U.S. patent application number 17/190068 was filed with the patent office on 2021-06-17 for method for treating cancer patients with severe renal impairment.
This patent application is currently assigned to TAIHO PHARMACEUTICAL CO., LTD.. The applicant listed for this patent is TAIHO PHARMACEUTICAL CO., LTD.. Invention is credited to Kenichiro YOSHIDA.
Application Number | 20210177850 17/190068 |
Document ID | / |
Family ID | 1000005432647 |
Filed Date | 2021-06-17 |
United States Patent
Application |
20210177850 |
Kind Code |
A1 |
YOSHIDA; Kenichiro |
June 17, 2021 |
METHOD FOR TREATING CANCER PATIENTS WITH SEVERE RENAL
IMPAIRMENT
Abstract
A method for treating cancer in patients with creatinine
clearance of 15 mL/min or more and less than 30 mL/min, including
dividing a combination drug containing
.alpha.,.alpha.,.alpha.-trifluorothymidine (FTD) and
5-chloro-6-[(2-iminopyrrolidine-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione
hydrochloride in a molar ratio of 1:0.5, in a dose of 30 to 50
mg/m.sup.2/day as FTD-equivalent, into two to four times a day, and
orally administering it to the patient.
Inventors: |
YOSHIDA; Kenichiro;
(Tsukuba-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TAIHO PHARMACEUTICAL CO., LTD. |
Tokyo |
|
JP |
|
|
Assignee: |
TAIHO PHARMACEUTICAL CO.,
LTD.
Tokyo
JP
|
Family ID: |
1000005432647 |
Appl. No.: |
17/190068 |
Filed: |
March 2, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16574180 |
Sep 18, 2019 |
10960004 |
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17190068 |
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16054073 |
Aug 3, 2018 |
10456399 |
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16574180 |
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PCT/JP2017/003994 |
Feb 3, 2017 |
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16054073 |
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62291799 |
Feb 5, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 13/12 20180101; A61K 31/7072 20130101; A61K 31/513 20130101;
A61K 31/506 20130101 |
International
Class: |
A61K 31/513 20060101
A61K031/513; A61K 31/506 20060101 A61K031/506; A61K 31/7072
20060101 A61K031/7072; A61P 13/12 20060101 A61P013/12; A61P 35/00
20060101 A61P035/00 |
Claims
1. A method for treating cancer in patients with creatinine
clearance of less than 30 mL/min, comprising dividing a combination
drug containing .alpha.,.alpha.,.alpha.-trifluorothymidine (FTD)
and
5-chloro-6-[(2-iminopyrrolidine-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione
hydrochloride in a molar ratio of 1:0.5, in a dose of 30 to 50
mg/m.sup.2/day as FTD-equivalent, into two to four times a day, and
orally administering it to the patient.
2. The method for treating cancer according to claim 1, wherein the
patient is a patient with a creatinine clearance of 15 mL/min or
more and 29 mL/min or less.
3. The method for treating cancer according to claim 1, wherein a
dose of 40 mg/m.sup.2/day as FTD-equivalent is divided into twice a
day and orally administered.
4. The method for treating cancer according to claim 1, wherein the
administration schedule is 5-day consecutive oral administrations
and 2-day rest, per week.
5. The method for treating cancer according to claim 1, wherein an
administration schedule of 5-day consecutive oral administrations
and 2-day rest are repeated twice, followed by rest for 14
days.
6. The method for treating cancer according to claim 1, wherein the
cancer is gastrointestinal cancer or breast cancer.
7. The method for treating cancer according to claim 1, wherein the
cancer is large bowel cancer.
8. A therapeutic agent for treating cancer in patients with
creatinine clearance of less than 30 mL/min, wherein a combination
drug containing .alpha.,.alpha.,.alpha.-trifluorothymidine (FTD)
and
5-chloro-6-[(2-iminopyrrolidine-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione
hydrochloride in a molar ratio of 1:0.5 is orally administered to
the patient in a dose of 30 to 50 mg/m.sup.2/day as FTD-equivalent
by being divided into two to four times a day.
9. The therapeutic agent according to claim 8, wherein the patient
is a patient with a creatinine clearance of 15 mL/min or more and
29 mL/min or less.
10. The therapeutic agent according to claim 8, wherein a dose of
40 mg/m.sup.2/day as FTD-equivalent is divided into twice a day and
orally administered.
