WO2023038030A1 - 固形腫瘍治療用医薬組成物 - Google Patents
固形腫瘍治療用医薬組成物 Download PDFInfo
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Definitions
- the present invention relates to a pharmaceutical composition for treating solid tumors.
- the Wnt/ ⁇ -catenin signaling pathway is a signaling pathway that is highly conserved in the evolutionary process of animals, and regulates gene expression involved in cell proliferation and differentiation, body axis and organogenesis, etc. Abnormal activation of the Wnt/ ⁇ -catenin signaling pathway is known to occur in various cancers including colon cancer and hepatocellular carcinoma.
- GSK-3 ⁇ Glycogensynthase kinase
- Dvl Intracellular molecule
- ⁇ -catenin is released from the (catenin-beta-1) complex. Released and stabilized ⁇ -catenin translocates to the cell nucleus and forms a complex with the transcription factor TCF/LEF (T-cell factor/lymphoid enhancer factor).
- TCF/LEF transcription factor/lymphoid enhancer factor
- This complex requires the CREP binding protein (CBP) or P300 protein as a transcriptional coactivator.
- CBP CREP binding protein
- TCF/LEF Activated TCF/LEF induces expression of various genes including MYC, cyclin D, own TCF/LEF, and others.
- TCF/LEF is known to regulate gene expression by the Wnt/ ⁇ -catenin signaling pathway as a major downstream factor (eg, Patent Documents 1 and 2).
- Patent Document 1 6-S,9aS)-N-benzyl-8-( ⁇ 6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl ⁇ methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo- 2-(Prop-2-en-1-yl
- formula (I) is used as the structural formula, and (6S,9aS)-N-benzyl-8-( ⁇ 6-[3-(4-ethylpiperazin-1-yl ) azetidin-1-yl]pyridin-2-yl ⁇ methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro- 2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide is used.
- an object of the present invention is to provide a pharmaceutical composition or formulation containing compound A or a pharmaceutically acceptable salt thereof that is suitable for administration to human subjects.
- the present invention also provides a method for suppressing gastrointestinal symptoms associated with administration of compound A.
- the present invention provides the following [1] to [18] and [P1] to [P14].
- [1] (6S,9aS)-N-benzyl-8-( ⁇ 6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl ⁇ methyl represented by formula (I) )-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2 , 4]
- a pharmaceutical composition for treating solid tumors comprising triazine-1(6H)-carboxamide or a pharmaceutically acceptable salt thereof, (6S,9aS)-N-benzyl-8-( ⁇ 6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl ⁇ methyl)-6-(2-fluoro -4-hydroxy
- the gastrointestinal symptoms are (6S,9aS)-N-benzyl-8-( ⁇ 6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl) in human subjects.
- the 5- HT3 receptor antagonist is at least one selected from the group consisting of azasetron, ondansetron, indisetron, ramosetron, granisetron and palonosetron, or a pharmaceutically acceptable salt thereof [1] to [ 4], the pharmaceutical composition according to any one of the items.
- the 5-HT 3 receptor antagonist is ondansetron hydrochloride hydrate.
- the 5-HT 3 receptor antagonist is palonosetron hydrochloride.
- the gastrointestinal symptoms are (6S,9aS)-N-benzyl-8-( ⁇ 6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl) in human subjects.
- the gastrointestinal symptoms are (6S,9aS)-N-benzyl-8-( ⁇ 6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl) in human subjects. ⁇ methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1 ,2,4]triazine-1(6H)-carboxamide or gastrointestinal symptoms resulting from administration of a pharmaceutically acceptable salt thereof.
