  • Figures 2A and 2B show the time course of CPT-11 and Sn- 38 uptake by isolated intestinal cells:
  • the uptake of [ 14 C] CPT-11 (20 ⁇ M) and [ 14 C] SN-38 (2 ⁇ M) in lactone and carboxylate form, respectively, by isolated intestinal cells from jejunum was measured as a function of time.
  • the respective agent was added to the intestinal cell suspension maintained at 37°C under permanent shaking.
  • At 15, 30, 45, 60, 90, 120, 240 and 480 sec aliquots of cell suspension were removed, and processed as described in Materials and Methods.
  • the results shown are mean + SE of n experiments.
  • Figures 3A, 3B, 3C and 3D show the relationship between initial rate of uptake of CPT-11 and its concentration:
  • the initial uptake rate was determined from the linear slope of the cellular uptake over the initial 90 sec incubation period.
  • Figures 4A and 4B show the relationship between initial rate of uptake of SN-38 and its concentration.
  • the initial uptake rate was determined as described in legend of Fig. 3 and in Materials and Methods. The data were fitted by least- square linear regression. Because of limited solubility, only concentrations of SN-38 up to 2 ⁇ M were investigated.
  • Fig. 5 shows the effect of taurocholate (TCA) on respective CPT-11 and SN-38 micelle formation: [ 14 C] CPT-11 (20 ⁇ M) and [ 14 C] SN-38 (2 ⁇ M) were stored overnight in Hank's solution in the presence of absence of TCA (20 mM) .
  • TCA taurocholate
  • Figures 6A and 6B show the effect of pH on the initial rate of uptake of CPT-11 and SN-38: [ 1 C] CPT-11 (20 ⁇ M) and [ 1 C] SN-38 (2 ⁇ M) were dissolved in PBS at pH 6.2, 6.8, 7.4 and 8.0 and stored overnight. By adding the drugs to Hank ' s solution containing intestinal cells from whole small- intestine, uptake studies were performed. The difference in the initial uptake rate by pH was analyzed by Kruskal-Wallis test (p ⁇ 0.001 and p ⁇ 0.001 for CPT-11 and SN-38, respectively) and Student-Newman-Keuls method ( * p ⁇ 0.05).
  • Figure 7 shows the effect of pH on the initial uptake rate of HT29 cells.
  • [ 1 C]SN-38 (2 ⁇ M) were dissolved in PBS at pH 6.2, 6.8, 7.4 and 8.0 overnight.
  • the uptake study was initiated by adding the compounds to Hanks' solution containing HT29 cells.
  • the comparative initial rate of uptake as function of pH was analyzed by Kruskal-Wallis test (p ⁇ 0.001) and Dunn's method (*p ⁇ 0.05).
  • Figure 8 shows the relationship between the initial uptake rate and the cytotoxicity of SN-38.
  • the effect of physiological pH on the initial uptake rate of 2 ⁇ M [ 1 C] SN-38 was estimated as described in legend of Figure 3.
  • the 0.4 ⁇ M SN-38-induced cytotoxicity in HT29 cells was studied by the described MTT assay.
  • the relationship between the initial rate of uptake and the cytotoxicity of SN-38 was plotted by a simple least-squares regression method.
  • camptothecin compounds such as CPT-11 and its metabolites by the intestine
  • the inventors reviewed the uptake of several camptothecin compounds, CPT-11 and SN-38, by intestinal epithelial cells. The results provide for the new design of an approach to prevent diarrhea and large interpatient variability in pharmacokinetics in clinical practice of the treatment of cancer and tumors with irinotecan hydrochloride and its related compounds.
  • the invention provides a method of inhibiting a diarrhea side effect of camptothecin compounds such as irinotecan hydrochloride (CPT-11) , SN-38-Glu, SN-38 and its derivatives comprising administering irinotecan hydrochloride while maintaining the bile and/or intestinal lumen at an alkaline pH.
  • camptothecin compounds such as irinotecan hydrochloride (CPT-11) , SN-38-Glu, SN-38 and its derivatives
  • administering irinotecan hydrochloride while maintaining the bile and/or intestinal lumen at an alkaline pH.
  • the intestinal lumen is maintained at an alkaline pH by administration of bicarbonate and alkaline H 2 0.
  • the amount of bicarbonate and alkaline pH is suitable to reduce the uptake of the camptothecin compound and thus reduce the cytotoxic side effects including a diarrhea side effect.
  • the camptothecin compound or irinotecan hydrochloride may be administered intravenously, orally or intramuscularly.
