U.S. patent application number 13/686240 was filed with the patent office on 2013-07-18 for methods for administering dpd inhibitors in combination with 5-fu and 5-fu prodrugs.
The applicant listed for this patent is Brian Huber, Donald W. Kufe, William Paul Peters, Thomas Spector. Invention is credited to Brian Huber, Donald W. Kufe, William Paul Peters, Thomas Spector.
Application Number | 20130184232 13/686240 |
Document ID | / |
Family ID | 36087538 |
Filed Date | 2013-07-18 |
United States Patent
Application |
20130184232 |
Kind Code |
A1 |
Spector; Thomas ; et
al. |
July 18, 2013 |
METHODS FOR ADMINISTERING DPD INHIBITORS IN COMBINATION WITH 5-FU
AND 5-FU PRODRUGS
Abstract
Methods for improved administration and dosing of DPD inhibitors
in combination with 5-FU and/or 5-FU prodrugs are provided,
comprising first administering to a patient in need thereof a DPD
inhibitor that substantially eliminates activity of the enzyme and
thereafter administering 5-FU or a 5-FU prodrug, wherein the level
of 5-FU or 5-FU prodrug is in substantial excess of DPD inhibitor
in the patient.
Inventors: |
Spector; Thomas; (Durham,
NC) ; Peters; William Paul; (Fernandina Beach,
FL) ; Kufe; Donald W.; (Wellesley, MA) ;
Huber; Brian; (Durham, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Spector; Thomas
Peters; William Paul
Kufe; Donald W.
Huber; Brian |
Durham
Fernandina Beach
Wellesley
Durham |
NC
FL
MA
NC |
US
US
US
US |
|
|
Family ID: |
36087538 |
Appl. No.: |
13/686240 |
Filed: |
November 27, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11294643 |
Dec 5, 2005 |
8318756 |
|
|
13686240 |
|
|
|
|
60633034 |
Dec 3, 2004 |
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Current U.S.
Class: |
514/51 ; 514/274;
514/49; 514/50 |
Current CPC
Class: |
A61K 31/505 20130101;
A61P 35/00 20180101; A61K 31/7072 20130101; A61K 31/513 20130101;
A61K 31/505 20130101; A61P 43/00 20180101; A61K 31/513 20130101;
A61K 31/7072 20130101; A61K 45/06 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/51 ; 514/274;
514/50; 514/49 |
International
Class: |
A61K 31/513 20060101
A61K031/513 |
Claims
1. A method for treating cancer in a patient comprising first
administering a DPD inhibitor and thereafter administering 5-FU or
a 5-FU prodrug, wherein the DPD inhibitor is administered at a dose
between 2.5-5 mg/m.sup.2, and at least about four hours thereafter
administering 5-FU or a 5-FU prodrug, wherein the 5-FU or 5-FU
prodrug is administered at a dose such that at its time of
administration the 5-FU or 5-FU prodrug is present in the patient
in excess of the DPD inhibitor.
2. (canceled)
3. The method of claim 1, wherein the 5-FU or 5-FU prodrug is
administered at least about 12 hours after the DPD inhibitor is
administered.
4. (canceled)
5. The method of claim 1, wherein the 5-FU or 5-FU prodrug is
administered at a time when at least 1-4 elimination half-lives for
the DPD inhibitor have passed since the DPD inhibitor was
administered.
6. (canceled)
7. The method of claim 1, wherein the 5-FU or 5-FU prodrug is
administered at a dose such that at its time of administration the
5-FU or 5-FU prodrug is present in the patient in at least 2-fold
excess, at least 3-fold excess, or at least 5-fold excess of the
DPD inhibitor.
8. (canceled)
9. The method of claim 1, wherein the DPD inhibitor is an
irreversible DPD inhibitor.
10. (canceled)
11. The method of claim 1, wherein the 5-FU or 5-FU prodrug is
selected from the group and their 5'-esters, including phosphate
esters: consisting of 5-fluorouridine, 5-fluorocytidine,
5-fluoro-2-deoxyuridine, 5-fluoro-2-deoxycytidine,
5'-deoxy-4',5-fluorouridine, and 5-fluoro arabinosyluracil.
5'-Deoxy-5-fluorouridine, 1-(2-tetrahydrofuranyl)-5-fluorouracil,
1-C.sub.1-8 alkylcarbamoyl-5-fluorouracil derivative,
1-(2-tetrahydrofuryl)-5-fluorouracil,
5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine (capecitabine),
or a compound that is converted to 5-FU in vivo.
12. The method of claim 1, wherein the 5-FU or 5-FU prodrug is 5-FU
or capecitabine.
13. The method of claim 1, wherein the DPD inhibitor is eniluracil
or a prodrug thereof.
14. The method of claim 1, wherein the DPD inhibitor is eniluracil
and the 5-FU or 5-FU prodrug is 5-FU or capecitabine.
15-18. (canceled)
19. The method of claim 1, wherein the DPD inhibitor is eniluracil,
the 5-FU or 5-FU prodrug is 5-FU, the eniluracil is administered at
a dose between about 2.5-5 mg/m.sup.2, and the 5-FU is administered
at a dose between about 0.5-80 mg/m.sup.2 or between about 0.5-40
mg/m.sup.2.
20. The method of claim 1, wherein the DPD inhibitor comprises a
5-substituted uracil compound or a prodrug thereof.
21. (canceled)
22. The method of claim 1, wherein the DPD inhibitor comprises a
uracil compound selected from the group consisting of eniluracil,
5-propynyluracil, 5-cyanouracil, 5-propynyluracil,
5-bromoethynyluracil, 5-(1-chlorovinyl)uracil, 5-iodouracil,
5-bromovinyluracil, (E)-5-(2-bromovinyl)uracil 5-hex-1-ynyluracil,
5-vinyluracil, 5-trifluorouracil, 5-bromouracil and
5-(2-bromo-l-chlorovinyl)uracil.
23. (canceled)
24. A method for treating cancer in a patient comprising first
administering eniluracil at a dose between 2.5-5 mg/m.sup.2 and
thereafter administering 5-FU at least about 4 hours after the
eniluracil is administered, wherein the 5-FU is administered at a
dose such that at its time of administration the 5-FU is present in
the patient in excess of the DPD inhibitor.
25. (canceled)
26. The method of claim 24, wherein the 5-FU is administered at
least about 12 hours after the eniluracil is administered.
27. The method of claim 24, wherein the 5-FU is administered when
at least about 1-4 elimination half-lives for eniluracil have
passed since the eniluracil was administered.
28. (canceled)
29. The method of claim 24, wherein the 5-FU is administered at a
dose such that at its time of administration the 5-FU is present in
the patient in at least 2-fold excess, at least 3-fold excess, or
at least 5-fold excess of the DPD inhibitor.
30. (canceled)
31. (canceled)
32. The method of claim 24, wherein the 5-FU is administered at a
dose between about 0.5-40 mg/m.sup.2.
33-42. (canceled)
43. A method for treating cancer in a patient comprising first
administering eniluracil and thereafter administering capecitabine,
wherein the eniluracil is administered at a dose between about
2.5-5 mg/m.sup.2, and wherein the 5-FU is administered after at
least 1-4 elimination half-lives for eniluracil have passed since
the eniluracil was administered.
44. The method of claim 43, wherein the capecitabine is
administered at least about 4 hours, about 14 hours, or about 24
hours after the eniluracil is administered.
45-46. (canceled)
47. The method of claim 43, wherein the capecitabine is
administered at a dose such that at its time of administration the
capecitabine is present in the patient in at least 2-fold excess,
in at least 3-fold excess, or in at least five-fold excess of the
DPD inhibitor.
48. (canceled)
49. The method of claim 43, wherein the capecitabine is
administered at a dose between about 1.5-4 mg/m.sup.2.
50-57. (canceled)
58. The method of claim 1, wherein the doses of the DPD inhibitor
and the 5-FU or 5-FU prodrug are at a ratio of 1:3 to 1:20, a ratio
of 1:5 to 1:15, or a ratio of 1:8 to 1:12.