11. The therapeutic agent according to claim 8, wherein the
administration schedule is 5-day consecutive oral administrations
and 2-day rest, per week.
12. The therapeutic agent according to claim 8, wherein an
administration schedule of 5-day consecutive oral administrations
and 2-day rest are repeated twice, followed by rest for 14
days.
13. The therapeutic agent according to claim 8, wherein the cancer
is gastrointestinal cancer or breast cancer.
14. The therapeutic agent according to claim 8, wherein the cancer
is large bowel cancer.
15. A combination drug containing
.alpha.,.alpha.,.alpha.-trifluorothymidine (FTD) and
5-chloro-6-[(2-iminopyrrolidine-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione
hydrochloride in a molar ratio of 1:0.5 for treating cancer in
patients with creatinine clearance of less than 30 mL/min, wherein
the combination drug is orally administered to the patient in a
dose of 30 to 50 mg/m.sup.2/day as FTD-equivalent by being divided
into two to four times a day.
16. The combination drug according to claim 15, wherein the patient
is a patient with a creatinine clearance of 15 mL/min or more and
29 mL/min or less.
17. The combination drug according to claim 15, wherein a dose of
40 mg/m.sup.2/day as FTD-equivalent is divided into twice a day and
orally administered.
18. The combination drug according to claim 15, wherein the
administration schedule is 5-day consecutive oral administrations
and 2-day rest, per week.
19. The combination drug according to claim 15, wherein an
administration schedule of 5-day consecutive oral administrations
and 2-day rest are repeated twice, followed by rest for 14
days.
20. The combination drug according to claim 15, wherein the cancer
is gastrointestinal cancer, breast cancer or large bowel cancer.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of and claims the
benefit of priority to U.S. application Ser. No. 16/574,180, filed
Sep. 18, 2019, which is a continuation of and claims the benefit of
priority to U.S. application Ser. No. 16/054,073, filed Aug. 3,
2018, now U.S. Pat. No. 10,456,399, which is a continuation of and
claims the benefit of priority to International Application No.
PCT/JP2017/003994, filed Feb. 3, 2017, which is based upon and
claims the benefit of priority to U.S. Provisional Application No.
62/291,799, filed Feb. 5, 2016. The entire contents of all of the
above applications are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a method for treating
cancer patients with severe renal impairment.
BACKGROUND OF THE INVENTION
[0003] Trifluridine (also known as:
.alpha.,.alpha.,.alpha.-trifluorothymidine; hereinafter, also
referred to as "FTD") exhibits an antitumor effect by DNA synthesis
inhibition by thymidylate production-inhibiting action and DNA
function inhibition by incorporation into DNA. Tipiracil
hydrochloride (chemical name:
5-chloro-6-[(2-iminopyrrolidine-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione
hydrochloride; hereinafter, also referred to as "TPI") has
inhibitory effect against thymidine phosphorylase. It is known that
TPI suppresses the decomposition of FTD by thymidine phosphorylase
in the living body, thereby potentiating the antitumor effect of
FTD (Patent Literature 1).
[0004] Currently, a combination drug containing FTD and TPI in a
molar ratio of 1:0.5 (hereinafter also referred to as "FTD/TPI
combination drug") is under development as a therapeutic agent for
a solid cancer. It was approved as a therapeutic agent for advanced
and recurrent colorectal cancer in the U.S., as a trade name,
LONSURF.RTM. (trifluridine and tipiracil) tablets (Non-patent
Literature 1 and 2). The dosage and administration of the FTD/TPI
combination drug in a clinical practice are typically, for adults,
based on the body surface area, 70 mg/m.sup.2/day as FTD-equivalent
is orally administered twice a day for 5 consecutive days, followed
by rest for 2 days. This procedure is repeated twice, and followed
by rest for 14 days. It is defined that the administration is
repeated with the above procedure as one cycle.
[0005] TPI is a renal excretory drug, thus it is theoretically
considered that, when the FTD/TPI combination drug is administered
to the patients with impaired renal function, exposure to FTD can
be increased. Also in a clinical trial, as a result of comparing
the incidence of adverse events among the levels of renal
impairment, based on the creatinine clearance (hereinafter, also
referred to as "CLcr") value of the patients who had the FTD/TPI
combination drug, it is recognized that the incidence of side
effects related to myelosuppression (decrease in platelet count,
decrease in erythrocyte count, decrease in hemoglobin, decrease in
neutrophil count) tends to be higher in mild renal impairment
(CLcr: 60 to 89 mL/min) and moderate renal impairment (CLcr: 30 to
59 mL/min), as compared to normal renal function (CLcr: 90 mL/min).