  • the method of the invention inhibits the reabsorption and decreases the lactone uptake of CPT-11 and SN-38 by the intestines and thus reduces the diarrhea side effect associated with camptothecin compounds such as irinotecan hydrochloride.
  • the invention also provides a method of treating cancer comprising administering irinotecan hydrochloride and its derivatives or mixtures thereof, while maintaining the intestinal lumen at an alkaline pH.
  • the cancer is selected from the group consisting of, but not limited to breast cancer, ovarian .cancer, colon cancer, malignant melanoma, small cell lung cancer, thyroid cancers, lymphomas and leukemias.
  • the alkaline pH may be a pH from about 7 to about 10.
  • the cancer is treated by administering a compound selected from 7- hydroxymethyl camptothecin, irinotecan hydrochloride, aminocamptothecin, DX-8951F, SN-38, HAR4, HAR5, HAR6, HAR7 , HAR8 and topotecan, while maintaining the intestinal lumen at an alkaline pH.
  • a compound selected from 7- hydroxymethyl camptothecin, irinotecan hydrochloride, aminocamptothecin, DX-8951F, SN-38, HAR4, HAR5, HAR6, HAR7 , HAR8 and topotecan while maintaining the intestinal lumen at an alkaline pH.
  • a bicarbonate selected from sodium bicarbonate, magnesium bicarbonate and potassium bicarbonate.
  • irinotecan hydrochloride (CPT-11) may be administered in combination with a composition comprising borbic acid. This chemical has been used in buffers composition, such as the
  • the invention also provides for a method of administering a camptothecin compound comprising prior to or simultaneously administering said camptothecin compound, orally administering a composition comprising urso-deoxycholic acid.
  • This composition may optionally be administered with bicarbonate. It is believed that urso-deoxycholic acid stimulates bicarbonate secretion into bile.
  • the following example shows the ability to reduce the diarrhea side effect of irinotecan hydrochloride compounds in accordance with the method of the invention.
  • the lactone and carboxylate forms of 14 C-labeled CPT-11 and SN-38 were produced by dissolving the compound overnight in 50 mM phosphate buffer at pH 6. or 9, respectively.
  • DNP-SG was made from glutathione and CDNB (l-chloro-2 , 4-dinitro benzene) chemically. All other reagents were of analytical grade.
  • Adult male Golden Syrian hamsters (6-8 weeks age) whose model presents a bile acid profile similar to that observed in human (28) , were used.
  • Intestinal cells were isolated as previously described (28, 29). Briefly, male hamsters were anesthetized with sodium pentobarbital (Nembutol 70 g/kg body weight) . The entire intestine was removed. The intestinal lumen was washed with 37°C Hank's solution. Sacs of the ileum (12.5 cm from cecum) and jejunum (remaining small intestine) were rinsed, as well as the intestinal sacs of the anal site of small intestine (12.5 cm from cecum) and oral site (the other small intestine) .
  • the sacs were rinsed with oxygenated buffer solution containing sodium citrate (96 mM NaCl, 1.5 mM KCl, 5.6 mM KH 2 P0 4 , 27 mM sodium citrate, pH 7.3), and incubated for 10 min in the same buffer at 37°C.
  • the sacs were then emptied, filled with oxygenated buffer solution containing EDTA (140 mM NaCl, 16 mM Na 2 HP0 4 , 2 mM EDTA, 0.5 mM dithiothreitol, pH 7.3), incubated for 10 min at 37°C.
  • each sac was placed onto a petri dish and gently vortexed for 1 min.
  • the buffer containing intestinal cells was recovered in 50 mL of Hanks' solution, washed twice and adjusted at 10 6 cells/ml in Hanks' medium (cellular stock solution containing 0.5% bovine serum albumin, pH 7.4)..
  • Uptake of 14 C-labeled CPT-11 and SN-38 was measured by rapid vacuum filtration assay (28, 29).
  • the cellular suspension of 0.95 ml was incubated for 15 min in a 37°C water bath with stirring. Uptake was started by the addition of 0.05 ml PBS (at pH 3 or 9) containing labeled SN-38 or CPT-11 at 37°C.
  • PBS pH 3 or 9
  • sample aliquots were diluted into 3 mL of Hank's medium at 4°C to stop the uptake.
  • the stop solution containing the cells was filtered through a glass microfiber filter (Glass Fiber Filter Circles G4 , Fisherbrand, PA) under vacuum (20psi) .