59-60. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates generally to cancer therapy, and more
particularly to cancer therapy using DPD inhibitors in combination
with 5-FU and/or 5-FU prodrugs.
[0003] 2. Description of Related Art
[0004] 5-Fluorouracil (5-FU) has been clinically used to treat
solid tumors in cancer patients for over three decades (Ansfield et
al., Cancer 39: 34-40, 1977; Grem et al., Cancer Treat Rep 71:
1249-1264, 1987; Chabner et al., Cancer, Principles and Practice of
Oncology, 2nd Ed, pp 287-328 Philadelphia, Pa.: J B Lippincott Co,
1985). 5-FU must be activated by metabolic conversion to fraudulent
uridine nucleotides (e.g., FUMP, FUDP, FUTP) and deoxyuridine
nucleotides (e.g., FdUMP, FdUDP, FdUTP) that interfere with DNA
synthesis and RNA functions (reviewed in Meyers, Pharmacol Rev, 33:
1-15, 1981; Dasher et al., Pharmac Ther 48: 189-222, 1990). Because
5-FU differs from uracil, its natural counterpart, by only a
fluorine substitution in the 5-position, it is readily activated in
cancer patients. Unfortunately, its structural similarity to uracil
also accounts for its rapid and extensive conversion to breakdown
products that have no antitumor activity. This metabolic process is
referred to as inactivation. 5-FU is rapidly inactivated by the
enzyme dihydropyrimidine dehydrogenase (DPD: EC 1312, uracil
reductase) (Meyers, Pharmacol Rev, 33: 1-15, 1981; Dasher et al.,
Pharmac Ther 48: 189-222, 1990). Therefore, the antitumor efficacy
of 5-FU for treating cancer relies on the delicate balance between
metabolic conversion to antitumor nucleotides (activation) and
metabolic conversion to useless metabolites (inactivation).
[0005] Furthermore, several clinical issues arise due to the
metabolic inactivation of 5-FU. First, because the levels of DPD
vary among individuals (Fleming et al., Cancer Res 52: 2899-2902,
1992; Grem et al., Cancer Chemother Pharmacol 40: 117-125, 1997)
and within individuals during the course of a day (Grem et al.,
Cancer Chemother Pharmacol 40: 117-125, 1997; Harris et al., Cancer
Res 50: 197-201, 1990; Petit et al., Cancer Res 48: 1676-1679,
1988), the systemic levels of 5-FU produced from a given dose vary
greatly and therefore render efficacy and toxicity highly
unpredictable. At the extreme, patients genetically deficient in
DPD experience severe and sometimes fatal toxicity when treated
with `standard` therapeutic doses of 5-FU (reviewed in Morrison et
al., Oncol Nurs Forum 24: 83-88, 1997). Second, variable levels of
gastro-intestinal DPD (Ho et al., Anticancer Res 6: 781-784, 1986;
Naguib et al., Cancer Res 45: 5405-5412, 1985; Spector et al.,
Biochem Pharmacol 46: 2243-2248, 1993) create highly variable
absorption of orally dosed 5-FU (Christophidis et al., Clin
Pharmacokinetics 3: 330-336, 1978; Cohen et al., Cancer Chemother
Rep 58: 723-731, 1974; Finch et al., Br J Clin Pharmacol 7:
613-617, 1979) and therefore can result in unpredictable plasma
levels of drug and produce undesirable toxicity or inadequate
efficacy. Third, tumors containing high levels of DPD are less
likely to respond to 5-FU-treatment (Etienne et al., J Clin Oncol
13: 1663-1670, 1995; Fischel et al., Clin Cancer Res 1: 991-996,
1995). Finally, the breakdown products of 5-FU may produce
neurotoxicity (Okeda et at., Acta Neuropathol 81: 66-73, 1990;
Koenig et al. Arch Neurol 23: 155-160, 1970), cardiotoxicity (et
al., Lancet 337: 560, 1991; Lemaire et al., Br J Cancer 66:
119-127, 1992), palmer-plantarerythrodysaesthesia (hand-foot
syndrome) (Hohneker, Oncology 12: 52-56, 1998), and GI toxicity
(Spector et al., Cancer Res 55: 1239-1241, 1995) and appear to
interfere with the antitumor activity (Spector et al., Cancer Res
55: 1239-1241, 1995; Cao, et al., Pharmacol 59: 953-960, 2000).
[0006] DPD is a ubiquitous enzyme that is the first and the
rate-limiting step in the degradation (inactivation) of 5-FU.
Studies have shown that inhibition of DPD prolongs the half-life of
5-FU in plasma. Several DPD inhibitors have been studied, including
those that irreversibly inactivate DPD as well as those that
reversibly inhibit DPD.
[0007] 5-Ethynyluracil, also referred to as eniluracil, is an
example of a DPD inhibitor that is an irreversible inactivator of
DPD that reduces or eliminates the metabolic inactivation of 5-FU
(for reviews see Spector et al., Drugs of The Future 19: 565-571,
1994; Paff et at, Invest. New Drugs: 18,365-371 (2000)). Due to the
structural similarity between eniluracil and 5-FU, eniluracil is a
substrate for DPD. As DPD attempts to break down eniluracil, the
latter is converted to a highly reactive compound that irreversibly
binds to DPD and thereby inactivates the enzyme. Thus, in the
presence of very low amounts of eniluracil, DPD is destroyed and is
no longer capable of inactivating 5-FU. Active DPD only reappears
in such patients as a result of de novo DPD enzyme synthesis over a
course of days.
[0008] Eniluracil has been tested in Phase I clinical trials in
cancer patients (reviewed in Levin et al., Invest New Drugs
18:383-90, 2000; Baker et al., J Clin Oncol 18: 915-926 2000;
Schilsky et al., J Clin Oncol 4:1450-7, 1998). It very potently
eliminated DPD activity without causing toxicity. A dose of 0.74
mg/m.sup.2 (about 1 mg total) eliminated greater than 90% of all
DPD for prolonged periods. In fact, 24 hours after one dose of
eniluracil, the level of DPD was only 3% of the predose level. The
elimination half-life of 5-FU was increased from about 10 minutes
to 3.5 hours by one dose of eniluracil. A dose of 3.7 mg/m.sup.2
eniluracil increased the half-life of 5-FU to 4.5 hours. Higher
doses added no apparent benefit.
[0009] Eniluracil has also been orally administered in Phase II and
Phase III clinical trials (reviewed in Levin et al., Invest New
Drugs 18:383-90, 2000; Schilsky et al., J Clin Oncol: 20:1519-26,
2002). Two dosing regimens were used in these trials. In the `5-day
schedule`, eniluracil was administered at a fixed dose of 50 mg per
day on day-1 through day-7. 5-FU was dosed at approximately 20
mg/m.sup.2 on day-2 through day-6 after the dose of eniluracil. In
the `28-day schedule`, eniluracil and 5-FU were co-administered in
a fixed ratio of ten eniluracil to one 5-FU b.i.d. (twice daily)
for 28 days. The dose of 5-FU was approximately 1 mg/m.sup.2.
Eniluracil abrogated the 5-FU-associated hand-foot syndrome
toxicity, enabled 5-FU to be safely dosed orally, and resulted in
highly predictable 5-FU plasma levels. However, the antitumor
activity of these regimens was unfortunately disappointing. In two
multicenter Phase III studies using the 28-day eniluracil regimen
for colorectal cancer, patients receiving eniluracil and 5-FU
tended to have less antitumor activity than those treated with the
standard 5-FU regimen without eniluracil (Schilsky et al., J Clin
Oncol: 20:1519-26, 2002).
[0010] Thus, there remains an important and unmet need in the art
for identifying optimal dosing and administration schedules for DPD
inhibitors used in combination with 5-FU and 5-FU prodrugs in order
to maximize the antitumor efficacy and therapeutic index of 5-FU
and 5-FU prodrugs, to improve the predictability of dosing and to
enable 5-FU and 5-FU prodrugs to be effectively dosed by oral
administration. The present invention fulfills these needs and
offers other related advantages.