The creatinine clearance (CLcr) value of the patient is calculated
using Cockcroft-Gault equation, and classified based on the
classification criteria of renal function in the Food and Drug
Administration (FDA), Guidance for Industry, Pharmacokinetics in
Patients with Impaired Renal Function--Study Design, Data Analysis,
and Impact on Dosing and Labeling. Therefore, the patients with
severe renal impairment (CLcr: 15 to 29 mL/min) have not been
applicable, thus the FTD/TPI combination drug is not administered
to the patient either in the clinical trial performed so far, and
there is no information of safety and efficacy.
[0006] Generally, it is necessary to adjust the dose or dosing
interval depending on the degree of renal function in drug
administration to the patients with renal impairment, and it is
recommended to select the dose based on pharmacokinetics (PK)
according to the FDA guidance.
[0007] However, it is not easy to perform cancer treatment that is
safer and has high effectiveness on a cancer patient with severe
renal impairment.
Non-Patent Literature
[0008] [Non-patent Literature 1] Invest New Drugs 26(5): 445-54,
2008 [0009] [Non-patent Literature 2] Lancet Oncol. 13
(10):993-1001, 2012
PATENT LITERATURE
[0009] [0010] [Patent Literature 1] WO 1996/30346
SUMMARY OF THE INVENTION
[0011] The present invention relates to provision of a method for
treating cancer of cancer patients with severe renal
impairment.
[0012] The present inventor has tried cancer treatment by an
FTD/TPI combination drug on cancer patients with severe renal
impairment with CLcr of 15 to 29 mL/min, and found that, when a
dose of 30 to 50 mg/m.sup.2 a day as FTD-equivalent is divided into
two to four times a day and orally administered, a remarkable
anticancer effect is recognized while avoiding severe side
effects.
[0013] That is, the present invention provides the following
inventions [1] to [28]:
[1] A method for treating cancer in patients with creatinine
clearance of less than 30 mL/min, including dividing a combination
drug containing .alpha.,.alpha.,.alpha.-trifluorothymidine (FTD)
and
5-chloro-6-[(2-iminopyrrolidine-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione
hydrochloride in a molar ratio of 1:0.5, in a dose of 30 to 50
mg/m.sup.2/day as FTD-equivalent, into two to four times a day, and
orally administering it to the patient; [2] The method for treating
cancer according to [1], where the patient is a patient with a
creatinine clearance of 15 mL/min or more and 29 mL/min or less;
[3] The method for treating cancer according to [1] or [2], where a
dose of 40 mg/m.sup.2/day as FTD-equivalent is divided into twice a
day and orally administered; [4] The method for treating cancer
according to any one of [1] to [3], where the administration
schedule is 5-day consecutive oral administrations and 2-day rest,
per week; [5] The method for treating cancer according to any one
of [1] to [4], where an administration schedule of 5-day
consecutive oral administrations and 2-day rest are repeated twice,
followed by rest for 14 days; and [6] The method for treating
cancer according to any one of [1] to [5], where the cancer is
gastrointestinal cancer or breast cancer. [7] The method for
treating cancer according to any one of [1] to [6], wherein the
cancer is large bowel cancer. [8] A therapeutic agent for treating
cancer in patients with creatinine clearance of less than 30
mL/min, wherein a combination drug containing
.alpha.,.alpha.,.alpha.-trifluorothymidine (FTD) and
5-chloro-6-[(2-iminopyrrolidine-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione
hydrochloride in a molar ratio of 1:0.5 is orally administered to
the patient in a dose of 30 to 50 mg/m.sup.2/day as FTD-equivalent
by being divided into two to four times a day. [9] The therapeutic
agent according to [8], wherein the patient is a patient with a
creatinine clearance of 15 mL/min or more and 29 mL/min or less.
[10] The therapeutic agent according to [8] or [9], wherein a dose
of 40 mg/m.sup.2/day as FTD-equivalent is divided into twice a day
and orally administered. [11] The therapeutic agent according to
any one of [8] to [10], wherein the administration schedule is
5-day consecutive oral administrations and 2-day rest, per week.