  • the cells were washed once with 5 mL of 0.5% bovine serum albumin-containing Hanks' medium (4°C) and once with 20 L of Hanks' solution (4°C) .
  • the filters were placed in a vial containing 4 mL of scintillation liquid (Ultra Gold, Packard, CT) and the radioactivity was counted in a ⁇ scintillation counter (LS3801, Beckman, MD) .
  • the effect of the metabolic inhibitor, 2,4 dinitrophenol (1 mM) was studied by adding this agent to the cells 3 min prior to either 14 C-CPT-11 or 14 C-SN-38 (2 ⁇ M) .
  • the effect of 20 mM of taurocholic acid (TCA) on the uptake of both CPT-11 and SN-38 was investigated following overnight incubation of 14 C-CPT-11 (20 ⁇ M) and 14 C-SN-38 (2 ⁇ M) in Hank's solution, at pH 7.4 and in the presence and absence of TCA.
  • TCA taurocholic acid
  • the effect of 200 ⁇ M of DNP-SG or SN-38-Glu was also studied by adding these agents to the cell preparation 7 min prior to either 14 C-CPT-11 (20 ⁇ M) and 1 C-SN-38 (2 ⁇ M) .
  • CPT-11 and SN-38 form micelles
  • these agents were incubated overnight at pH 4 and 9 in a calcium and magnesium free Hank's solution containing 10 mM TCA.
  • the respective solution was filtered through a 1000- molecular weight cut-off membrane YMl (Diaflo, Amicon, MA) at a steady speed of 0.04 l/min. Once the filtration was stopped, the radioactivity in the initial solution as well as in the filtrate and in the retained solution after filtration was determined as described previously.
  • HT29 cells were seeded into a 12-well plate (Falcon-3043 , Lincoln Park, NJ) , and, after 48 h, SN-38 (0.4 ⁇ M) at pH 6.2, 6.8, 7.4 and 8.0 was added. After 24 h-exposure, the cells were washed twice, and subjected to a drug-free incubation for 24 h.
  • the cells were incubated with 0.5 mg/ml 3- (4, 5- dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) for 4 h, and the blue formazan crystals were solubilized by addition of 10% n-dodecylsulfate sodium salt (SDS) in 0.01N HCl and overnight incubation.
  • SDS n-dodecylsulfate sodium salt
  • the time-dependent uptake of 20 ⁇ M 14 C-CPT-11 and 2 ⁇ M 14 C- SN-38 in both lactone and carboxylate forms by isolated jejunal cells is shown in Fig. 2.
  • the extrapolation of the uptake value at time 0 yields a positive intercept, indicative of non-specific binding, such as adsorption to labeled agents on the cell surface.
  • the respective uptake of the lactone and carboxylate forms of both CPT-11 and SN-38 was linear for up to 90 sec. Therefore, the initial uptake rate was determined by linear regression fit of the uptake over the initial period of time. Comparison of the uptake rate between the lactone and carboxylate form of the respective agent clearly showed a more rapid uptake of both CPT-11 and SN-38 lactone, as compared to carboxylate form (Fig. 2) .
  • Table 1 summarizes the respective initial uptake rate of 20 ⁇ M 14 C-CPT-11 and 2 ⁇ M 14 C-SN-38 by jejunal and ileal cells.
  • CPT-11 and SN-38 lactone were more rapidly taken up than their carboxylate forms in cells from both intestinal regions but without significant differences between jejunal and ileal cells.
  • the saturable component of the curve was characterized by a maximum rate of uptake (V max ) of 147 and 157 pmol " 10 6 cell “1 " min “1 " ⁇ M "1 and a Michaelis constant (K of 51.3 and 50.5 ⁇ M in jejunal and ileal cells, respectively.
  • the minor non-saturable component was characterized by a diffusion constant (K d ) ⁇ 0.05 pmol " 10 6 cell “1 " min "1 ' ⁇ M '1 and represented less than one twentieth of that for CPT-11 lactone in cells of both intestinal regions (Table 2) . Furthermore, the Kd for CPT-11 lactone was 1.8-2.5 fold lower than that of SN-38 lactone.
  • the initial uptake rate of SN-38 lactone and carboxylate was plotted as a function of the concentration (Fig. 4) .
  • the maximum concentration of SN-38 used in this study was lower than 2 ⁇ M due to the poor solubility of the compound and therefore rendered the determination of the saturable and unsaturable component of the uptake difficult.
  • the uptake of SN-38 lactone and carboxylate was mostly non-saturable (Fig. 4) .