SUMMARY OF THE INVENTION
[0011] The present invention relates generally to improved methods
for administering DPD inhibitors, such as eniluracil, in
combination with 5-FU and 5-FU prodrugs. Therefore, according to
one aspect of the present invention, there is provided a method for
treating cancer in a patient comprising first administering a DPD
inhibitor that substantially eliminates this enzyme and thereafter
administering 5-FU or a 5-FU prodrug, wherein the 5-FU or 5-FU
prodrug is administered at a dose such that at its time of
administration the 5-FU or 5-FU prodrug is present in the patient
in substantial excess of the free DPD inhibitor.
[0012] In one embodiment according to this aspect of the invention,
the 5-FU or 5-FU prodrug is administered at least about 4 hours, at
least about 6 hours, at least about 8 hours, at least about 10
hours, at least about 12 hours, at least about 14 hours, at least
about 24 hours, or at least about 36 hours after the DPD inhibitor
is administered.
[0013] In another embodiment according to this aspect of the
invention, the 5-FU or 5-FU prodrug is administered about 4-72
hours, 4-36 hours, 4-24 hours, 4-14 hours, 6-14 hours or 8-14 hours
after the DPD inhibitor is administered.
[0014] In another embodiment according to this aspect of the
invention, the 5-FU or 5-FU prodrug is administered at a time when
at least about 0.1-4 elimination half-lives, 1-4 elimination
half-lives, 2-4 elimination half-lives or 3-4 elimination
half-lives for the DPD inhibitor have passed since the DPD
inhibitor was administered.
[0015] In another embodiment according to this aspect of the
invention, the DPD inhibitor is administered at a dose sufficient
to reduce DPD activity in the patient to less than about 10%, less
than about 5%, less than about 3% or less than about 1% of baseline
DPD activity in the patient.
[0016] In another embodiment according to this aspect of the
invention, the 5-FU or 5-FU prodrug is administered at a dose such
that at its time of administration the 5-FU or 5-FU prodrug is
present in the patient in at least about 2-fold, at least about
3-fold, at least about 5-fold or at least about 100-fold excess of
the DPD inhibitor.
[0017] In another embodiment according to this aspect of the
invention, the DPD inhibitor is an irreversible DPD inhibitor.
[0018] In another embodiment according to this aspect of the
invention, the DPD inhibitor is a reversible DPD inhibitor. In such
embodiments, it will be understood that certain preferred
reversible DPD inhibitors include tight-binding inhibitors that
dissociate from DPD more slowly than excess inhibitor is eliminated
from the body and therefore will not be present in substantial
excess when 5-FU or the 5-FU prodrug is administered. Other
preferred inhibitors include those that inhibit DPD activity but do
not substantially inhibit other enzymes that activate fluorouracil,
such as uridine phosphorylase (UPase), orotate
phosphoribosyltransferase (OPRTase) and thymidine phosphorylase
(TP).
[0019] In another embodiment according to this aspect of the
invention, the 5-FU or 5-FU prodrug is selected from the group
consisting of the following compounds and their 5'-esters,
including phosphate esters: 5-fluorouridine, 5-tluorocytidine,
5-fluoro-2-deoxyuridine, 5-fluoro-2-deoxycytidine, and
5-fluoroarabinosyluracil.
[0020] In another embodiment according to this aspect of the
invention, the 5-FU or 5-FU prodrug is selected from the group
consisting of 5'-deoxy-4',5-fluorouridine,
5'-deoxy-5-fluorouridine, 1-(2-tetrahydrofuranyl)-5-fluorouracil, a
1-C.sub.1-8 alkylcarbamoyl-5-fluorouracil derivative,
1-(2-tetrahydrofuryl)-5-fluorouracil,
5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine (capecitabine),
or a compound that is converted to 5-FU in vivo.
[0021] In another embodiment according to this aspect of the
invention, the DPD inhibitor is eniluracil or a prodrug
thereof.
[0022] In another embodiment according to this aspect of the
invention, the DPD inhibitor is eniluracil, and is administered at
a dose of 0.8-15, 2-15, 5-15 or 2.5-5 mg/m.sup.2.
[0023] In another embodiment according to this aspect of the
invention, the DPD inhibitor is eniluracil and the 5-FU or 5-FU
prodrug is 5-FU.
[0024] In another embodiment according to this aspect of the
invention, the 5-FU or 5-FU prodrug is 5-FU, and is administered at
a dose 0.5-80, 0.5-40, 10-80, 10-60, 10-30 or 20-60 mg/m.sup.2.
[0025] In another embodiment of the invention, the eniluracil and
5-FU or 5-FU prodrug are dosed at a ratio of about 1:3 to 1:20, 1:5
to 1:15, or 1:8 to 1:12.
[0026] In one preferred embodiment, eniluracil is first
administered at a dose of about 2.5-5 mg/m.sup.2 at least about
10-14 hours before administering 5-FU or 5-FU prodrug at a dose of
about 15-30 mg/m.sup.2 or before administering capecitabine at a
dose of about 5-100 mg/m.sup.2. Optionally, additional doses of
5-FU or capecitabine can be thereafter administered with or without
additional dosing of eniluracil.
[0027] In another embodiment according to this aspect of the
invention, the DPD inhibitor is eniluracil and the 5-FU or 5-FU
prodrug is capecitabine.
[0028] In another embodiment according to this aspect of the
invention, the DPD inhibitor is eniluracil, the 5-FU or 5-FU
prodrug is 5-FU or capecitabine, and the eniluracil is administered
at a dose between about 0.8-15, 2.5-15, 5-15 or 2.5-5
mg/m.sup.2.
[0029] In another embodiment according to this aspect of the
invention, the DPD inhibitor is eniluracil, the 5-FU or 5-FU
prodrug is 5-FU, the eniluracil is administered at a dose between
about 2.5-5 mg/m.sup.2, and the 5-FU is administered at a dose
between about 0.5-40 mg/m.sup.2, depending on the dosing schedule
used.
[0030] One illustrative schedule, e.g., a twice per day (b.i.d.)
for 28 days (28-day) schedule, employs a 5-FU dose from between
about 0.5-1.5 mg/m.sup.2. Another illustrative schedule, e.g., a
once per day for 5 days (5-day) schedule, employs a 5-FU dose from
between about 10-60 mg/m.sup.2. In a more particular embodiment,
the 5-FU dose is between about 10-30 mg/m.sup.2. In another
embodiment, the 5-FU dose is between about 20-60 mg/m.sup.2.
[0031] Another illustrative schedule, e.g., a once per week
(weekly) schedule, can employ a 5-FU dose between about 10-80
mg/m.sup.2. In a more particular embodiment, 5-FU is dosed between
about 15-40 or 10-30 mg/m.sup.2. In another embodiment, 5-FU is
dosed between about 30-80 mg/m.sup.2.
[0032] In another embodiment according to this aspect of the
invention, the DPD inhibitor is eniluracil, the 5-FU or 5-FU
prodrug is capecitabine, the eniluracil is administered at a dose
between about 0.8-15, between about 2-15, between about 5-15 or
between about 2.5-5 mg/m.sup.2, and the capecitabine is
administered at a dose between about 0.8-200 mg/m.sup.2. In a more
particular embodiment, the capecitabine is administered at a dose
between about 0.8-10 mg/m.sup.2 or 1.3-4 mg/m.sup.2 (e.g., for
certain illustrative protracted b.i.d. daily schedules).
[0033] In another embodiment according to this aspect of the
invention, the DPD inhibitor comprises a 5-substituted uracil
analog or a prodrug thereof.
[0034] In another embodiment according to this aspect of the
invention, the DPD inhibitor comprises a uracil analog substituted
in the 5-position by a halogen atom, a C.sub.2-4 alkenyl group, a
C.sub.2-4 alkenyl group substituted by halogen, a C.sub.2-6 alkynyl
group, a C.sub.2-6 alkynyl group substituted by a halogen, a cyano
group or a C.sub.1-4 alkyl group substituted by halogen.
