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WO1996000076A1 - Utilisation des enantiomeres d'oxazophosphorines, par exemple ifosfamide, en therapie anti-tumeur afin de limiter les effets secondaires - Google Patents

Utilisation des enantiomeres d'oxazophosphorines, par exemple ifosfamide, en therapie anti-tumeur afin de limiter les effets secondaires Download PDF

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Publication number
WO1996000076A1
WO1996000076A1 PCT/GB1995/001475 GB9501475W WO9600076A1 WO 1996000076 A1 WO1996000076 A1 WO 1996000076A1 GB 9501475 W GB9501475 W GB 9501475W WO 9600076 A1 WO9600076 A1 WO 9600076A1
Authority
WO
WIPO (PCT)
Prior art keywords
iff
ifosfamide
substantially free
enantiomers
oxazophosphorine
Prior art date
Application number
PCT/GB1995/001475
Other languages
English (en)
Inventor
Helen Frances Baker
Original Assignee
Chiroscience Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from PCT/GB1994/002171 external-priority patent/WO1996000075A1/fr
Application filed by Chiroscience Limited filed Critical Chiroscience Limited
Priority to EP95922649A priority Critical patent/EP0772444A1/fr
Priority to AU27474/95A priority patent/AU2747495A/en
Publication of WO1996000076A1 publication Critical patent/WO1996000076A1/fr
Priority to NO965528A priority patent/NO965528L/no
Priority to FI965171A priority patent/FI965171L/fi

Links

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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate

Definitions

  • This invention relates to oxazophosphorines and their 5 therapeutic use.
  • Oxazophosphorines are cytotoxic al ylating agents, examples being ifosfamide and cyclophosphamide. Ifosfamide has been shown to be more effective and less toxic than
  • Ifosfamide is licensed for use in refractory testicular cancer in the US, and for tumours of lung, ovary, cervix, breast and testis and soft tissue sarcoma in the UK. It is used as a single agent and in combination
  • Ifosfamide (by way of example only) is a cytotoxic compound and effects other than the antitumour effect are expected. Myelosuppression. alopecia, nausea and vomiting are all unwanted effects of the compound.
  • the compound has other unwanted toxicities, e.g. on the urinary tract, and neurotoxicity, which limit the dosing and make the compound difficult to use.
  • Combination with the uroprotective agent mesna has reduced the incidence of hae orrhagic cystitis, but nephrotoxicity is
  • Ifosfamide is a chiral compound. Its enantiomers dexifosfamide (herein sometimes ••(R)-IFF”) and levoifosfamide (herein sometimes "(S)-IFF”) are known, and may be prepared by classical resolution. Processes for their preparation are described in US Patent No.4,684,742, Polish Patent No. 119,971, and British Patent No. 1,553,984.
  • Ifosfamide requires metabolic activation.
  • One of the two main metabolic pathways produces the active species, the isophosphoramide mustard.
  • the 4-hydroxy-ifosfamide may also be an active species.
  • the second main pathway, N- dechloroethylation produces 2 and 3-dechloro metabolites, with the release of chloroacetaldehyde.
  • S-Ifosfamide produces R-3-dechloroifosfamide (R-3DCE) and S-2- dechloroifosfamide (S-2DCE) .
  • R-ifosfamide produces S-3- dechloroifosfamide (S-3DCE) and R-2-dechloroifosfamide (R- 2DCE) .
  • Metabolism is induced by dividing the dose over several days; the main increase being in the route to the mustard. On a single dose, between 20-40% of the drug is excreted unchanged, and 15-50% of the compound is metabolised through the N- dechloroethylation pathway.
  • FIG. 1 shows the mean plasma concentration ⁇ SEM ( ⁇ m) versus time (hours) profiles of (R)-IFF and (S)-IFF over 24 hours, following a 3 hour infusion of 3 g/m 2 (R,S)-IFF, in 14 cancer patients.
  • the data indicate a significantly greater rate of metabolism of the (S) enantiomer compared with the (R) .
  • Figure 2 shows the mean area ⁇ SEM ( ⁇ M.hr) under the plasma concentration versus time curve (AUC) for ifosfamide and for its dechloroethylated metabolites, following a 3 hour infusion of 3 g/m (R,S)-IFF in 14 cancer patients.
  • the present invention is based on the discovery that the known side-effects can be reduced by the administration of enantiomeric ifosfamide.
  • the discovery should apply to all oxazophosphorines.
  • the desired enantiomer is substantially free of the other enantiomer and is preferably in an enantiomeric excess of at least 60% and more preferably at least 80%, most preferably 90% or more.
  • the drug used in this invention may be formulated in conventional media. It may be administered orally or by intravenous infusion.
  • the formulation may include any suitable carrier. Such administration of the drug may avoid hospitalisation.
  • discrete unit dosage forms may be provided.
  • "blister packs” of such unit dosages may be used, e.g. of tablets, capsules, vials, ampoules and the like.
  • An integral package or “kit” of the dosages may be provided with instructions or coding, to indicate the appropriate order of administration.
  • the enantiomer used in the invention is administered in an amount determined by the nature of the tumour and the skill of the physician, such as 100 to 5000, e.g. 600, mg/m per day/single dose; see also De Kraker, Anticancer Drugs 2:339-341 (1991), the contents of which are incorporated herein by reference.
  • An advantage of the present invention is to allow higher/more frequent dosing, e.g.
  • the invention is based on a comparison of the metabolism of ifosfamide enantiomers with that of the racemic compound and measurement of certain metabolites. By means of the invention, active rather than toxic metabolites are preferentially obtained in vivo.
  • the pharmacokinetics of (R)- IFF and (S)-IFF were examined in 14 cancer patients treated with a 3 hour infusion of (R,S)-IFF. The results are shown in the drawings.
  • the area under the curve (AUC) of (R)-IFF was significantly larger than that of (S)-IFF (2480 ⁇ 200 versus 1960 ⁇ 150 ⁇ m/hour) .
  • the terminal half-lives (7.57 ⁇ 0.99 hours) and mean residence times (11.17 ⁇ 1.10 hours) of (R)-IFF were significantly longer than those of (S)-IFF, 6.03 ⁇ 0.82 hours and 9.37 ⁇ 0.88 hours, respectively.
  • (S)-IFF was metabolised more rapidly than (R)-IFF. As metabolism to the active moiety is required for the therapeutic effect of this product, the administration of an equivalent dose of (S)-IFF alone will result in the more rapid production of effective substance and an enhanced clinical benefit.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Produit contenant des énantiomères respectifs d'une oxazophosphorine, chacun étant sensiblement exempt de l'autre, en tant que préparation combinée s'utilisant séparément, simultanément ou consécutivement dans une thérapie anti-cancer. Le constituant actif peut être ifosfamide. Le lévoifosfamide est préféré dans une thérapie utilisant un agent thérapeutique unique, étant donné son métabolisme plus rapide.
PCT/GB1995/001475 1994-06-23 1995-06-23 Utilisation des enantiomeres d'oxazophosphorines, par exemple ifosfamide, en therapie anti-tumeur afin de limiter les effets secondaires WO1996000076A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP95922649A EP0772444A1 (fr) 1994-06-23 1995-06-23 Utilisation des enantiomeres d'oxazophosphorines, par exemple ifosfamide, en therapie anti-tumeur afin de limiter les effets secondaires
AU27474/95A AU2747495A (en) 1994-06-23 1995-06-23 Use of the enantiomers of oxazophosphorines, e.g. ifosfamide, in anti-tumour therapy, for reducing side-effects
NO965528A NO965528L (no) 1994-06-23 1996-12-20 Anvendelse av enantiomerer av oxazofosforiner som ifosfamid, i anti-kreft terapi for redusering av bivirkninger
FI965171A FI965171L (fi) 1994-06-23 1996-12-20 Oksatsofosforiinien, esimerkiksi ifosfamidin, enantiomeerien käyttö kasvainten hoidossa sivuvaikutuksien vähentämiseksi

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9412618A GB9412618D0 (en) 1994-06-23 1994-06-23 Cytotoxic agent and its use
GB9412618.2 1994-06-23
GBPCT/GB94/02171 1994-10-05
PCT/GB1994/002171 WO1996000075A1 (fr) 1994-06-23 1994-10-05 Utilisation des enantiomeres d'ifosfamide en therapie antitumorale afin de limiter les effets secondaires

Publications (1)

Publication Number Publication Date
WO1996000076A1 true WO1996000076A1 (fr) 1996-01-04

Family

ID=10757213

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1995/001475 WO1996000076A1 (fr) 1994-06-23 1995-06-23 Utilisation des enantiomeres d'oxazophosphorines, par exemple ifosfamide, en therapie anti-tumeur afin de limiter les effets secondaires

Country Status (6)