- a method of treating a solid tumor comprising: (6S,9aS)-N-benzyl-8-( ⁇ 6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl ⁇ methyl represented by formula (I) )-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2 ,4]triazine-1(6H)-carboxamide or a pharmaceutically acceptable salt thereof twice daily with (6S,9aS)-N-benzyl-8-( ⁇ 6-[3- (4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl ⁇ methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2 -en-1-yl)he
- a method of treating solid tumors while suppressing gastrointestinal symptoms comprising: (6S,9aS)-N-benzyl-8-( ⁇ 6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl ⁇ methyl represented by formula (I) )-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2 ,4]triazine-1(6H)-carboxamide or a pharmaceutically acceptable salt thereof twice daily with (6S,9aS)-N-benzyl-8-( ⁇ 6-[3- (4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl ⁇ methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2 -en
- a method of treating a solid tumor comprising: selecting a 5- HT3 receptor antagonist to suppress gastrointestinal symptoms in a human subject; (6S,9aS)-N-benzyl-8-( ⁇ 6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridine-2-) in human subjects for the treatment of solid tumors yl ⁇ methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][ 1,2,4]triazine-1(6H)-carboxamide or a pharmaceutically acceptable salt thereof co-administered with a 5- HT3 receptor antagonist; Gastrointestinal symptoms have been associated with (6S,9aS)-N-benzyl-8-( ⁇ 6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]
- [P8] The medicament according to [P7] above, wherein the gastrointestinal symptom is at least one selected from nausea and vomiting.
- [P9] The medicament of [P7] or [P8] above, wherein the 5-HT 3 receptor antagonist is administered in a daily dose of about 0.3 mg to about 8 mg.
- [P10] The medicament according to any one of [P1] to [P9], which is used for the treatment of solid cancer.
- [P11] The pharmaceutical according to [P10] above, wherein the solid cancer is gastrointestinal cancer, gastrointestinal endocrine tumor, uterine cancer, malignant melanoma, or lung cancer.
- a medicament or formulation containing compound A or a pharmaceutically acceptable salt thereof which is suitable for administration to human subjects. Also, a method for suppressing gastrointestinal symptoms associated with administration of compound A or a pharmaceutically acceptable salt thereof can be provided.
- Figure 1 is a graph showing the relationship between pharmacokinetics of compound A or a pharmaceutically acceptable salt thereof and vomiting flag, AUC of each subject at the time of Cycle1Day8 (C1D8) (AUC (0-tau), ss ) .
- FIG. 2 is a graph showing the relationship between the pharmacokinetics of compound A or a pharmaceutically acceptable salt thereof and the vomiting flag. Show relationship.
- Figure 3 is a graph showing the relationship between the pharmacokinetics of Compound A or a pharmaceutically acceptable salt thereof and the vomiting flag (relationship of the final vomiting control of the dose escalation part, including additional cases), Cycle1Day8
- FIG. 10 is a diagram showing the relationship between AUC and vomiting flag of each subject at time (C1D8).
- FIG. 10 is a diagram showing the relationship between AUC and vomiting flag of each subject at time (C1D8).
- FIG. 3 is a graph showing the relationship between the pharmacokinetics of Compound A or a pharmaceutically acceptable salt thereof and the vomiting flag (relationship of the final vomiting control of the dose escalation part, including additional cases), Cycle1Day8
- FIG. 10 is a diagram showing the relationship between Cmax and vomiting flag of each subject at time (C1D8).
- the vertical axis indicates Cmax (Cmax, ss)
- the horizontal axis indicates the vomiting flag value.
- FIG. 5 is a diagram of the final vomiting management relationship for the dose escalation part, including additional cases.
- the vertical axis indicates the dose (mg) of Compound A per administration
- the horizontal axis indicates the vomiting flag value.
- human subjects shall mean any administration group that exhibits clinical signs or symptoms of cancer.
- bioequivalent or “bioequivalence” is a term of art for therapeutic equivalence published by the U.S. Department of Health and Human Services and commonly known as the "Orange Book.” Intended to be defined in accordance with Approved Drug Products with Therapeutic Equivalence Evaluations, 34th edition.
- Bioequivalence of different formulations of the same drug substance includes equivalence with respect to rate and extent of drug absorption. To determine if the two formulations are bioequivalent, the extent and rate of absorption of the test formulation are compared to the standard formulation.
- a standard bioequivalence study consists of administering a single dose of a test drug and a reference drug to a number of volunteers, usually 12-24 healthy adults, followed by blood levels of the drug over time or Extensive testing, including measuring plasma levels, is done in a crossover fashion.
