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WO1996000075A1 - Utilisation des enantiomeres d'ifosfamide en therapie antitumorale afin de limiter les effets secondaires - Google Patents

Utilisation des enantiomeres d'ifosfamide en therapie antitumorale afin de limiter les effets secondaires Download PDF

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Publication number
WO1996000075A1
WO1996000075A1 PCT/GB1994/002171 GB9402171W WO9600075A1 WO 1996000075 A1 WO1996000075 A1 WO 1996000075A1 GB 9402171 W GB9402171 W GB 9402171W WO 9600075 A1 WO9600075 A1 WO 9600075A1
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WO
WIPO (PCT)
Prior art keywords
ifosfamide
iff
tumor
enantiomers
dexifosfamide
Prior art date
Application number
PCT/GB1994/002171
Other languages
English (en)
Inventor
Irving William Wainer
Camille Pierre Granvil
Gerald Batist
Julie Ducharme
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
Application filed by Chiroscience Limited filed Critical Chiroscience Limited
Priority to AU77893/94A priority Critical patent/AU695347B2/en
Priority to AU27474/95A priority patent/AU2747495A/en
Priority to PCT/GB1995/001475 priority patent/WO1996000076A1/fr
Priority to EP95922649A priority patent/EP0772444A1/fr
Publication of WO1996000075A1 publication Critical patent/WO1996000075A1/fr
Priority to NO965528A priority patent/NO965528L/no
Priority to FI965171A priority patent/FI965171A0/fi
Priority to US09/046,066 priority patent/US6037337A/en