[12] The therapeutic agent according to any one of [8] to [11],
wherein an administration schedule of 5-day consecutive oral
administrations and 2-day rest are repeated twice, followed by rest
for 14 days. [13] The therapeutic agent according to any one of [8]
to [12], wherein the cancer is gastrointestinal cancer or breast
cancer. [14] The therapeutic agent according to any one of [8] to
[13], wherein the cancer is large bowel cancer. [15] Use of a
combination drug containing
.alpha.,.alpha.,.alpha.-trifluorothymidine (FTD) and
5-chloro-6-[(2-iminopyrrolidine-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione
hydrochloride in a molar ratio of 1:0.5 for the production of a
therapeutic agent for treating cancer in patients with creatinine
clearance of less than 30 mL/min, wherein the combination drug is
orally administered to the patient in a dose of 30 to 50
mg/m.sup.2/day as FTD-equivalent by being divided into two to four
times a day. [16] The use according to [15], wherein the patient is
a patient with a creatinine clearance of 15 mL/min or more and 29
mL/min or less. [17] The use according to [15] or [16], wherein a
dose of 40 mg/m.sup.2/day as FTD-equivalent is divided into twice a
day and orally administered. [18] The use according to any one of
[15] to [17], wherein the administration schedule is 5-day
consecutive oral administrations and 2-day rest, per week. [19] The
use according to any one of [15] to [18], wherein an administration
schedule of 5-day consecutive oral administrations and 2-day rest
are repeated twice, followed by rest for 14 days. [20] The use
according to any one of [15] to [19], wherein the cancer is
gastrointestinal cancer or breast cancer. [21] The use according to
any one of [15] to [20], wherein the cancer is large bowel cancer.
[22] A combination drug containing
.alpha.,.alpha.,.alpha.-trifluorothymidine (FTD) and
5-chloro-6-[(2-iminopyrrolidine-1-yl)methyl]pyrimidine-2,4(1H,3-
H)-dione hydrochloride in a molar ratio of 1:0.5 for treating
cancer in patients with creatinine clearance of less than 30
mL/min, wherein the combination drug is orally administered to the
patient in a dose of 30 to 50 mg/m.sup.2/day as FTD-equivalent by
being divided into two to four times a day. [23] The combination
drug according to [22], wherein the patient is a patient with a
creatinine clearance of 15 mL/min or more and 29 mL/min or less.
[24] The combination drug according to [22] or [23], wherein a dose
of 40 mg/m.sup.2/day as FTD-equivalent is divided into twice a day
and orally administered. [25] The combination drug according to any
one of [22] to [24], wherein the administration schedule is 5-day
consecutive oral administrations and 2-day rest, per week. [26] The
combination drug according to any one of [22] to [25], wherein an
administration schedule of 5-day consecutive oral administrations
and 2-day rest are repeated twice, followed by rest for 14 days.
[27] The combination drug according to any one of [22] to [26],
wherein the cancer is gastrointestinal cancer or breast cancer.
[28] The method for treating cancer according to any one of [22]to
[27], wherein the cancer is large bowel cancer.
Effect of the Invention
[0014] According to the treatment method of the present invention,
an excellent effect of treating cancer of cancer patients with
severe renal impairment is obtained without causing severe side
effects.
BRIEF DESCRIPTION OF DRAWINGS
[0015] FIG. 1 is a graph showing a relationship between creatinine
clearance and oral clearance of FTD on Day 12 after
administration.
DETAILED DESCRIPTION OF THE INVENTION
[0016] In the present invention, a combination drug containing
.alpha.,.alpha.,.alpha.-trifluorothymidine and
5-chloro-6-[(2-iminopyrrolidine-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione
hydrochloride in a molar ratio of 1:0.5 is used.
[0017] FTD and TPI are each known compounds, and can be
synthesized, for example, according to a method described in WO
1996/30346. Also, a FTD/TPI combination drug is publicly known (Non
Patent Literatures 1 and 2). In addition, the FTD/TPI combination
drug in a tablet formulation was approved as a therapeutic agent
for advanced and recurrent colorectal cancer in the U.S.
