EP0772444A1

EP0772444A1 - Use of the enantiomers of oxazophosphorines, e.g. ifosfamide, in anti-tumour therapy, for reducing side-effects

Info

Publication number: EP0772444A1
Application number: EP95922649A
Authority: EP
Inventors: Helen Frances Baker
Original assignee: Chiroscience Ltd
Current assignee: Darwin Discovery Ltd
Priority date: 1994-06-23
Filing date: 1995-06-23
Publication date: 1997-05-14
Also published as: GB9412618D0; NO965528D0; WO1996000076A1; AU2747495A; FI965171A; FI965171A0; NO965528L

Abstract

A product containing respective enantiomers of an oxazophosphorine, each substantially free of the other, as a combined preparation for separate, simultaneous or sequential use in anti-tumour therapy. The active component may be ifosfamide. Levoifosfamide is preferred for single drug therapy, owing to its more rapid metabolism.

Description

USE OF THE ENANTIOMERS OF OXAZOPHOSPHORINES, E.G. IFOSFAMIDE, IN ANTI-TUMOUR THERAPY, FOR REDUCING SIDE-EFFECTS

Field of the Invention

This invention relates to oxazophosphorines and their 5 therapeutic use.

Background of the Invention

Oxazophosphorines are cytotoxic al ylating agents, examples being ifosfamide and cyclophosphamide. Ifosfamide has been shown to be more effective and less toxic than

10 cyclophosphamide when given by pulsed or infusional regimes. 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

15 with radiotherapy, surgery and other cytotoxic agents.

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.

20 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

25 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

30 doses. It is thought that they are caused by a metabolite, possibly chloroacetaldehyde. This is a significant problem: the drug must be administered in hospital because of the occurrence of these side-effects.

CNS side-effects were a major dose-limiting side-

35 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. 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) . Other metabolic routes are responsible for a very small amount of the total metabolism. 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 al. 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. 5fi: 252-255 (1990), studied the efficacy and toxicity of IFF enantiomers in CBA/CaJ mice. The results indicated that there were no statistically significant differences between the efficacies of (R)-IFF, (S)-IFF, and (R,S)-IFF against childhood rhabdo yosarcoma (HxRh28) grown in vivo as a xenograft in immunoincompetent female CBA/CaJ mice. The same was true regarding the acute toxicities of the stereoisomers. No statistically significant differences were found in the plasma pharmacokinetics of (S)-IFF, or in the in vitro N-dechloroethylation.

Wainer et al. Cancer Res. 5.J 393-4397 (1994), report the pharmacokinetics of ifosfamide and its enantiomers in rats. It is concluded that, because (R)-IFF is metabolised to a greater extent than (S)-IFF via the activation pathway, the former "may be an effective way to deliver active cytotoxic drug while limiting the generation of neurotoxic metabolites". Summary of the Invention

Surprisingly, it has been found that individual enantiomers of oxazophosphorines, e.g. levoifosfamide, have improved therapeutic benefit, since one enantiomer may be more rapidly metabolised. This is based on the results of the analysis of the pharmacokinetics of (R)-IFF and (S)-IFF in 14 cancer patients treated with an infusion of (R,S)- IFF. (S)-IFF was found to be more rapidly metabolised than (R)-IFF, a phenomenon that will result in the more rapid production of the active species and therefore improved efficacy. Accordingly, contrary to the conclusion expressed by Wainer et al, supra, the use of levoifosfamide may give improved results, including reduced side-effects.

Another aspect of the invention is based on an appreciation of the relative effects of the enantiomers of oxazophosphorines such as ifosfamide. It has now been appreciated that, especially for longer-term administration of ifosfamide, it is desirable to use a combination therapy, i.e. one enantiomer (dexifosfamide) initially, and the other enantiomer (levoifosfamide) thereafter. Brief Description of the Drawings Figure 1 of the accompanying drawings shows the mean plasma concentration ± SEM (μm) versus time (hours) profiles of (R)-IFF and (S)-IFF over 24 hours, following a 3 hour infusion of 3 g/m² (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 (μM.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. These data indicate that the AUC values for all of the DCE metabolites from (S)-IFF were significantly greater than those from (R)-IFF. Description of the Invention

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.

Especially for the novel combined therapy, discrete unit dosage forms may be provided. For example, "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. 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 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. In a first investigation, 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.

Assessing the concentrations of each enantiomer in plasma and urine, the area under the curve (AUC) of (R)-IFF was significantly larger than that of (S)-IFF (2480 ± 200 versus 1960 ± 150 μm/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. These data indicate that (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.

In the same study, an examination of the 2- and 3-N- dechloroethylated (DCE) metabolites of ifosfamide revealed that the AUC values for all of the DCE metabolites from (S)-IFF were significantly greater than those from (R)-IFF, with 47% of the measured AUC accounted for by DCE from (S)- IFF compared with only 20% for (R)-IFF. Therefore, the administration of (S)-IFF alone may result in the initial production of greater quantities of unwanted metabolites. This effect may decrease with time, as the desired pathway to the active mustard is induced by the usual mechanisms associated with liver metabolism.

Therefore, optimum clinical benefit may be achieved by initial administration of (R)-IFF for a period of time to induce the metabolic pathway to the active species with minimum production of toxic metabolites, followed by a switch to (S)-IFF to utilise the benefits of increased metabolic rate resulting in more rapid production of active drug.

Claims

1. A product containing respective enantiomers of an oxazophosphorine, each substantially free of the other, as a combined preparation for separate, simultaneous or sequential use in anti-tumour therapy.

2. A product according to claim 1, which comprises a plurality of unit dosage forms of each of the respective enantiomers of an oxazophosphorine, each substantially free of the other, the dosage forms being discretely packaged as part of an integral package.

3. A product according to claim 1 or claim 2, wherein the oxazophosphorine is ifosfamide.

4. A method for treating a tumour in a human patient, which comprises the administration to said patient of an anti-tumour effective amount of one enantiomer of an oxazophosphorine, substantially free of the other.

5. A method according to claim 4, which comprises the administration of levoifosfamide substantially free of dexifosfamide.

6. Use of one enantiomer of an oxazophosphorine, substantially free of the other, for the manufacture of a medicament for anti-tumour therapy.

7. Use according to claim 6, wherein said one enantiomer is more rapidly metabolised.

8. Use of levoifosfamide, substantially free of dexifosfamide, for the manufacture of a medicament for anti-tumour therapy.