Country Link
EP (1) EP0772444A1 (fr)
AU (1) AU2747495A (fr)
FI (1) FI965171L (fr)
GB (1) GB9412618D0 (fr)
NO (1) NO965528L (fr)
WO (1) WO1996000076A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022614A1 (fr) * 1995-12-19 1997-06-26 Darwin Discovery Limited Ifosfamide, analogues de ladite substance et leur preparation
US6153150A (en) * 1998-01-12 2000-11-28 Advanced Technology Materials, Inc. Apparatus and method for controlled decomposition oxidation of gaseous pollutants
US6261524B1 (en) 1999-01-12 2001-07-17 Advanced Technology Materials, Inc. Advanced apparatus for abatement of gaseous pollutants

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
B. TESTA ET AL.: "Racemates Versus Enantiomers in Drug Development: Dogmatism or Pragmatism?", CHIRALITY, vol. 2, 1990, pages 129 - 133 *
BLASCHKE, G. ET AL: "Preparative isolation and pharmacological-toxicological studies of the enantiomers of ifosfamide", ARZNEIM.-FORSCH., 1986, VOL. 36, PAGE(S) 1493-5 *
G. BLASCHKE ET AL.: "Metabolismus der Enantiomere des Zytostatikums Ifosfamid", ARZNEIM.-FORSCH., vol. 39, no. 2, 1989, pages 223 - 226 *
KLEINROK, ZDZISLAW ET AL: "Pharmacological evaluation of ifosfamide and its enantiomers in laboratory animals", ARCH. IMMUNOL. THER. EXP., 1986, VOL. 34, PAGE(S) 293-304 *
KUSNIERCZYK, H. ET AL: "Antitumor activity of optical isomers of cyclophosphamide, ifosfamide and trofosfamide as compared to clinically used racemates", J. IMMUNOPHARMACOL., 1986, VOL. 8, PAGE(S) 455-80 *
M. PAPROCKA ET AL.: "Comparative studies on biological activity of (+)R and (-)S enantiomers of cyclophosphamide and ifosfamide", ARCH. IMMUNOL. THER. EXP., vol. 34, no. 3, 1986, pages 275 - 284 *
M. PAPROCKA ET AL.: "Comparative studies on biological activity of (+)R and (-)S enantiomers of cyclophosphamide and ifosfamide", ARCH. IMMUNOL. THER. EXP., vol. 34, no. 3, 1986, pages 285 - 291 *
MASUREL, DOMINIQUE ET AL: "Efficacy, toxicity, pharmacokinetics, and in vitro metabolism of the enantiomers of ifosfamide in mice", CANCER RES., 1990, VOL. 50, PAGE(S) 252-5 *
WAINER, I. W. ET AL: "Efficacy and toxicity of ifosfamide stereoisomers in an in vivo rat mammary carcinoma model", CANCER RES., 1994, VOL. 54, PAGE(S) 4393-7 *
Z. KLEINROK ET AL.: "Comparison of pharmacological properties of cyclophosphamide and its enantiomers", ARCH . IMMUNOL. THER. EXP., vol. 34, no. 3, 1986, pages 263 - 273 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022614A1 (fr) * 1995-12-19 1997-06-26 Darwin Discovery Limited Ifosfamide, analogues de ladite substance et leur preparation
US6153150A (en) * 1998-01-12 2000-11-28 Advanced Technology Materials, Inc. Apparatus and method for controlled decomposition oxidation of gaseous pollutants
US6464944B1 (en) 1998-01-12 2002-10-15 Advanced Technology Materials, Inc. Apparatus and method for controlled decomposition oxidation of gaseous pollutants
US6511641B2 (en) 1998-01-12 2003-01-28 Advanced Technology Materials, Inc. Method for abatement of gaseous pollutants
US7138096B2 (en) 1998-01-12 2006-11-21 Applied Materials, Inc. Method for decomposition oxidation of gaseous pollutants
US7790120B2 (en) 1998-01-12 2010-09-07 Applied Materials, Inc. Apparatus and method for controlled decomposition oxidation of gaseous pollutants
US6261524B1 (en) 1999-01-12 2001-07-17 Advanced Technology Materials, Inc. Advanced apparatus for abatement of gaseous pollutants

Also Published As

Publication number Publication date
FI965171A0 (fi) 1996-12-20
NO965528L (no) 1997-02-19
EP0772444A1 (fr) 1997-05-14
NO965528D0 (no) 1996-12-20
FI965171L (fi) 1996-12-20
AU2747495A (en) 1996-01-19
GB9412618D0 (en) 1994-08-10

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