  • the carrier-mediated transport is known to be inhibited by metabolic poisons, such as 2 , 4-dinitrophenol, which interferes with cell metabolism and reduces energy-producing reactions (23). Therefore, 2 , 4-dinitrophenol was used in applicants study to determine the mechanism of uptake of CPT- 11 and SN-38 lactone and carboxylate, respectively.
  • the results of this study are summarized in Table 3. Although, the uptake rat e of both CPT-11 and SN-38 lactone was not significantly affected by the addition of 2 , 4-dinitrophenol, the uptake rate of CPT-11 and SN-38 carboxylate was reduced to 22.6 and 30.8%, respectively by 2 ,,4-dinitrophenol, suggesting an active transport mechanism for both of these compounds.
  • DNP-SG 2,4-dinitrophenol-S-glutathione
  • cMOAT active multispecific organic anion transporter
  • the conjugation by UDP-glucuronyltransferase of SN-38 leads to the formation of SN-38-Glu which is also a substrate for the hepatic cMOAT (12,17).
  • the uptake rate of CPT-11 and SN-38 was studied in the presence or absence of both DNP-SG and SN-38-Glu. The results are summarized in Table 3.
  • DNP-SG and SN-38-Glu significantly inhibited the the uptake of the carboxylate form of SN-38 by over 60 % while that of CPT-11 carboxylate remained unchanged.
  • the uptake rates of the lactone forms of CPT-11 and SN-38 were not significantly affected by the presence of either DNP-SG or SN38-G1U.
  • TCA Taurocholic acid
  • Isolated hamster intestinal cells are not the best model to estimate the cytotoxic effect of SN-38 due to their limited viability to around 2 hours (Gore et al., 1993). Therefore, HT29 cells were also used to study the comparative effects of physiological pH on both the initial uptake rate of 2 ⁇ M [ 14 C] SN-38 and the cytotoxicity of 0.4 ⁇ M SN-38. The initial rate of uptake of SN-38 was lower in HT-29 cells than in isolated hamster intestinal cells . ( Figure 3 and 4).
  • the percentage of the monomer concentration ranged from 38 to 47%. These concentrations differed from those of long-chain fatty acids (i.e. 2.3% for oleic acid) and from cholesterol (3%). Furthermore, micelle formation inhibited CPT-11 uptake, differing from the positive role bile acid micelle formation plays in the intestinal uptake of long-chain fatty acid and cholesterol. These results support data showing that micelle formation inhibited the uptake of short-chain fatty acids, such as palmitic acid..
  • alkalini- zation of bile and luminal content reduce the intestinal uptake of CPT-11 and SN-38.
  • the biliary content of CPT-11 and its metabolites was determined for two men who were treated by cisplatin and received CPT-11 intravenously (9) .
  • the major component of the bile was CPT-11 (75.6-91.9%) while SN-38 and SN-38-Glu were minor components, 0.9-3.3% and 7.3-18.9%, respectively.
  • the pH of human bile has been reported to range from 6.5 to 8.0 (31).
  • SN-38 is active mainly as the lactone form, while SN-38 carboxylate exhibits qnly minor topoisomerase I-inhibitory activity (32) .
  • SN-38 Using rat whole body autoradiography, 24 h after IV injection of 14 C-SN-38, the radioactivity was found exclusively in the gastrointestinal tract (33) .
  • SN-38 exhibits strong cytotoxicity
  • SN38-Glu is a deactivated glucuronidated form of SN-38
  • CPT-11 is much less cytotoxic compared to SN-38 (Kawato et al., 1991).
  • a mechanism for CPT-11-induced diarrhea is believed to include the reabsorption of mainly lactone SN-38 and CPT-11, by the intestinal epithelium, resulting in a high exposure of the intestinal epithelium .to these metabolites which causes structural and functional injuries to the intestinal tract.
  • a prevention treatment of camptothecin and CPT-11-induced diarrhea focuses on two objectives: 1) alkalinization of the intestinal lumen, and 2) clearance of CPT-11 and SN-38 from the body (i.e. stool control) .
  • a combination of sodium bicarbonate, magnesium oxide and water at pH greater than 7 is administered orally to patients prior and/or simultaneously with standard IV administration of CPT-11. The incidence of diarrhea is decreased.
  • CPT-11-induced diarrhea might include the reabsorption of SN-38 lactone by the intestinal epithelium, resulting in structural and functional injuries to the intestinal tract.