- Detailed guidelines for establishing bioequivalence of drug products have been published by the FDA, Office of Generic Drugs, Division of Bioequivalence.
- PK parameters Two formulations that differ by -20%/+25% or less in PK parameters, such as Cmax, AUC or tmax, are generally considered to be "bioequivalent".
- Another approach for mean bioequivalence involves calculating a 90% confidence interval for the ratio of the means of measurements for test and reference products (population geometric mean). In order to establish biocompatibility, the calculated confidence interval should typically fall within the range of 80-125% for the mean ratio of the product.
- other approaches including (1) logarithmic transformation of pharmacokinetic data, (2) methods to assess ordinal effects, and (3) methods to assess outlier data have been used in biology. can be useful in establishing legal equivalence. For example, in (1) above, the confidence interval should typically fall within the range of 80-125% for the difference in mean values of log-transformed PK parameters.
- pharmaceutical product refers to a means for administering a drug substance (active pharmaceutical ingredient (API)) or to facilitate the dosing, administration and delivery of a drug to patients and other mammals.
- API active pharmaceutical ingredient
- Formulations are classified in terms of route of administration and site of application, including, for example, oral, topical, rectal, vaginal, intravenous, subcutaneous, intramuscular, intraocular, intranasal, intraaural and inhalation administration.
- formulations are classified in terms of physical form, eg, solid, semi-solid, or liquid.
- the formulation is a tablet, capsule or injection as described in the Japanese Pharmacopoeia 18th Edition (JP18) or United States Pharmacopoeia - NF (37) (USP37) General Edition ⁇ 1151> Pharmaceutical formulation article It is subdivided based on its form, function and characteristics, including but not limited to.
- excipient shall mean a typical inactive ingredient used as a constituent of a formulation or pharmaceutical composition.
- a pharmacokinetic parameter eg, "mean Cmax” or “mean AUC” refers to the geometric mean value of Cmax or AUC.
- AUC Area under the plasma concentration-time curve AUC (0-tau) : Area under the plasma concentration-time curve AUC (0-inf) : In plasma from 0 hours to infinity Area under the concentration-time curve
- CL/F apparent systemic clearance after extravascular (e.g., oral) administration
- Cmax maximum observed concentration t1/2: terminal elimination half-life tmax: time taken to reach maximum (peak) concentration after drug administration
- Time Cmax, ss Maximum plasma concentration in steady state tmax, ss: Time to reach maximum plasma concentration in steady state AUC (0-tau), ss: Area under the plasma concentration-time curve for each dosing interval in steady state
- Effective t1/2 (h) effective elimination half-life Vz/F
- Ranges can be expressed using the symbol “to” as from “about” one particular value to “about” another particular value.
- the specific values that are the endpoints of each range are inclusive of that range.
- singular forms of words such as “a,””an,” and “the,” unless the context clearly dictates otherwise, include: Contains its corresponding multiple references.
- the amount of compound A or a pharmaceutically acceptable salt thereof contained in the medicament, pharmaceutical composition (also simply referred to as “pharmaceutical") or oral preparation according to the present disclosure is expressed as the amount of compound A in free form.
- a dose of about 10 mg per dose of Compound A refers to Compound A or a pharmaceutically acceptable salt thereof equivalent to about 10 mg of free form of Compound A per dose.
- an oral formulation containing about 10 mg of compound A or a pharmaceutically acceptable salt thereof is one dosage unit containing about 10 mg of compound A or a pharmaceutically acceptable salt thereof. or that the amount of Compound A or a pharmaceutically acceptable salt thereof contained in two or more dosage units can total about 10 mg.
- the dosage of the pharmaceutically acceptable salt of Compound A contained in the pharmaceutical composition or oral formulation according to the present disclosure is are given as values for the free form of Compound A.
- the amount of the pharmaceutically acceptable salt of Compound A contained in the pharmaceutical composition or oral formulation is Compound A is given as the value for the free form of
- the medicaments and pharmaceutical compositions according to the present disclosure contain compound A represented by formula (I) or a pharmaceutically acceptable salt thereof, and are used for the treatment of solid tumors (also referred to as solid cancer).