[0018] The FTD/TPI combination drug used in the present invention
should be in an orally-administrable formulation. Examples of the
formulation include tablets, coated tablets, pills, powders,
granules, capsules, solutions, suspensions, and emulsions. These
preparations can be formulated by a conventional formulation method
commonly known in the art, for example, using a pharmaceutically
acceptable carrier.
[0019] Also, it is possible to properly divide and package the
FTD/TPI combination drug, so as to divide a dose of 30 to 50
mg/m.sup.2/day into two to four times a day and administer it. The
packaging method is not particularly limited so long as it is a
conventional packaging method commonly known in the art. For
example, tablets can be packaged in a moisture proof and
deoxygenated packaging material.
[0020] Examples of the pharmaceutically acceptable carrier include
various ones which are commonly used in conventional drugs, such as
excipients, binders, disintegrators, lubricants, disintegration
inhibitors, absorption promoters, humectants, adsorbents, coating
agents, solvents, solubilizers, suspending agents, isotonic agents,
pH adjusting agents, buffering agents, stabilizers, coloring
agents, flavoring agents, and odor improving agents.
[0021] Examples of the excipients include lactose, sucrose,
D-mannitol, starch, crystalline cellulose, and calcium
silicate.
[0022] Examples of the binders include hydroxypropylcellulose,
methylcellulose, polyvinylpyrrolidone, maltose syrup powder, and
hypromellose.
[0023] Examples of the disintegrators include starch, sodium
glycolate, carmellose calcium, croscarmellose sodium, crospovidone,
low substituted hydroxy-propylcellulose, and partially
pregelatinized starch.
[0024] Examples of the lubricants include talc, magnesium stearate,
sucrose fatty acid ester, stearic acid, and sodium stearyl
fumarate.
[0025] Examples of the disintegration inhibitors include sucrose,
stearic acid, cacao butter, and hydrogenated oil.
[0026] Examples of the absorption promoters include a quaternary
ammonium base and sodium lauryl sulfate.
[0027] Examples of the humectants include glycerin and starch.
[0028] Examples of the adsorbents include starch, lactose, kaolin,
bentonite, and colloidal silicic acid.
[0029] Examples of the coating agents include ethylcellulose,
aminoalkyl methacrylate copolymer RS, hypromellose, and
sucrose.
[0030] Examples of the solvents include water, propylene glycol,
and physiological saline.
[0031] Examples of the solubilizers include polyethylene glycol,
ethanol, .alpha.-cyclodextrin, macrogol 400, and polysorbate
80.
[0032] Examples of the suspending agents include carrageenan, a
crystalline cellulose-carmellose sodium, and polyoxyethylene
hydrogenated castor oil.
[0033] Examples of the isotonic agents include sodium chloride,
glycerin, and potassium chloride.
[0034] Examples of the pH adjusting agents and buffering agents
include sodium citrate, hydrochloric acid, lactic acid, phosphoric
acid, and sodium dihydrogen phosphate.
[0035] Examples of the stabilizers include sodium pyrosulfite,
edetate sodium, erythorbic acid, magnesium oxide, and
dibutylhydroxytoluene.
[0036] Examples of the coloring agents include titanium oxide, iron
sesquioxide, Food Blue No. 1, and copper chlorophyll.
[0037] Examples of the flavoring and odor improving agents include
aspartame, saccharin, sucralose, 1-menthol, and mint flavor.
[0038] In the present invention, the FTD/TPI combination drug in a
dose of 30 to 50 mg/m.sup.2/day as FTD-equivalent is divided into
two to four times a day and orally administered.
[0039] The dose of the FTD/TPI combination drug is 30 to 50
mg/m.sup.2/day, preferably 30 to 48 mg/m.sup.2/day, preferably 35
to 45 mg/m.sup.2/day, and preferably 40 mg/m.sup.2/day, as
FTD-equivalent.
[0040] In addition, the number of administration per day is two to
four times, preferably two to three times, and more preferably
twice.
[0041] The interval between administrations is preferably 6 hours
or more.
[0042] Here, the dose to patients is determined based on the body
surface area (BSA) calculated from the patient's height and body
weight. As a method for calculating a body surface area, a
conventional method is appropriately used, depending on, for
example, the race, sex, health condition and symptom of the
patient, for example, the following calculation formulae 1 to 6,
and preferably the following 1 or 2(a).