[0035] In another embodiment according to this aspect of the
invention, the DPD inhibitor comprises a uracil analog selected
from the group consisting of eniluracil, 5-propynyluracil,
5-cyanouracil, 5-propynyluracil, 5-bromoethynyluracil,
5-(1-chlorovinyl)uracil, 5-iodouracil, 5-bromovinyluracil,
(E)-5-(2-bromovinyl)uracil 5-hex-1-ynyluracil, 5-vinyluracil,
5-trifluorouracil, 5-bromouracil, and
5-(2-bromo-1-chlorovinyl)uracil.
[0036] In another embodiment according to this aspect of the
invention, the DPD inhibitor is selected from the group consisting
of 5-(phenylselenenyl)uracil (PSU), 5-(phenylthio)uracil (PTU),
5-(phenylselenenyl)barbituric acid and 5-(phenylthio)barbituric
acid.
[0037] According to another aspect of the invention, there is
provided a method for treating cancer in a patient comprising first
administering eniluracil and thereafter administering 5-FU, wherein
the 5-FU is administered at a dose such that at its time of
administration the 5-FU is present in the patient in substantial
excess of the DPD inhibitor.
[0038] In one embodiment according to this aspect of the invention,
the 5-FU is administered at least about 4 hours, 6 hours, 8 hours,
10 hours, 12 hours, 14 hours, 24 hours or 36 hours after the
eniluracil is administered. In one preferred embodiment, the 5-FU
is administered at least about 4 hours, at least about 8 hours or
at least about 12 hours after the eniluracil is administered.
[0039] In another embodiment according to this aspect of the
invention, the 5-FU is administered about 4-72 hours, 4-36 hours,
4-24 hours, 4-14 hours, 6-14 hours or 8-14 hours after the
eniluracil is administered. In one preferred embodiment, the 5-FU
is administered about 4-14 hours after the eniluracil is
administered.
[0040] In another embodiment of the invention, the 5-FU is
administered at a time when between about 0.1-4 elimination
half-lives, 1-4 elimination half-lives, 2-4 elimination half-lives
or 3-4 elimination half-lives for the eniluracil have passed since
the eniluracil was administered.
[0041] In another embodiment according to this aspect of the
invention, the eniluracil is administered at a dose sufficient to
reduce DPD activity in the patient to less than about 10%, less
than about 5%, less than about 3% or less than about 1% of baseline
DPD activity.
[0042] In another embodiment according to this aspect of the
invention, the 5-FU is administered at a dose such that at its time
of administration the 5-FU is present in the patient in at least
about 2-fold, at least about 3-fold, at least about 5-fold or at
least about 100-fold excess of the eniluracil.
[0043] In another embodiment according to this aspect of the
invention, the eniluracil is administered at a dose between about
0.7-15 mg/m.sup.2. In another embodiment of the invention, the
eniluracil is administered at a dose between about 2.5-5
mg/m.sup.2. In another embodiment of the invention, the eniluracil
is administered at a dose between about 5-15 mg/m.sup.2.
[0044] In another embodiment according to this aspect of the
invention, the eniluracil is administered at a dose between about
2.5-5 mg/m.sup.2 and the 5-FU is administered at a dose between
about 0.5-40 mg/m.sup.2.
[0045] According to another aspect of the present invention, there
is provided a method for treating cancer in a patient comprising
first administering eniluracil and thereafter administering 5-FU,
wherein the eniluracil is administered at a dose between about
2.5-5 mg/m.sup.2, and wherein the 5-FU is administered when between
about 1-4, 2-4 or 3-4 elimination half-lives for eniluracil have
passed since the eniluracil was administered.
[0046] In one embodiment according to this aspect of the invention,
the 5-FU is administered at least about 4 hours, 6 hours, 8 hours,
10 hours, 12 hours or 14 hours after the eniluracil is
administered.
[0047] In one embodiment according to this aspect of the invention,
the 5-FU is administered between about 4-36 hours, 4-24 hours, 4-14
hours, 6-14 hours or 8-14 hours after the eniluracil is
administered.
[0048] In another embodiment according to this aspect of the
invention, the 5-FU is administered at a dose such that at its time
of administration the 5-FU is present in the patient in at least
about 2-fold, at least about 3-fold, at least about 5-fold or at
least about 100-fold excess of the eniluracil.
[0049] In another embodiment according to this aspect of the
invention, the 5-FU is administered at a dose between about 0.5-40
mg/m.sup.2.
[0050] In a more particular embodiment, eniluracil (or another DPD
inhibitor) is first administered and then multiple doses of 5-FU or
5-FU prodrug are thereafter administered at desired time points,
before eniluracil (or another DPD inhibitor) is optionally
administered again. For example, in one preferred embodiment,
eniluracil is first administered at about 2.5 to 5 mg/m.sup.2 at
least about 10 to 14 hours before administration of the 5-FU or
5-FU prodrug, for example on the evening prior to the first day
that either 5-FU is administered at about 15 to 30 mg/m.sup.2 or
capecitabine at about 5-100 mg/m.sup.2 and then similar multiple
doses of 5-FU or capecitabine are thereafter administered. For
example, in one illustrative embodiment, eniluracil is first dosed
and then multiple 5-FU or capecitabine doses are administered daily
for three days each week, for example, before eniluracil is
optionally administered again and the cycle repeated.
[0051] According to another aspect of the present invention, there
is provided a method for treating cancer in a patient comprising
first administering eniluracil and thereafter administering 5-FU,
wherein the eniluracil is administered at a dose between about
2.5-5 mg/m.sup.2, the 5-FU is administered when between 1-4, 2-4 or
3-4 elimination half-lives for eniluracil have passed since the
eniluracil was administered, and the 5-FU is administered at a dose
between about 0.5-40 mg/m.sup.2.
[0052] According to another aspect of the present invention, there
is provided an oral pharmaceutical time-release formulation
comprising a DPD inhibitor and 5-FU or a 5-FU prodrug, wherein
following administration of the formulation to a patient the 5-FU
or 5-FU prodrug is not substantially released until about 0.5-36,
4-36, 4-24 or 4-14 hours after the DPD inhibitor has been
released.
[0053] According to another aspect of the invention, there is
provided a pharmaceutical formulation comprising a DPD inhibitor
and a delivery vehicle for administering the DPD inhibitor to a
patient. In another embodiment, the formulation comprises a DPD
inhibitor and 5-FU or a 5-FU prodrug. In another embodiment, the
formulation comprises a delivery vehicle, a DPD inhibitor and 5-FU
or a 5-FU prodrug. In a particular embodiment, the delivery vehicle
is a microsphere. In a related embodiment, the delivery vehicle is
a microsphere that allows for the preferential or selective
targeting of the DPD inhibitor to cancer cells using formulation
and delivery techniques known in the art.
[0054] These and other aspects of the invention will be apparent
upon reference to the following detailed description and attached
figures. Patent and other documents cited herein to more
specifically set forth various aspects of this invention are hereby
incorporated by reference in their entireties.
BRIEF DESCRIPTION OF THE DRAWINGS
[0055] FIG. 1 shows the chemical structures of eniluracil and
5-FU.
[0056] FIG. 2 shows that eniluracil causes increased plasma uridine
levels following administration in mice.
[0057] FIG. 3 shows an illustrative oral time-release formulation
comprising eniluracil and 5-FU in a tablet form.
DETAILED DESCRIPTION OF THE INVENTION
[0058] As noted above, the present invention relates generally to
methods for treating cancer which comprise administering to a
patient at least one DPD inhibitor in combination with at least one
5-FU or 5-FU prodrug, and to compositions and formulations useful
in such methods. The methods described herein are thus applicable
to the treatment of essentially any cancer type in which 5-FU
and/or 5-FU prodrugs have activity, including, by way of
illustration but not by way of limitation, breast cancer, lung
cancer, colon cancer, pancreatic cancer, gastric cancer, bladder,
renal cancer, head and neck cancer, esophageal cancer,
hepatocellular cancer, and all malignant leukemias and lymphomas.