- pharmaceuticals and pharmaceutical compositions according to the present disclosure can be administered to humans in an amount of about 10 mg to about 150 mg of Compound A twice a day, or a pharmaceutically acceptable salt thereof. It is co-administered with an amount of a 5- HT3 receptor antagonist administered to a subject effective to suppress gastrointestinal symptoms resulting from administration of Compound A or a pharmaceutically acceptable salt thereof.
- the medicaments and pharmaceutical compositions according to this disclosure may be administered simultaneously with the 5- HT3 receptor antagonist or separately.
- a 5-HT 3 receptor antagonist may be administered before or after administration of the medicaments and pharmaceutical compositions of this disclosure.
- pharmaceutical compositions of this disclosure comprise both Compound A, or a pharmaceutically acceptable salt thereof, and a 5- HT3 receptor antagonist.
- a “5-HT 3 receptor antagonist” according to this disclosure means any compound or biomolecule that blocks the binding of serotonin (5-HT: 5-hydroxytryptamine) to the 5-HT 3 receptor.
- “Suppression of gastrointestinal symptoms” means partially or completely alleviating, reversing, alleviating, suppressing, reducing the severity of and/or reducing the incidence of gastrointestinal symptoms. .
- administered with a 5-HT 3 receptor antagonist or “administered with a 5-HT 3 receptor antagonist” according to the present disclosure refer to the medicament, pharmaceutical composition or oral formulation of the present disclosure and 5- This means that the HT3 receptor antagonists may be administered simultaneously or separately. Furthermore, the 5-HT 3 receptor antagonist may be administered after the human subject develops gastrointestinal symptoms associated with administration of the medicament, pharmaceutical composition or oral formulation of the present disclosure, or may be administered prophylactically in advance or It also means that they may be administered at the same time.
- an “effective amount” of a drug, compound, or 5- HT3 receptor antagonist is an amount sufficient to produce any one or more beneficial or desired results. is.
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is administered to a human subject at a dose of about 10 mg to about 150 mg per dose of Compound A, A medicament is provided that is used to be administered orally twice daily.
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is administered to a human subject twice daily at a dosage of about 10 mg to about 150 mg of Compound A per dose.
- a pharmaceutical composition for use as a single oral administration is provided, wherein said pharmaceutical composition comprises from about 7.58 h ⁇ ng/mL to about 31 h ⁇ ng/mL of Compound A after a single administration to a human subject.
- a mean AUC (0-12h) of 0.3 h ⁇ ng/mL is achieved.
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is administered to a human subject twice daily at a dosage of about 10 mg to about 150 mg of Compound A per dose.
- a pharmaceutical composition for use as a single oral administration is provided, wherein said pharmaceutical composition has a concentration of about 71.4 h*ng/mL to about 3040 h*ng/mL after a single administration to a human subject. Achieving an average AUC (0-12h) .
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is administered to a human subject twice daily at a dosage of about 10 mg to about 150 mg of Compound A per dose.
- a pharmaceutical composition for use as a single oral administration is provided, wherein said pharmaceutical composition contains from about 2.79 ng/ml to about 11.3 ng/mg of Compound A after a single administration to a human subject. A mean Cmax of /ml is achieved.
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is administered to a human subject twice daily at a dosage of about 10 mg to about 150 mg of Compound A per dose.
- a pharmaceutical composition for use as a single oral dose is provided, wherein said pharmaceutical composition achieves a mean Cmax of from about 23.5 ng/ml to about 1100 ng/ml after a single administration to a human subject. do.
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is administered to a human subject twice daily at a dosage of about 10 mg to about 150 mg of Compound A per dose.
- a pharmaceutical composition for use as a single oral administration wherein said pharmaceutical composition has an AUC (0-tau),ss of about 7700 h ⁇ ng/ mL or less.
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is administered to a human subject twice daily at a dosage of about 10 mg to about 150 mg of Compound A per dose.