[0043] 1. The Mosteller formula (See N Engl J Med Oct. 22, 1987;
317(17): 1098 (letter))
BSA (m.sup.2)=([Height (cm).times.Weight (kg)]/3600).sup.1/2
[0044] 2. The DuBois and DuBois formula (See Arch Int Med 1916 17:
863-71; J Clin Anesth. 1992; 4(1): 4-10)
(a)BSA (m.sup.2)=0.20247.times.Height (m).sup.0.725.times.Weight
(kg).sup.0.425
(b)BSA (m.sup.2)=0.007184.times.Height (cm).sup.0.725.times.Weight
(kg).sup.0.425
[0045] 3. The Haycock formula (See The Journal of Pediatrics 1978
93: 1: 62-66)
BSA (m.sup.2)=0.024265.times.Height (cm).sup.0.3964.times.Weight
(kg).sup.0.5378
[0046] 4. The Gehan and George formula (See Cancer Chemother Rep
1970 54: 225-35)
BSA (m.sup.2)=0.0235.times.Height (cm).sup.0.42246.times.Weight
(kg).sup.0.51456
[0047] 5. The Boyd formula (See Minneapolis: university of
Minnesota Press, 1935)
BSA (m.sup.2)=0.0003207.times.Height (cm).sup.0.3.times.Weight
(gram).sup.(0.7285-(0.0188.times.LOG(gram))
[0048] 6. The Fujimoto formula (See Nihon Eiseigaku Zasshi, 1968
23(5): 443-450)
BSA (m.sup.2)=0.008883.times.Height (cm).sup.0663.times.Weight
(kg).sup.0.444
[0049] For example, when the body surface area of a cancer patient
of 175 cm in height and 70 kg in weight is calculated using the
above calculation formula 1, the body surface area is calculated as
([175 (cm).times.70 (kg)]/3600).sup.1/2=1.84 (m.sup.2). When the
dose is 50 mg/m.sup.2/day as FTD-equivalent in the patient, the
total daily dose is calculated as 1.84.times.50=92 mg, and set to
about 92 mg.
[0050] In the present invention, the subject to be administered is
a cancer patient with CLcr of less than 30 mL/min, more preferably,
a cancer patient with CLcr of 15 mL/min or more and less than 30
mL/min, and particularly preferably, a cancer patient with CLcr of
15 mL/min or more and 29 mL/min or less.
[0051] The value of CLcr of the patient is an index of renal
function, and the patients with CLcr of 15 to 29 mL/min include the
patients with severe renal impairment (patient with severe renal
dysfunction). The patient with severe renal impairment is also
referred to as advanced renal dysfunction.
[0052] In the present invention, CLcr is calculated using
Cockcroft-Gault equation shown below.
Male: CLcr (mL/min)={(140-age).times.Weight (kg)}/{value of serum
creatinine (mg/dL).times.72}
Female: CLcr (mL/min)={(140-age).times.Weight (kg)}/{value of serum
creatinine (mg/dL).times.72}.times.0.85 [Cockcroft-Gault
equation]
[0053] Here, the value of serum creatinine can be measured by a
conventional method.
[0054] In the present invention, the administration schedule is
preferably orally administered for 5 consecutive days, followed by
rest for 2 days, per week. It is also preferred that 5-day
consecutive oral administrations and 2-day rest are repeated twice,
followed by rest for 14 days, and the administration is repeated
with this procedure as one cycle.
[0055] Examples of the cancer to be a target of the treatment
method of the present invention include head and neck cancer,
gastrointestinal cancer (e.g., esophageal cancer, gastric cancer,
duodenal cancer, liver cancer, biliary tract cancer
(gallbladder/bile duct cancer), pancreatic cancer, small intestinal
cancer, large bowel cancer (colorectal cancer, colon cancer, rectal
cancer)), lung cancer (non-small cell lung cancer, small cell lung
cancer), breast cancer, ovarian cancer, uterine cancer (cervical
cancer, endometrial cancer), renal cancer, bladder cancer, prostate
cancer, and skin cancer. The cancer includes not only a primary
tumor but also a tumor derived from a solid cancer that has
metastasized to other organs (such as liver) Among them, from the
viewpoint of antitumor effects and side effects, the target of the
treatment method of the present invention is preferably head and
neck cancer, gastrointestinal cancer, lung cancer, breast cancer,
renal cancer and skin cancer, more preferably gastrointestinal
cancer or breast cancer, more preferably esophageal cancer, large
bowel cancer and gastric cancer, and especially preferably large
bowel cancer. The treatment method of the present invention may be
postoperative adjuvant chemotherapy that is performed for
preventing the recurrence after having extracted the tumor
surgically, and also may be preoperative adjuvant chemotherapy that
is performed in advance for extracting the tumor surgically.