  • the present study is the first to estimate the uptake of CPT-11 and SN-38 by intestinal epithelial cells.
  • CPT-11 and SN-38 lactone are both passively transported, while both CPT-11 and SN-38 carboxylate are actively absorbed.
  • the uptake rate of CPT-11 and SN-38 lactone is several times greater than that of the respective carboxylate form.
  • the higher uptake rate of SN-38 is associated with an increased cytotoxic effect in HT29 cells.
  • camptothecin compounds which are cleared through the liver such as irinotecan hydrochloride and its derivatives.
  • the inventors provide for oral alkalinization with the administration of camptothecin compounds which are cleared through the liver, including CPT-11.
  • CPT-11 and SN-38 lactone are both passively transported by intestinal cells. Both CPT-11 and SN-38 carboxylate are actively absorbed, although through different transport mechanisms. The formation of micelles with TCA reduced the uptake of both CPT-11 and SN-38.
  • the uptake rate of CPT-11 and SN-38 lactone is several times greater than that of the carboxylate form while the uptake rate decreased in the presence of bicarbonate and under condition of increased pH.
  • sodium bicarbonate, magnesium oxide and water are administered at more than a pH of about 7 , preferably pH of 8 to 10 and most preferably a pH of 8 to 9 , provided to patients treated with camptothecin compounds such as CPT-11 and its derivatives.
  • the CPT-11 compounds of the present invention are useful in pharmaceutical compositions for systemic administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions or suspensions oral solutions or suspensions, oil in water or water in oil emulsions and the like, containing suitable quantities of an active ingredient.
  • unit dosage forms such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions or suspensions oral solutions or suspensions, oil in water or water in oil emulsions and the like, containing suitable quantities of an active ingredient.
  • unit dosage forms such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions or suspensions oral solutions or suspensions, oil in water or
  • the CPT-11 can be mixed with conventional ingredients such as dicalciumphosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methyl cellulose and functionally similar materials as pharmaceutical excipients or carriers.
  • a sustained release formulation may optionally be used.
  • Capsules may be formulated by mixing the compound with a pharmaceutical diluent which is inert and inserting this mixture into a hard gelatin capsule having the appropriate size. If soft capsules are desired a slurry of the compound with an acceptable vegetable, light petroleum, or other inert oil can be encapsulated by machine into a gelatin capsule.
  • Suspensions, syrups and elixirs may be used for oral administration of fluid unit dosage forms.
  • a fluid preparation including oil may be used for oil soluble forms.
  • a vegetable oil such as corn oil, peanut oil or safflower oil, for example, together with flavoring agents, sweeteners and any preservatives produces an acceptable fluid preparation.
  • a surfactant may be added to water to form a syrup for fluid unit dosages.
  • Hydro-alcoholic pharmaceutical preparations may be used having an acceptable sweetener such as sugar, saccharine or a biological sweetener and a flavoring agent in the form of an elixir.
  • compositions for parenteral and suppository administration can also be obtained using techniques standard in the art.
  • Suitable pharmaceutical carriers include sterile water; saline, dextrose; dextrose in water or saline; condensation products of castor oil and ethylene oxide combining about 30 to about 35 moles of ethylene oxide per mole of castor oil; liquid acid; lower alkanols; oils such as corn oil; peanut oil, sesame oil and the like, with emulsifiers such as mono- or di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin, and the like; glycols; polyalkylene glycols; aqueous media in the presence of a suspending agent, for example, sodium carboxymethylcellulose; sodium alginate; poly (vinylpyrolidone) ; and the like, alone, or with suitable dispensing agents such as lecithin; polyoxyethylene stearate; and the like.
  • a suspending agent for example, sodium carboxymethylcellulose; sodium alginate; poly (vinylpyrolidone)
  • the carrier may also contain adjuvants such as preserving stabilizing, wetting, emulsifying agents and the like together with the penetration enhancer of this invention.
  • the effective dosage for mammals may vary due to such factors as age, weight activity level or condition of the subject being treated.
  • an effective dosage of a compound according to the present invention is about 10 mg/m 2 to 700 mg/m 2 when administered by either oral or rectal dose from 1 to 3 times daily.
  • CPT-11 may preferably be administered once a week for a 1 to 5 week period.
  • Camptothecin compounds may also be administered alone or in combination with combination chemotherapy regimens including leucovorin, cisplatin, 5-FU, oxiplatin as well as other known chemotherapeutics .
  • camptothecin compounds such as irinotecan hydrochloride may also be administered with loperamide.