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 ifosfamide and its therapeutic use.
  • Ifosfamide is a cytotoxic alkylating agent. It has a similar spectrum of activity to cyclophosphamide. It has been shown to be more effective and less toxic than cyclophosphamide when given by pulsed or infusional regimes.
  • the compound is licensed for use in refractory testicular cancer in the US, and for tumors of lung, ovary, cervix, breast and testis and soft tissue sarcoma in the UK. It is used as a single agent and in combination with radiotherapy, surgery and other cytotoxic agents. Ifosfamide is a cytotoxic compound and effects other than the antitumor 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 haemorrhagic cystitis, but nephrotoxicity is a potentially serious side-effect.
  • Neurotoxic effects range from mild somnolence to severe encephalopathy, hallucinations and coma. In most cases, they are reversible, but in some they are not. They are more prevalent after oral dosing and large single IV doses. It is thought that they are caused by a metabolite, possibly chloroacetaldehyde.
  • CNS side-effects were a major dose-limiting side- effect when the compound was in development as an oral formulation.
  • the side-effects appeared at a much lower dose than they did during iv administration, and this meant that cytotoxic doses could not be reached. It is known that there is much more metabolism of the compound after oral dosing; in particular, higher levels of chloroacetaldehyde are produced, indicating more N- dechloroethylation. Ifosfamide is a chiral compound.
  • 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.
  • Boos et aJL Cancer Chemother. Pharmacol. 28:455-460 (1991) , investigated the urinary excretion of the enantiomers of ifosfamide, following administration of the racemate. It was concluded that "Theoretically, an advantage in the form of reduced side-chain metabolism could be expected from the use of the S form of ifo in nearly half of our patients and the R form in the other half", and "stereospecific metabolism does not indicate that any clear-cut advantage can be gained from the application of an individual enantiomer.” Masurel et al. Cancer Res. 5J): 252-255 (1990), studied the efficacy and toxicity of IFF enantiomers in CBA/CaJ mice.
  • dexifosfamide gives reduced side-effects. This is based on the results of the analysis of the urine of 11 patients who received a 3 hour infusion of race ic ifosfamide. Patients had not received chemotherapy for a year and ifosfamide was the only drug administered during the pharmacokinetic study. It is clearly shown in all patients that the side-chain metabolites come from S-ifosfamide more than from R- ifosfamide. There is also evidence to suggest that R- ifosfamide is more myelotoxic in the Fischer rat. This is suggestive of R-ifosfamide producing more of the mustard. The same results show that there is a trend to the R-isomer being more effective in treating the tumors in the rats.
  • results of incubating racemic ifosfamide with human liver microsomes, and measuring the 2 and 3- dechlorometabolites using chiral assays show that the S- ifosfamide produces greater amounts of these metabolites than the R-ifosfamide.
  • the results are broadly the same when the experiments were carried out separately with R and S-ifosfamide.
  • Another aspect of the invention is based on an appreciation of the relative effects of the enantiomers of ifosfamide.
  • the undesirable effect of administering levoifosfamide may be due to its quicker induction of undesirable metabolites, an effect which is reduced with time, while the corresponding effect of administering dexifosfamide increases more slowly.
  • a combination therapy i.e. dexifosfamide initially, and levoifosfamide thereafter.
  • Figure 1 shows peripheral blood counts obtained in tumor-bearing rats that received saline or ifosfamide treatment.
  • Fig. 1A shows WBC results
  • Fig. IB the effect of treatment on platelets. There were 3-5 animals in each group. The following abbreviations etc. apply: T: tumor-bearing heavy columns: controls shaded columns: groups treated with (R,S)-IFF, (R)-IFF or (S)-IFF
  • the present invention is based on the discovery that the known side-effects can be reduced by the administration of enantiomeric ifosfamide.
  • 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 ifosfamide enantiomer used in the invention is administered in an amount determined by the nature of the tumor 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. by a factor of 1.5, 2 or more.
  • the frequency and duration may be determined by similar consideration.
  • the invention is based on a comparison of the metabolism of R-ifosfamide 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.
  • the analysis of IFF in plasma was performed using gas chromatography-mass spectrometry.
  • the gas chromatography was a Varian 3400 gas chro atograph equipped with a Finnigan A 200S gas chromatograph autosampler operating in the splitless mode.
  • the mass spectrometer was a Finnigan Mat Model Incos 50 operating in the electron impact and selective ion monitoring mode.
  • the chromatographic separation was carried out on a fused silica capillary column (DB-5; 30 m x 0.25 mm, inside diameter; film thickness, 0.25 ⁇ ) .
  • the column oven temperature was linearly programmed from 80°C to 250°C.
  • the injector temperature was 250°C in the splitless mode, the helium pressure was 8 psi, and the transfer line was maintained at 260°C.
  • the mass spectrometer was operated in the electron impact ionization mode at an ion source temperature of 180°C and an ionization energy of 70 eV.
  • Plasma Preparation To 0.1 ml of plasma sample were added 20 ⁇ l IS (hexobarbital, 100 ⁇ g/ml in methanol) and 3 ml chloroform. The mixture was vortexed for 1 min and centrifuged at 1000 x g for 10 min. The aqueous phase was discarded and the organic phase was transferred to another tube and evaporated to dryness in a speed-Vac concentrator. The residue was reconstituted in 100 ⁇ l methanol and 1 ⁇ l was injected onto a Varian 3400 gas chromatograph.
  • the AUC area under plasma concentration-time curve
  • the values were subjected to an analysis of variance comparison.
  • the extrapolated AUC was estimated as the last measured plasma concentration divided by the terminal elimination rate constant.
  • Animal Model and Tumor Cells MatB cells are maintained in vitro in ⁇ -minimum essential medium (GIBCO, Grand. Island, NY) supplemented with 1.3% sodium pyruvate, 2.6% glutamine, 1.3% non-essential amino acids, 10% fetal calf serum, and 100 units/ml gentamicin. Cells are maintained at 37 °C under 5% C0 2 . A suspension of 5 x 10 5 cells is injected s.c. into the flanks of female F344 rats weighing 160-200 g.
  • the rats are lightly anesthetized with ether, and a single i.v. dose of ifosfamide is injected via the tail vein.
  • the tumor size and animal weights are monitored every other day.
  • the dose of 100 mg/kg in the rat represents approximately 600 mg/m in humans, which is in the general range of clinical single doses, as described by De Kraker, supra.
  • Statistical analysis was performed using an impaired Student's s test or Pearson's ⁇ analysis.
  • FIG. 1 demonstrates the results of measurement of WBC (Fig. 1A) and platelet (Fig. IB) counts in blood obtained by cardiac puncture in non- tumor-bearing and tumor-bearing rats. Measurements were made prior to and 1 week after i.v. injection of 125 mg/kg of (R,S)-, (R)-, or (S)-ifosfamide.
  • the wild-type MatB tumors are responsive to ifosfamide. While tumors in saline-treated rats continue to grow, in all treatment groups there was complete disappearance of measurable tumors within 14 days.
  • a MatB subline selected for resistance to nitrogen mustards was grown in the rats, which are at least 4-fold resistant to another nitrogen mustard, melphalan, in vivo. All three formulations resulted in equivalent significant tumor growth delay; there is no difference among the formulations regarding tumor growth duration.