EXAMPLES
[0056] Next, the present invention will be explained in further
detail by way of examples. However, this invention should not be
limited to these examples in any manner, and many variations are
possible by a person with ordinary skill in the art within the
technical idea of the present invention.
(Example 1) Dose Estimation in Cancer Patients with Severe Renal
Impairment
[0057] Pharmacokinetic of FTD was studied in patients with solid
cancer including colorectal cancer, when performing a treatment of
repeating an administration schedule of orally administering an
FTD/TPI combination drug (mixture of FTD and TPI in a molar ratio
of 1:0.5) in 35 mg/m.sup.2 per once (as FTD, the same applies
hereinafter) for 5 consecutive days twice a day, followed by rest
for 2 days twice, followed by rest for 14 days, and repeating this
procedure as one cycle.
[0058] Renal function was evaluated by calculating the value of
CLcr by the Cockcroft-Gault equation before start of
administration, and the patients were assigned into groups of
control (normal, CLcr: .gtoreq.90 mL/min), mild (CLcr: 60 to 89
mL/min) and moderate (CLcr: 30 to 59 mL/min). Blood collection was
performed after administration of the FTD/TPI combination drug on
Day 1 and Day 12, at predose and at 0.5, 1, 2, 4, 6, 8, 10, 12
hours after administration, and FTD and TPI concentrations in
plasma were measured. Pharmacokinetic parameters of FTD and TPI
were calculated using the resulting concentrations in the plasma,
and the results were shown in Table 1.
TABLE-US-00001 TABLE 1 Pharmacokinetic parameters of FTD and TPI
(Cohort 0: normal, Cohort 1: mild renal impairment, Cohort 2:
moderate renal impairment) Day 1 Day 12 C.sub.max AUC.sub.0-12
t.sub.1/2 CL/F C.sub.max AUC.sub.0-12 t.sub.1/2 CL/F Compound
Cohort Subject (ng/mL) (hr*ng/mL) (hr) (L/hr) (ng/mL) (hr*ng/mL)
(hr) (L/hr) FTD 0 N 10 10 10 10 10 10 10 10 Mean 2882 7873 1.26
8.72 5235 20124 2.09 3.29 SD 1372 2819 0.38 4.20 2662 7395 0.67
1.12 CV % 47.6 35.8 30.1 48.1 50.9 36.7 32.0 33.9 1 N 12 12 12 12
11 11 11 11 Mean 3161 7292 1.79 10.08 4667 23383 2.40 4.1 SD 1363
2634 0.49 5.95 2676 13634 0.75 3.71 CV % 43.1 36.1 27.5 59.0 57.3
5E3.3 31.3 90.6 2 N 11 11 11 11 10 8 8 8 Mean 2763 8135 1.90 9.17
6014 30405 3.22 2.1 SD 1362 3556 0.43 4.86 2273 7747 1.02 0.41 CV %
49.3 43.7 22.8 53.0 37.8 25.5 31.7 19.6 TPI 0 N 10 9 9 9 10 9 9 9
Mean 46.5 234 2.04 148.5 48.8 247 2.61 128.3 SD 18.3 121 0.37 81.8
21.9 100 0.73 58.2 CV % 39.4 51.8 18.2 55.1 44.9 40.3 28.1 45.3 1 N
12 11 11 11 11 9 9 9 Mean 93.9 380 2.33 105.1 67.8 383 2.54 83.1 SD
40.9 193 0.68 86.1 27.9 105 0.73 17.5 CV % 43.5 50.9 29.3 81.9 41.1
27.5 28.7 21 2 N 11 10 10 10 10 8 8 8 Mean 100.4 494 2.42 64.8
111.7 602 2.63 62 SD 40.2 181 0.40 18.6 53.5 321 0.44 32.7 CV %
40.0 36.7 16.4 28.7 47.9 53.4 16.7 52.8
[0059] FTD is an active component showing anticancer activity in
the FTD/TPI combination drug, and TPI is a modulator to increase
the concentration of FTD in the plasma. Therefore, the FTD
concentration in the plasma after repeated administrations is most
strongly related to the effect and safety of the FTD/TPI
combination drug. The AUC.sub.0-12 of FTD in patients with mild
renal impairment (Cohort 1) and patients with moderate renal
impairment (Cohort 2) are higher by about 16% and about 51%,
respectively, as compared to that in patients with normal renal
function. Thus, the AUC of FTD increases with the deterioration of
renal function, and the need for reducing the dose of the FTD/TPI
combination drug is suggested for patient with severe renal
impairment. The elimination half-time of FTD is 2.40 hours and 3.22
hours in the patient with mild renal impairment and the patient
with moderate renal impairment, respectively, and a major
prolongation is not seen, as compared to 2.09 hours in the patients
with normal renal function. The half-time of FTD is sufficiently
short as compared to the administration interval when
administrating twice a day, 12 hours, thus the effect of the
FTD/TPI combination drug can be maintained by reducing to the
appropriate dose without changing the administration interval.