  • CPT-I I high-dose escalation using intensive high-dose loperamide to control diarrhea.
  • HOSHI A., Relationship between development of diarrhea and the concentration of SN-38, an active metabolite of CPT-11, in the intestine and the blood plasma of athymic mice following intraperitoneal administration of CPT-11. Jpn . J. Cancer Res . , 84, 697-702 (1993).
  • Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J . Pharmacol . Exp . Ther . , 281, 304-314 (1997a).
  • CHU, X.Y., KATO, Y., SUGIYAMA, Y. Multiplicity of biliary excretion mechanisms for irinotecan, CPT-11, and its metabolites in rats. Cancer Research, 57, 1934-1938 (1997b).
  • CUNNINGHAM D. , PYRHONEN, S., JAMES, R.D., PUNT, C.J.A.,
  • KOBAYASHI K. , BOUSCAREL, B. , MATSUZAKI , Y., CERYAK, S., FROMM, H. , Uptake mechanism of irinotecan (CPT-11) and its metabolite (SN-38) by hamster intestinal cells. Ga ⁇ troenterology, 114 (4) , A626, proceeding (1998a).
  • KOBAYASHI K., SHINBARA, A., KAMIMURA, M. , TAKEDA, Y., KUDO, K., KABE, J., HIBINO, S., HINO, M. , SHIBUYA, M. , KUDOH, S., Irinotecan (CPT-11) in combination with weekly administration of cisplatin (CDDP) for non-small-cell lung cancer. Cancer Chemother . Pharmacol . , 42, 53-58 (1998b).
  • MCCLOUD E., MATHIS, R.K., GRANT, K.E., SAID, H.M. , Intestinal uptake of uridine in suckling rats: mechanism and ontogeny.
  • MOSMANN, T. Rapid colorimetiric assay for cellular growth and survival: Application to proliferation and cytotoxicity assay.
  • RIVORY L.P., RIOU, J.F., HAAZ , M.C., SABLE, S., VUIHORGNE, M. , COMERSON, A., POND, S.M., ROBERT, J. Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients. Cancer Res . , 56, 3689-

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Abstract

La présente invention concerne des procédés permettant l'administration de composés camptothéciniques tels que l'hydrochlorure d'irinotécane de façon à réduire la diarrhée qui lui est habituellement associée. L'invention concerne également des traitements anticancéreux et anti-SIDA à base de composés camptothéciniques. Ces traitements prévoient l'administration de tels composés camptothéciniques tout en maintenant à un pH alcalin l'intestin et la bile.
EP99935334A 1998-06-18 1999-06-18 Administration de composes camptotheciniques de cancerotherapie avec reduction de leurs effets secondaires Withdrawn EP1003516A4 (fr)

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IL134592A0 (en) * 1998-06-18 2001-04-30 Univ George Washington Compositions comprising camptothecin compounds for the treatment of cancer with reduced side effects
EP1749540B1 (fr) 1999-05-17 2010-10-13 Cancer Research Ventures Limited Compositions pour ameliorer la biodisponibilite des medicaments administres par voie orale
CA2295429A1 (fr) * 2000-01-06 2001-07-06 Michael Michael Traitement ou prevention de la diarrhee
US7691872B2 (en) * 2001-03-20 2010-04-06 University Of Kentucky Research Foundation Methods and compositions for optimizing blood and tissue stability of camptothecin and other albumin-binding therapeutic compounds
AU2007232206B2 (en) 2006-03-30 2013-04-04 Drais Pharmaceuticals, Inc. Camptothecin-cell penetrating peptide conjugates and pharmaceutical compositions containing the same
JP5919593B2 (ja) * 2006-10-11 2016-05-18 フージョン アンティボディーズ リミテッド 併用療法
US20170246190A1 (en) * 2014-10-21 2017-08-31 Johnpro Biotech Inc. Methods and formulation for improving oral availability of cpt-11 while reducing cpt-11 induced gastrointestinal toxicity in cancer therapy
KR102293907B1 (ko) 2015-06-30 2021-08-26 한미약품 주식회사 이리노테칸 함유 경구용 고형제제 및 그 제조방법
CN107281462A (zh) * 2017-08-21 2017-10-24 滨州医学院 沙奎拉韦减轻伊立替康毒性的医药新用途
US11000540B1 (en) * 2019-11-22 2021-05-11 Al Siamon Treatment for reducing adverse events including chemotherapy discomfort and other conditions

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See also references of WO9965493A1 *

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