- a medicament or pharmaceutical composition for oral administration is provided, wherein said medicament or pharmaceutical composition is characterized by gastrointestinal symptoms associated with administration of said medicament or Compound A or a pharmaceutically acceptable salt thereof. It is used to be administered with a 5- HT3 receptor antagonist that inhibits
- “administered with a 5-HT 3 receptor antagonist” means that a drug containing Compound A or a pharmaceutically acceptable salt thereof and a 5-HT 3 receptor antagonist are administered simultaneously or separately. It also means that the 5- HT3 receptor antagonist may be administered after the patient develops gastrointestinal symptoms, or may be administered prophylactically in advance or at the same time. .
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is administered to a human subject twice daily at a dosage of about 10 mg to about 150 mg of Compound A per dose.
- a pharmaceutical composition for use as a single oral administration is provided, wherein said pharmaceutical composition comprises at least one of nausea and vomiting associated with administration of said pharmaceutical agent or Compound A or a pharmaceutically acceptable salt thereof. It is used to be administered with a 5- HT3 receptor antagonist that inhibits one.
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 80 mg as Compound A per dose. wherein said pharmaceutical composition provides about 2.32 ng/ml to about 3.45 ng/ml per mg of Compound A after a single administration to a human subject or A mean Cmax of about 0.663 ng/ml to about 17.3 ng/ml is achieved.
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 80 mg as Compound A per dose. is provided, wherein said pharmaceutical composition is about 6.06 h ⁇ ng/mL to 9.48 h ⁇ ng/mL after a single administration to a human subject, or about A mean AUC (0-12 h) of 2.14 h ⁇ ng/mL to about 37.2 h ⁇ ng/mL is achieved.
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 100 mg as Compound A per dose. wherein said pharmaceutical composition provides about 3.54 ng/ml to about 5.54 ng/ml per mg of Compound A after a single administration to a human subject; or achieve an average Cmax of about 2.63 ng/ml to about 11.8 ng/ml.
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 100 mg as Compound A per dose.
- the pharmaceutical composition is about 11.3 h ⁇ ng/mL to about 17.8 h ⁇ ng/mL after a single administration to a human subject, or A mean AUC (0-12 h) of about 3.82 h ⁇ ng/mL to about 30.4 h ⁇ ng/mL is achieved.
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 120 mg as Compound A per dose. wherein said pharmaceutical composition provides about 3.71 ng/ml to about 5.80 ng/ml per mg of Compound A after a single administration to a human subject or A mean Cmax of about 2.02 ng/ml to about 11.5 ng/ml is achieved.
- the present invention provides that Compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 120 mg as Compound A per dose. is provided, wherein said pharmaceutical composition is about 12.7 h ⁇ ng/mL to 19.9 h ⁇ ng/mL after a single administration to a human subject, or about A mean AUC (0-12h) of 11.7 h ⁇ ng/mL to about 21.2 h ⁇ ng/mL is achieved.
- the present invention provides for gastrointestinal symptoms associated with administration of an oral formulation containing Compound A or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- Compound A or a pharmaceutically acceptable salt thereof comprising administering a 5- HT3 receptor antagonist with an oral formulation containing Compound A or a pharmaceutically acceptable salt thereof to a patient who develops and at least one pharmaceutically acceptable excipient.
- compositions for treating solid tumors are provided herein.
- a pharmaceutical composition for treating solid tumors comprising Compound A represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein Compound A or a pharmaceutically acceptable salt thereof a 5- HT3 receptor antagonist in an amount effective to suppress gastrointestinal symptoms at a dose of about 10 mg to about 150 mg as Compound A per dose, twice a day. to a human subject, wherein said gastrointestinal symptom is a gastrointestinal symptom resulting from administration of Compound A or a pharmaceutically acceptable salt thereof to the human subject.
- the gastrointestinal symptom is at least one selected from nausea and vomiting.
- Compound A or a pharmaceutically acceptable salt thereof is administered at a dosage of about 120 mg of Compound A per dose.
- compositions of this disclosure are co-administered with a 5- HT3 receptor antagonist, either simultaneously or separately.
- the 5- HT3 receptor antagonist is at least one selected from the group consisting of azasetron, ondansetron, indisetron, ramosetron, granisetron and palonosetron, or a pharmaceutically acceptable salt thereof .
- compositions of the present disclosure are co-administered with said 5-HT 3 receptor antagonist in a daily dose of about 0.1 mg to about 16 mg.