[0060] In order to determine the appropriate dose for the patients
with severe renal impairment, a regression analysis of oral
clearance (CL/F) and creatinine clearance (CLcr) of FTD on Day 12
after administration was performed. The result is shown in FIG.
1.
[0061] As shown in FIG. 1, it is possible to approximate the
relationship of both parameters to the following power function
curve.
FTD CL/F (L/hr)=0.3432.times.CLcr (mL/min).sup.0.4870
[0062] CL/F of FTD in each renal impairment level was calculated
from CLcr using this regression equation, further, the ratio of the
AUC of FTD to the patient with normal renal function was
calculated, and these results were shown in Table 2. At this time,
the ratio was calculated using a median CLcr (109 mL/min) of the
patient with normal renal function as a control (1.00). It is
suggested that the AUC of FTD when administering the FTD/TPI
combination drug to the patient with severe renal impairment in 15
mg/m.sup.2, 20 mg/m.sup.2 and 25 mg/m.sup.2 is similar to the AUC
when administering 35 mg/m.sup.2 to the patients with normal renal
function, the patients with mild renal impairment, and the patients
with moderate renal impairment. On the other hand, it is considered
that, when administering the FTD/TPI combination drug in 35
mg/m.sup.2 as it is to the patient with severe renal impairment,
the AUC of FTD is increased to more than twice of the patients with
normal renal function.
TABLE-US-00002 TABLE 2 Range of FTD oral clearance estimated from
power regression equation and range of AUC in each dose CLcr
(mL/min) FTD CL/F on Day 12 (L/hr) Dose AUC ratio to Control Min
Mid Max Min Mid Max (mg/m.sup.2) Min Mid Max Normal 90 109 3.07
3.37 35 1.10 1.00 Mild 60 75 89 2.52 2.81 3.05 35 1.34 1.20 1.10
Moderate 30 45 59 1.80 2.19 2.50 35 1.87 1.54 1.35 15 1.13 0.92
0.82 Severe 15 22.5 29 1.28 1.56 1.77 20 1.50 1.23 1.09 25 1.88
1.54 1.36
[0063] In the safety profile of this test, any of the patient with
normal renal function, the patient with mild renal impairment, and
the patient with moderate renal impairment was tolerable to 35
mg/m.sup.2 of the FTD/TPI combination drug. Therefore, any of the
AUC of FTD when administering the FTD/TPI combination drug to the
patient with severe renal impairment in 15 mg/m.sup.2, 20
mg/m.sup.2 and 25 mg/m.sup.2 is tolerable level. However, there is
a possibility that the AUC of FTD when administered in 15
mg/m.sup.2 is lower than the AUC of the patient with normal renal
function, and the effect is attenuated. On the other hand, since
renal function of the patient with severe renal impairment is
unstable, there is a possibility that the AUC of FTD exceeds the
prediction when administering in 25 mg/m.sup.2. Based on the above,
in the patient with severe renal impairment (CLcr: 15 to 29
mL/min), it is most preferred that the FTD/TPI combination drug is
administered in 20 mg/m.sup.2.
[0064] In the patient with severe renal impairment, the dose of the
FTD/TPI combination drug is reduced to 30 to 50 mg/m.sup.2/day as
FTD-equivalent, and particularly, reduced to 40 mg/m.sup.2/day as
FTD-equivalent, whereby efficacy can be expected while maintaining
safety.
* * * * *