Moreover, because the present invention improves the antitumor
efficacy of 5-FU and 5-FU prodrugs, cancer types that may have
shown less than desirable responsiveness to 5-FU previously may
show improved responsiveness when administered according to the
methods described herein.
[0059] It has been unexpectedly discovered that DPD inhibitors such
as eniluracil can inhibit the metabolic activation of 5-FU and 5-FU
prodrugs and thereby compromise their antitumor activity.
Therefore, according to a general aspect of the present invention,
by ensuring that 5-FU or 5-FU prodrug levels are in sufficient
excess of DPD inhibitor levels at the time the 5-FU or 5-FU prodrug
is administered to a patient, the extent to which the DPD inhibitor
may interfere with the metabolic activation of the 5-FU or 5-FU
prodrug is advantageously minimized, and antitumor efficacy of
these agents is thereby improved. Accordingly, in certain
embodiments, an irreversible DPD inhibitor such as eniluracil
should be dosed at the lowest dose that effectively inactivates DPD
and sufficient time should preferably lapse to clear excess
inhibitor from the blood stream before dosing with 5-FU. Moreover,
as DPD can be substantially eliminated from the patient prior to
administration of 5-FU or a 5-FU prodrug, the dose(s) of 5-FU or
5-FU prodrug required to achieve a desired level of therapeutic
activity can be significantly reduced, thereby providing economic
advantages in addition to the therapeutic advantages described
herein.
[0060] It will be understood on the part of the skilled artisan, in
view of this disclosure, that there exist a multitude of
administration and dosing schedules that can be used in the methods
described herein while ensuring that the levels of 5-FU or 5-FU
prodrug at its time of administration are in a therapeutically
effective amount and are in sufficient excess of DPD inhibitor
level in the patient to minimize or eliminate inhibition of 5-FU
metabolic activation. All such administration and dosing schedules
are considered within the scope of the present invention.
[0061] In one illustrative embodiment of the invention, a DPD
inhibitor is first administered (i.e., pre-dosed) to a patient in
need thereof in order to substantially eliminate DPD activity in
the patient, followed by administration of 5-FU or a 5-FU prodrug.
By "substantially eliminate", it is meant that the level of DPD
activity in the patient is reduced to at least less than 20%, less
than 10%, less than 5%, less than 3% or less than 1% relative to
the baseline level of DPD activity in the patient prior to
administration of the DPD inhibitor. A baseline level of DPD
activity for a patient can be readily determined, for example in
PBMCs from the patient, using known techniques (e.g., Baker et al.,
J Clin Oncol 18: 915-926 2000; Schilsky et al., J Clin Oncol
4:1450-7, 1998).
[0062] After first administering at least one DPD inhibitor, and
thereby substantially eliminating DPD in the patient, 5-FU or a
5-FU prodrug, or a combination thereof, is then administered to the
patient after sufficient time has passed to allow the DPD inhibitor
to be substantially cleared from the patient by elimination. The
delay in time between administration of the DPD inhibitor and the
5-FU or 5-FU prodrug can vary provided that upon administration of
the 5-FU or 5-FU prodrug, it is present in the patient in
substantial excess relative to the level of DPD inhibitor remaining
in the patient at that time. In one illustrative embodiment, the
5-FU or 5-FU prodrug is administered at a dose such that the level
of 5-FU or 5-FU prodrug is present in the patient at least in molar
excess of the DPD inhibitor remaining in the patient, for example
at least about 2-fold, at least about 3-fold, at least about 5-fold
or at least about 100-fold excess relative to the level of DPD
inhibitor remaining in the patient at the time the 5-FU or 5-FU
prodrug is administered. The skilled artisan will recognize that
any of a number of known and available techniques may be used for
calculating and/or determining the level of excess of 5-FU or 5-FU
prodrug in a patient relative to DPD inhibitor in accordance with
the embodiments described herein. Such techniques may include, for
example, HPLC, LC-MS, ELISA, and others. As noted above, it is
believed that by ensuring that the 5-FU or 5-FU prodrug is present
in sufficient excess relative to the level of DPD inhibitor in the
patient at the time the 5-FU or 5-FU prodrug is administered,
interference by the DPD inhibitor with the metabolic activation of
the 5-FU or 5-FU prodrug is thereby minimized, and the efficacy of
the 5-FU or 5-FU prodrug is thereby improved.
[0063] In another embodiment of the invention, the 5-FU or 5-FU
prodrug is administered to the patient only after at least 0.1-4
elimination half-lives, 1-4 elimination half-lives, 2-4 elimination
half-lives, or 3-4 elimination half-lives of the DPD inhibitor have
passed since the DPD inhibitor was administered. The elimination
half-lives for certain DPD inhibitors have been determined and, for
those that have not, elimination half-lives can be readily
determined using well known and established
gas-chromatography/mass-spec and HPLC techniques (referenced in
Baker et al., J Clin Oncol 18: 915-926 2000; Schilsky et al., J
Clin Oncol 4:1450-7, 1998). The elimination half-life for
eniluracil in humans has been reported to be about 3.5 hours (e.g.,
Baker et al., J Clin Oncol 18: 915-926 2000; Ochoa et al., Ann
Oncol 11:1313-22, 2000), however it is possible that the half-life
for eniluracil and other DPD inhibitors may be dose-dependent and
this dose dependency should be considered when determining an
appropriate time delay between the administration of DPD inhibitor
and 5-FU or 5-FU prodrug. Accordingly, for certain embodiments of
the invention that employ eniluracil as the DPD inhibitor, in order
to allow the level of eniluracil to be sufficiently decreased by
elimination prior to administration of the 5-FU or 5-FU prodrug,
the 5-FU or 5-FU prodrug is administered at least about 0.5 hours,
about 2 hours, about 4 hours, about 6 hours, about 8 hours, about
10 hours, about 12 hours, about 14 hours, about 24 hours or about
36 hours after administration of the eniluracil. In certain other
embodiments, the 5-FU or 5-FU prodrug is administered about 4-72
hours, 4-36 hours, about 4-24 hours, about 4-14 hours, about 6-14
hours or about 8-14 hours after administration of the eniluracil.
Of course, it will be understood that these ranges are illustrative
in nature and can be varied as necessary or desired for a
particular dosing schedule provided that the presence of eniluracil
is minimized or absent when 5-FU is dosed.
[0064] The DPD inhibitors used in accordance with the present
invention may be either reversible or irreversible inhibitors of
the DPD enzyme. Illustrative examples of reversible inhibitors of
the DPD enzyme include uracil, CDHP and
3-cyano-2,6-dihydroxypyridine (CNDP). Other illustrative reversible
DPD inhibitors include those described in U.S. Pat. No. 5,476,855
and WO 95/012400, the contents of which are incorporated herein by
reference in their entireties, for example
5-(phenylselenenyl)uracil (PSU), 5-(phenylthio)uracil (PTU),
5-(phenylselenenyl)barbituric acid and 5-(phenylthio)barbituric
acid. It will be understood that certain preferred reversible DPD
inhibitors include tight-binding inhibitors that dissociate from
DPD more slowly than excess inhibitor is eliminated from the body
and/or those which inhibit DPD activity but do not substantially
inhibit other enzymes that activate fluorouracil, such as uridine
phosphorylase (UPase), orotate phosphoribosyltransferase (OPRTase)
and thymidine phosphorylase (TP).
[0065] In certain preferred embodiments of the invention, the DPD
inhibitor is one that irreversibly inactivates the DPD enzyme.
Illustrative DPD inhibitors in this regard include, but are not
limited to, DPD inhibitors comprising a 5-substituted uracil
compound, or a prodrug thereof, particularly a uracil compound
substituted in the 5-position by a halogen atom, a C.sub.2-4
alkenyl group (e.g. vinyl) optionally substituted by halogen (e.g.