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  • 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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

On administre (R)-Ifosfamide en tant qu'agent thérapeutique cytotoxique, afin de limiter des effets secondaires. On peut ensuite administrer (S)-Ifosfamide.
PCT/GB1994/002171 1994-06-23 1994-10-05 Utilisation des enantiomeres d'ifosfamide en therapie antitumorale afin de limiter les effets secondaires WO1996000075A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU77893/94A AU695347B2 (en) 1994-06-23 1994-10-05 Use of the enantiomers of ifosfamide in antitumor therapy for reducing side effects
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
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
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
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 FI965171A0 (fi) 1994-06-23 1996-12-20 Oksatsofosforiinien, esimerkiksi ifosfamidin, enantiomeerien käyttö kasvainten hoidossa sivuvaikutuksien vähentämiseksi
US09/046,066 US6037337A (en) 1994-06-23 1998-03-23 Use of the enantiomers of ifosfamide in antitumor therapy for reducing side effects

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9412689.3 1994-06-23
GB9412689A GB9412689D0 (en) 1994-06-23 1994-06-23 Cytotoxic agent and its use

Related Child Applications (1)

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US60517996A Continuation 1994-06-23 1996-06-10

Publications (1)

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WO1996000075A1 true WO1996000075A1 (fr) 1996-01-04

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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

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AU (1) AU695347B2 (fr)
CA (1) CA2170136A1 (fr)
GB (1) GB9412689D0 (fr)
WO (1) WO1996000075A1 (fr)

Cited By (2)

* 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
WO1998040053A1 (fr) * 1997-03-11 1998-09-17 Darwin Discovery Limited Formes galeniques comprenant des parties separees d'enantiomeres r et s

Non-Patent Citations (6)

* 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, XP002046572, DOI: doi:10.1002/chir.530020302 *
BLASCHKE, G. ET AL: "Preparative isolation and pharmacological-toxicological studies of the enantiomers of ifosfamide", ARZNEIM.-FORSCH., 1986, VOL. 36, PAGE(S) 1493-5 *
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 *
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 *

Cited By (5)

* 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
WO1998040053A1 (fr) * 1997-03-11 1998-09-17 Darwin Discovery Limited Formes galeniques comprenant des parties separees d'enantiomeres r et s
US6056968A (en) * 1997-03-11 2000-05-02 Darwin Discovery Limited Pharmaceutical drug dosage forms providing different release rates
US6221394B1 (en) * 1997-03-11 2001-04-24 Darwin Discovery, Ltd. Dosage forms
AU741821B2 (en) * 1997-03-11 2001-12-13 Arakis Limited Dosage forms comprising separate portions of R- and S-enantiomers

Also Published As

Publication number Publication date
AU695347B2 (en) 1998-08-13
CA2170136A1 (fr) 1996-01-04
AU7789394A (en) 1996-01-19
GB9412689D0 (en) 1994-08-10

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