- the 5-HT 3 receptor antagonist is at least one selected from ramosetron hydrochloride and granisetron hydrochloride.
- the 5-HT 3 receptor antagonist is granisetron hydrochloride, co-administered at a dosage of about 2 mg as granisetron once daily.
- the 5- HT3 receptor antagonist is ramosetron hydrochloride, administered at a dosage of about 0.1 mg as ramosetron once daily.
- Compound A or a pharmaceutically acceptable salt thereof is Compound A.
- Compound A of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a solid tumor comprising: 5-HT 3 receptor in an amount effective to suppress gastrointestinal symptoms, at a dose of from about 10 mg to about 150 mg of Compound A per dose, twice daily, at a dose of the 5-HT 3 receptor that is pharmaceutically acceptable; Compound A or a pharmaceutically acceptable compound thereof administered in combination with an antagonist to a human subject, wherein said gastrointestinal symptoms are gastrointestinal symptoms associated with administration of Compound A or a pharmaceutically acceptable salt thereof to the human subject Provide the salt that is used.
- An HT3 receptor antagonist is co-administered to a human subject, wherein said gastrointestinal symptom is a gastrointestinal symptom resulting from administration of Compound A or a pharmaceutically acceptable salt thereof to the human subject.
- a method of treating a solid tumor comprises administering Compound A represented by Formula (I), or a pharmaceutically acceptable salt thereof, twice daily to administering to a human subject at a dose of about 10 mg to about 150 mg as A; and co-administering to said human subject an amount of a 5- HT3 receptor antagonist effective to suppress gastrointestinal symptoms.
- said gastrointestinal symptom is a gastrointestinal symptom resulting from administration of Compound A or a pharmaceutically acceptable salt thereof to a human subject.
- a method of administering Compound A or a pharmaceutically acceptable salt thereof to a human subject comprising: to a human subject at a dosage of about 10 mg to about 150 mg of Compound A twice daily, and an amount of 5- HT3 receptor effective to suppress gastrointestinal symptoms. co-administering a body antagonist to said human subject, wherein said gastrointestinal symptom is a gastrointestinal symptom resulting from administration of Compound A or a pharmaceutically acceptable salt thereof to said human subject. do.
- a method of treating solid tumors while suppressing gastrointestinal symptoms comprises administering Compound A represented by Formula (I), or a pharmaceutically acceptable salt thereof, for 1 day administering to a human subject two doses of from about 10 mg to about 150 mg of Compound A per dose, and administering to said human subject an amount of a 5- HT3 receptor antagonist effective to suppress gastrointestinal symptoms; wherein said gastrointestinal symptoms are gastrointestinal symptoms resulting from administration of Compound A or a pharmaceutically acceptable salt thereof to a human subject.
- Compound A represented by Formula (I) or a pharmaceutically acceptable salt thereof
- a method of treating solid tumors wherein a 5- HT3 receptor antagonist is selected to suppress gastrointestinal symptoms in a human subject; in which Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a 5- HT3 receptor antagonist, and gastrointestinal symptoms are associated with administration of Compound A or a pharmaceutically acceptable salt thereof to a human subject. and wherein the gastrointestinal symptoms are suppressed in a human subject.
- a pharmaceutical composition is one that is administered to a human subject.
- an oral formulation is a formulation administered by the oral route.
- a medicament, pharmaceutical composition or oral formulation according to the present invention can be produced by mixing at least one pharmaceutically acceptable excipient with compound A or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition according to the present invention can be prepared by a known method such as the method described in, for example, the Japanese Pharmacopoeia 18th Edition (JP) General Rules for Formulations, United States Pharmacopoeia-NF (37) (USP37) General Edition ⁇ 1151> Pharmaceutical Preparations can be manufactured according to
- Compound A inhibits the ⁇ -catenin-CBP interaction, a critical step downstream of the Wnt/ ⁇ -catenin signaling pathway, whereas ⁇ -catenin-P300 interaction It is known to modulate TCF/LEF activity dependent on the Wnt/ ⁇ -catenin signaling pathway (eg WO2015/098853, WO2016/208576).