2-bromovinyl, 1-chlorovinyl or 2-bromo-1-chlorovinyl), a C.sub.2-6
alkynyl group optionally substituted by a halogen atom, a cyano
group, or a C.sub.1-4 alkyl group substituted by halogen (e.g.
trifluoromethyl).
[0066] In a more particular embodiment of the invention, the DPD
inhibitor is selected from the group consisting of eniluracil,
5-propynyluracil, 5-cyanouracil, 5-propynyluracil,
5-bromoethynyluracil, 5-(1-chlorovinyl)uracil, 5-iodouracil,
5-bromovinyluracil, (E)-5-(2-bromovinyl)uracil, 5-hex-1-ynyluracil,
5-vinyluracil, 5-trifluorouracil, 5-bromouracil, and
5-(2-bromo-1-chlorovinyl)uracil, or a prodrug thereof.
[0067] In another embodiment, the DPD inhibitor is a prodrug of
5-bromovinyluracil, one illustrative compound being represented by
the compound 1-.beta.-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil
(also referred to as BV-araU or sorivudine). Certain illustrative
prodrug compounds in this regard are described, for example, in
U.S. Pat. No. 4,386,076, the disclosure of which is incorporated
herein by reference.
[0068] In one preferred embodiment of the invention, the DPD
inhibitor is eniluracil or a prodrug of eniluracil, such as
5-ethynyl-2(1H)-pyrimidinone (eniluracil missing the 4-oxygen)
(Porter, et al., Biochem. Pharmacol 47: 1165-1171, 1994), a
nucleoside or deoxynucleoside derivative of eniluracil, a compound
that is converted to eniluracil in vivo, and/or a derivative of a
DPD inactivator that is converted to the inactivator in vivo. By
way of example, such compounds can include nucleoside derivatives
which contain a nucleobase corresponding to the above 5-substituted
uracil compounds, for example nucleoside derivatives containing a
ribose, 2'-deoxyribose, 2',3'-dideoxyribose, arabinose or other
cleavable sugar portion, which may additionally contain a 2'- or
3'-substituent such as a halogen or a 5'substituent such as an
ester. More particular examples of such nucleoside derivatives
include 1-(.beta.-D-arabinofuranosyl)-5-prop-1-ynyluracil and
2',3'-dideoxy-5-ethynyl-3'-fluorouridine.
[0069] Numerous 5-FU prodrugs are known which may also be used in
accordance with the present invention. A prodrug of 5-FU is a
compound which is metabolized in vivo to 5-fluorouracil and may
include, by way of illustration, 5-fluorouridine, 5-fluorocytidine,
5-fluoro-2-deoxyuridine, 5-fluoro-2-deoxycytidine,
5-fluoroarabinosyluracil, and their 5'-esters, including phosphate
esters. Other illustrative compounds include
5'-deoxy-4',5-fluorouridine, 5'-deoxy-5-fluorouridine,
1-(2-tetrahydrofuranyl)-5-fluorouracil, a 1-C.sub.1-8
alkylcarbamoyl-5-fluorouracil derivative,
1-(2-tetrahydrofuryl)-5-fluorouracil, Ftorafur (Tegafur, an oral
5-FU prodrug that is widely used in Asian countries), and
5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine (capecitabine,
marketed by Roche Laboratories Inc. as Xeloda.RTM.), or a compound
that is converted to 5-FU in vivo.
[0070] In a particularly preferred embodiment of the present
invention, the methods described herein employ eniluracil in
combination with 5-FU. As noted above, in order to maximize the
antitumor activity of 5-FU, eniluracil is administered at a dose to
substantially eliminate DPD activity in the patient while also
ensuring that eniluracil is not present in excess when 5-FU is
dosed. Because eniluracil is a very potent irreversible inactivator
of DPD, it is preferably dosed before 5-FU. Eniluracil rapidly
inactivates DPD and then is preferably given time to be
substantially cleared from the patient by elimination prior to
administering the 5-FU. Accordingly, DPD activity will be
substantially eliminated and the levels of eniluracil will be
advantageously low when 5-FU is administered to the patient.
[0071] It will be understood in view of this disclosure that the
methods of the present invention can also comprise administration
schedules of whatever duration and dosing characteristics desired,
provided the dosing schedule is properly selected so that the 5-FU
or 5-FU prodrug is present in excess of the level of eniluracil
remaining in the patient at the time the 5-FU or 5-FU prodrug is
administered. In one illustrative embodiment employing the
particular combination of eniluracil and 5-FU, a method of the
present invention comprises a once per day for 5 days (5-day)
schedule or a once-per-week (weekly) schedule. For 5-day or weekly
schedules, the dose-range of eniluracil will typically be between
about 0.8 and 10 mg/m.sup.2, preferably from about 2.5 to 5
mg/m.sup.2. Note that even higher doses of eniluracil may be used
provided that enough time elapses to clear the excess prior to
administering 5-FU.
[0072] For convenience, a simple fixed dose of eniluracil is
preferred in certain embodiments. As described herein, fixed doses
in the range of about 2.5-15 mg will generally be appropriate for
most patients. In certain preferred embodiments, the fixed dose is
in the range of about 2.5-5 mg. Illustrative fixed doses of
eniluracil that will eliminate DPD for longer than 24 hours, and in
some cases for longer than 3-5 days, in patients of different
sizes, are shown in the following Table.
TABLE-US-00001 Body Surface Area Dose Eniluracil mg/m.sup.2 (square
meters) (mg) (range) 0.5 to 1.0 2.5 2.5 to 5.0 >1.0 to 2.0 5.0
2.5 to 5.0 >2.0 to 4.0 10.0 2.5 to 5.0
[0073] In one illustrative embodiment, the time delay between
eniluracil administration and 5-FU administration is between about
4-72 hours, 4-36 hours, 4-24 hours or 4-14 hours (or at least about
1-4 elimination half-lives for eniluracil). For example, eniluracil
may be administered the night before 5-FU or, alternatively, can be
administered in the morning followed by 5-FU administration in the
evening. Using an illustrative dose for 5-FU of about 20 to 30
mg/m.sup.2 for these schedules (Levin et al., Invest New Drugs
18:383-90, 2000; Schilsky et al., J Clin Oncol 4:1450-7, 1998; Guo
et al., Cancer Chemother Pharmacol 52:79-85, 2003), for example,
5-FU should always be in substantial excess relative to
eniluracil.
[0074] In another embodiment, an extended administration schedule,
e.g., a 28-day administration schedule, may be used. One
illustrative 28-day b.i.d. schedule (e.g., twice daily for 28 days)
involves dosing 5-FU at about 0.5-2 mg/m.sup.2, preferably about 1
mg/m.sup.2 (e.g., Baker et al., J Clin Oncol 18: 915-926 2000). To
ensure that eniluracil is not present in excess of a low 5-FU dose,
eniluracil can be administered at about 2.5 to 5 mg/m.sup.2 at
least about 12 hours before starting the b.i.d. schedule, for
example on the evening prior to the first day that 5-FU is
administered. Then single daily eniluracil doses of between about
0.5-2 mg/m.sup.2, for example 1 mg/m.sup.2, can be administered
about 2-8 hours, preferably about 4-6 hours before the first 5-FU
dose of each day, for 28 days. This strategy ensures that 5-FU
levels from the first dose are in sufficient excess of eniluracil,
and that the 5-FU levels from the second 5-FU dose of the day are
in sufficient excess of eniluracil. During subsequent treatment
days, e.g., days 2 through 28, the level of eniluracil (e.g., when
dosed at 1 mg/m.sup.2) in the patient's blood should have decreased
by about 50% (to 0.5 mg/m.sup.2) within four hours (first daily
5-FU dose) and by about 94% (to 0.06 m g/m.sup.2) by the second
5-FU dose of the day. The initial 2.5 to 5 mg/m.sup.2 of eniluracil
and the subsequent 1 mg/m.sup.2 doses should serve to effectively
eliminate DPD activity in the patient for the 28 days of 5-FU
dosing.
[0075] In another illustrative embodiment, eniluracil (or another
DPD inhibitor) is first administered and then multiple doses of
5-FU or 5-FU prodrug are thereafter administered at desired time
points, before eniluracil is optionally administered again. For
example, in an illustrative embodiment, eniluracil is first dosed
and then multiple 5-FU doses are administered at illustrative time
points of about 12 hours, 36 hours, and even 54 hours thereafter,
if desired, before eniluracil is optionally again administered and
the cycle repeated.
[0076] In a particular embodiment, eniluracil and 5-FU are dosed at
a ratio of about 1:5 to 1:15 or 1:8 to 1:12.
[0077] In another embodiment of the present invention, 5-FU is
dosed relatively soon after eniluracil is administered, e.g.,
0-0.5-1 hour, provided in accordance with the present invention
that the 5-FU in molar excess relative to eniluracil when
administered.
[0078] The doses and schedules of eniluracil administration
described for embodiments of the present invention differ from
those used in the prior Phase II and Phase III human trials (Levin
et al., Invest New Drugs 18:383-90, 2000; Schilsky et al., J Clin
Oncol: 20:1519-26, 2002). Those studies used higher doses of
eniluracil and dosed 5-FU either simultaneously with eniluracil or
only one hour after eniluracil. Although some antitumor activity
was demonstrated in the Phase HI trials, the overall results were
less than desired and the trials were not considered successful. It
is believed that by using the methods of the present invention,
improved efficacy will be achieved by ensuring that excess
eniluracil is not present, and thus cannot inhibit 5-FU activation,
when the 5-FU or 5-FU prodrug is administered.
[0079] The present invention includes as a further feature
pharmaceutical formulations comprising at least one
pharmaceutically acceptable carrier or excipient and further
comprising a DPD inhibitor and/or 5-FU or a 5-FU prodrug, together
in a single formulation or present as separate formulations to be
administered at separate time points in accordance with the present
invention. In one embodiment, the eniluracil and 5-FU are present
in one or more formulations at a ratio of about 1:3 to 1:20, 1:5 to
1:15, or 1:8 to 1:12. A carrier or excipient is "pharmaceutically
acceptable" in the sense of being compatible with the other
ingredients of the formulation and not injurious to the patient.
Formulations include, for example, those adapted for oral, rectal,
nasal, topical (including buccal and sublingual), vaginal and
parenteral (including subcutaneous, intramuscular, intravenous and
intradermal) administration. The formulations may conveniently be
presented in unit dosage form and may be prepared by any methods
well known in the pharmaceutical arts. Such methods include the
step of bringing into association the active ingredient with the
carrier that constitutes one or more accessory ingredients. In
general, the formulations are prepared by uniformly and intimately
bringing into association the active ingredient with liquid
carriers or finely divided solid carriers or both, and then if
necessary shaping the product.
[0080] Formulations according to the present invention may be
prepared and/or administered using essentially any available
technique. Formulations of the present invention adapted for oral
administration, for example, may be presented as discrete units
such as capsules, cachets or tablets each containing a
predetermined amount of an active ingredient; as a powder or
granules; as a solution or a suspension in an aqueous or
non-aqueous liquid; or as an oil-in-water liquid emulsion or a
water-in-oil liquid emulsion. An active ingredient may also be
presented as a bolus, electuary or paste. Oral administration will
typically be a preferred route of administration.
[0081] A tablet may be made, for example, by compression or
molding, optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable
machine the active ingredient in a free-flowing form such as a
powder or granules, optionally mixed with a binder (e.g., povidone,
gelatin, hydroxypropylmethylcellulose), lubricant, inert diluent,
preservative, disintegrant (e.g., sodium starch glycollate,
cross-linked povidone, cross-linked sodium caroxymethylcellulose)
surface-active or dispersing agent. Molded tablets may be made by
molding in a suitable machine a mixture of the powdered compound
moistened with an inert liquid diluent. The tablets may optionally
be coated or scored and may be formulated so as to provide
controlled release of the active ingredient therein using, for
example, hydroxypropylmethylcellulose in varying proportions to
provide the desired release profile.
[0082] Formulations for topical administration in the mouth, for
example, include lozenges comprising the active ingredient in a
flavored basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier. Formulations for
rectal administration, for example, may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate. Formulation for vaginal administration, for
example, may be presented as pessaries, tampons, creams, gels,
pastes, foams or spray formulations containing in addition to the
active ingredient such carriers as are known in the art to be
appropriate.
[0083] Formulations for parenteral administration, for example,
include aqueous and non-aqueous isotonic sterile injection
solutions which may contain anti-oxidants, buffers, bacteriostats
and solutes which render the formulation isotonic with the blood of
the intended recipient; and aqueous and non-aqueous sterile
suspensions which may include suspending agents and thickening
agents. The formulations may be presented in unit-dose or
multi-dose sealed containers, for example, ampoules and vials, and
may be stored in a freeze-dried (lyophilized) condition requiring
only the addition of the sterile liquid carrier, for example water
for injections, immediately prior to use. Extemporaneous injection
solutions and suspensions may be prepared from sterile powders,
granules and tablets of the kind previously described.
[0084] Typically, liquid formulations including one or more active
agents are preferably buffered to a pH of 7 to 11, generally 9.5 to
10.5. Certain unit dosage formulations may include those containing
a daily dose or unit, daily sub-dose, as hereinabove recited, or an
appropriate fraction thereof, of an active ingredient.
[0085] Methods for making DPD inhibitors and 5-FU prodrugs
described herein are known and may be carried out using
conventional methodology. For example, DPD inhibitors referred to
above may be prepared by the methods described in Heterocycl. Chem.
19(3) 463-4 (1982) for the preparation of 5-ethynyluracil; J. Chem.
Soc. Perkin Trans. 1(16), 1665-70 (1981) for the preparation of
5-(2-bromovinyl)uracil, 5-bromoethynyluracil and
5-(2-bromo-l-chlorovinyl)uracil; Nucleic Acid Chemistry, Vol. 2,
927-30 (1978) for the preparation 5-cyano-uracil; Nucleic Acids
Research, 1 (1) 105-7 (1974) for the preparation of 5-vinyluracil;
Z. Chern 17(11) 415-16 (1977) for the preparation of
5-trifluoromethyluracil; Nucleic Acids Research 3 (10),2845 (1976)
for the preparation of 5-(1-chlorovinyl)uracil. Certain other
compounds of the invention can be prepared in accordance with
processes described in European Patent Specification No. 356166 for
the preparation of 3'-fluoro-2',3'-dideoxy5-alkynyluridine
compounds, such as 2',3'-dideoxy-5-ethynyl-3'-fluorouridine, and
European Patent Specification No.272065 for the preparation of
5-alkynyluracil arabinosides, such as
1-(b-D-arabinofuranosyl)-5-prop-1-ynyluracil. These and other
synthetic techniques are known and available for making compounds
for use in the present invention.
[0086] In one embodiment, the present invention provides a
combination oral formulation in which a DPD inhibitor and 5-FU or a
5-FU prodrug are dosed together in a manner that allows for the
desired temporal release of the components of the formulation into
the patient. Differential time-release delivery of two components
can be achieved using known techniques and materials. For example,
in one embodiment, an oral formulation, e.g., in the form of a
tablet, may be composed of three distinct layers, as depicted
illustratively in FIG. 3. The outer layer can contain eniluracil in
an immediate release formulation. The middle layer can be a
time-release component (e.g., time-release buffer) that delays the
release of 5-FU or 5-FU prodrug to a desired extent according to
the present invention, which 5-FU or 5-FU prodrug is located in the
core layer in an immediate release formulation. The DPD inhibitor
and 5-FU or 5-FU prodrug are formulated in the proper doses and
ratios described herein. In one preferred embodiment, the DPD
inhibitor is eniluracil and the 5-FU or 5-FU prodrug is 5-FU or
capecitabine.
[0087] In another embodiment, an alternative formulation can
comprise known delivery vehicles, such as microspheres comprising
5-FU or 5-FU prodrug. In one embodiment, for example, 5-FU or 5-FU
prodrug may be encapsulated within a shell of time-release
component (e.g., time-release disintegrating buffer) and an outer
layer providing immediate release of a DPD inhibitor. In one
preferred embodiment, the DPD inhibitor is eniluracil and the 5-FU
or 5-FU prodrug is 5-FU or capecitabine. These and other examples
of illustrative combination formulations can be designed and made
using known techniques to allow the appropriate time-delay between
the delivery of the DPD inhibitor and the 5-FU or 5-FU prodrug in a
single oral preparation.
[0088] In another embodiment, DPD inhibitor may be selectively or
preferentially targeted to cancer cells and tumors. The selective
effect of DPD in cancer cells and tumors will enable a longer
half-life of the compounds relative to their circulating half-life,
which will enable a higher steady-state level of activated
nucleotides and improved therapeutic index. In one embodiment,
selectively targeting DPD inhibitors such as eniluracil to tumors
can be accomplished using targeted microspheres, which are well
known in the art. In another embodiment, targeting is achieved
using a tissue specific receptor such as the asiolglycoprotein
receptor to target the compound to hepatocytes and hepatoma cells.
Such targeting can be accomplished, for example, by chemically or
otherwise modifying the DPD inhibitor (e.g., by placing 3-6
galactose residues on eniluracil).
[0089] In another embodiment, the methods described herein further
comprise the administration of leucovorin. Leucovorin, or isovorin,
the active isomer of leucovorin, is commonly used in conjunction
with 5-FU for treating cancer patients. It may also be added to the
above-described dosing regimens for eniluracil and 5-FU. Leucovorin
has been shown to improve the antitumor efficacy of eniluracil and
5-FU in tumor-bearing rats and in tissue culture (Cao et al.,
Cancer Res 90:1507-1510, 1993; Fischel et al., Biochem Pharmacol
53: 1703-1709, 1997) and has been administered to patients
receiving eniluracil and 5-FU (Schilsky et al., J Clin Oncol
4:1450-7, 1998; Guo et al., Cancer Chemother Pharmacol 52:79-85,
2003). Leucovorin is also advantageously available in an oral
formulation.
[0090] The invention can be further understood upon consideration
of the following non-limiting Example.
EXAMPLES
Example 1
Excess Eniluracil Diminishes the Antitumor Activity of Eniluracil
and 5-FU
[0091] Rats were implanted with Ward carcinoma tumors and were
treated with one of the following regimens after their tumors grew
to 3,000 mg in weight as previously described (Cao et al., Cancer
Res 90:1507-1510, 1993). Rats bearing 3,000 mg of tumor mass were
dosed at Day 0, Day 7, and Day 14 with the following
treatments.
TABLE-US-00002 STUDY TREATMENT ARM Eniluracil Eniluracil at 55
minutes 5-FU at 60 minutes Group (mg/kg) (mg/kg) (mg/kg) A 0 0 0 B
1 0 5 C 1 25 5
[0092] Group A rats received no treatment. Group B rats were
intraperitoneally (ip) dosed with 1 mg/kg eniluracil (time (t)=0)
followed by intravenous (iv) 5 mg/kg 5-FU at t=60. Group C rats
were dosed ip with 1 mg/kg eniluracil (t=0) followed by 25 mg/kg
eniluracil ip at t=55 minutes and by 5 mg/kg 5-FU iv at t=60
minutes. Animals were dosed once per week for three weeks.
Eniluracil was also dosed ip at 1 mg/kg to rats in Groups B & C
on Days 2 and 3 of each weekly treatment. The treatment for Group C
mimicked the clinical trials where high levels of eniluracil were
present when 5-FU was dosed.
[0093] The tumors in Group A rapidly grew to 10,000 mg and the rats
were sacrificed. Tumors in Group B were rapidly eliminated while
those in Group C on average decreased only slightly in size. These
results demonstrate that the excess eniluracil in Group C greatly
diminished the antitumor activity 5-FU, likely due to interference
of eniluracil with the metabolic activation of 5-FU.
Example 2
Eniluracil Inhibits the Metabolic Activation of 5-FU to Active
Nucleotides
[0094] HEK 293 cells were initially treated with eniluracil (10
.mu.M) for 1 hour. After a washout period ranging from 4-48 hours,
cells were treated with [6-.sup.14C]-5-FU (66 .mu.M) for 2 hours at
37 degrees C. Controls were HEK 293 cells treated for 2 hours
either with [6-.sup.14C]-5-FU (66 .mu.M) alone, or with eniluracil
(10 .mu.M) and [6-.sup.14C]-5-FU (66 .mu.M) co-administered
together without preincubation. Reverse phase HPLC with
radioactivity detection was utilized to quantify [6-.sup.14C]-5-FU
catabolites/anabolites present in cell lysates. In a separate set
of experiments cytotoxicity of 5-FU at different eniluracil dose
schedules was examined. HEK 293 cells were treated with a range of
5-FU concentrations for 72 hours at 37 degrees C. following 1 hour
eniluracil (5 .mu.M) preincubation, without eniluracil, or with
eniluracil (5 .mu.M) co-administered without preincubation.
Cytotoxicity was assessed by the MTS proliferation assay and the
EC.sub.50 values for 5-FU calculated.
[0095] Pre-treatment of cells with eniluracil for 1 hour, followed
by a 36 hour or a 48 hour wash out prior to [6-.sup.14C]-5-FU
treatment produced significant increases in [6-.sup.14C]-FUMP
anabolite formation compared to [6-.sup.14C]-5-FU treatment alone,
or eniluracil and [6-.sup.14C]-5-FU co-administration (p-values
<0.05). For example, the 48 hour washout produced a 70% increase
in [6-.sup.14C]-FUMP formation versus [6-.sup.14C]-5-FU treatment
alone, and a 41% increase in [6-.sup.14C]-FUMP formation versus
eniluracil and [6-.sup.14C]-5-FU co-administration. In cytotoxicity
experiments, pre-treatment with eniluracil for 1 hour increased the
cytotoxicity of 5-FU with a decreased EC.sub.50 value (264.0
nM.+-.1.7) (mean.+-.SE) compared to the 5-FU treatment alone (311.4
nM.+-.1.1) or the EU and 5-FU co-administration without
preincubation (307.8 nM.+-.1.03) (p<0.05).
[0096] These results further confirm a role for eniluracil in
inhibiting the anabolic pathways that convert 5-FU to active
anti-tumor nucleotides, in addition to its known role in inhibiting
the catabolic pathways that degrade 5-FU to inactive forms.
Example 3
Eniluracil Causes Plasma Uridine Levels to Increase
[0097] While eniluracil inhibition is known to cause an increase in
uracil levels due to DPD inhibition, inhibitory effects on other
enzymes that anabolize fluoropyrimidines would be expected to
quantitatively alter the levels of other anabolites, such as
uridine. Eniluracil was administered to mice at 2 mg/kg, 25 mg/kg
and 100 mg/kg. Plasma samples were taken at 0 minutes, 15 minutes,
30 minutes, 60 minutes, 2 hours, 24 hours and 48 hours. Uridine
levels were determined by LC-MS technology using known techniques
and standards were used to validate the assay.
[0098] Results from these experiments, shown in FIG. 2, demonstrate
that eniluracil causes an increase in uridine levels following
administration. This finding is consistent with eniluracil having
an inhibitory effect on anabolic enzymes such as uridine
phosphorylase, and further supports a role for eniluracil in
inhibiting the anabolic conversion of 5-FU to active
nucleotides.
[0099] From the foregoing it will be appreciated that, although
specific embodiments of the invention have been described herein
for purposes of illustration, various modifications may be made
without deviating from the spirit and scope of the invention.
Accordingly, the invention is not limited except as by the appended
claims.
* * * * *