- the APC gene and CTNNB1 gene are known as genes related to the Wnt signaling pathway.
- the APC gene exists on the long arm of chromosome 5 and is considered to be one of the causative genes of familial adenomatous polyposis (FAP).
- the CTNNB1 gene is a gene encoding ⁇ -catenin.
- the pharmaceutical composition or oral formulation may be more suitable for administration to human subjects having genetic mutations involved in WNT signaling, typified by genetic abnormalities in APC or CTNNB1.
- Compound A or a pharmaceutically acceptable salt thereof can be prepared by methods known in the art, such as International Publication No. 2015/098853 and International Publication No. 2016/208576.
- pharmaceutically acceptable salt is not particularly limited as long as it forms a salt with the compound represented by formula (I) and is pharmaceutically acceptable. Examples include, but are not limited to, inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, acidic or basic amino acid salts, and the like.
- Compound A or a pharmaceutically acceptable salt thereof includes, for example, Compound A, namely (6S,9aS)-N-benzyl-8-( ⁇ 6-[3- (4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl ⁇ methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2 -en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide.
- Oral preparations can usually contain 0.001 to 99.5% by mass, preferably 0.001 to 90% by mass of compound A.
- cancer refers to the physiological condition in mammals that is typically characterized by unregulated cell growth.
- the pharmaceutical composition or oral formulation according to this embodiment can be effective in treating solid tumors (also referred to as solid cancers).
- the solid tumors are usually abnormal growths or masses of tissue that do not contain cysts or fluid regions.
- Examples of solid tumors include gastrointestinal cancer (e.g., esophageal cancer, stomach cancer, pancreatic cancer, biliary tract cancer, colon cancer, small intestine cancer, liver cancer), gastrointestinal endocrine tumors, uterine cancer, malignant melanoma, and lung cancer. .
- a pharmaceutical composition or oral formulation according to this embodiment may be particularly useful for treating gastrointestinal cancer.
- the pharmaceutical composition or oral formulation according to this embodiment is particularly useful for treatment of colon cancer, small intestine cancer, and gastrointestinal endocrine tumors.
- the "subject", "human subject” or “patient” to whom the pharmaceutical composition or oral formulation is administered is a human subject in need thereof, preferably a solid tumor (solid cancer) as described above. Patients who have or are likely to have
- the dosage of the medicament, pharmaceutical composition or oral preparation is about 10 mg to about 150 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 45 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 150 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 45 mg, about 20 mg to about 30 mg, about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 30 mg to about 100 mg, about 30 mg to about 80 mg, about 30 mg to about 45 mg, about 45 mg to about 150 mg, about 45 mg to about 120 mg, about 45 mg about 100 mg, about 45 mg to about 80 mg, about 80 mg to about 150 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 80 mg, about 100 mg, or about 120 mg of Compound A.
- the dose per dose of the medicament, pharmaceutical composition or oral preparation is less than 160 mg of Compound A.
- the dose per dose is preferably about 80 mg, about 100 mg, or about 120 mg as compound A, more preferably about 100 mg or about 120 mg as compound A.
- the dosage of Compound A or a salt thereof is about 120 mg of Compound A per dose.
- the daily dose of Compound A is about 10 mg to about 300 mg, preferably about 20 mg to about 280 mg, about 160 mg to about 240 mg, or about 200 mg to about 240 mg, more preferably about 200 mg, or about 240 mg.
- the daily dose of the pharmaceutical composition or oral formulation is less than 320 mg of Compound A.
- the medicament, pharmaceutical composition or oral formulation is particularly preferably used at a dose of about 80 mg to about 120 mg of Compound A per dose, twice daily. If the dose per dose is 160 mg or more as compound A, it tends to be difficult to suppress gastrointestinal symptoms associated with (caused by) administration of compound A or a pharmaceutically acceptable salt thereof. . Therefore, the dose per administration is less than 160 mg as Compound A.
- the results of non-clinical studies and the like suggest that Compound A may have the risk of cardiotoxicity and drug-drug interactions (DDI) when its blood concentration increases. Therefore, it is preferable to administer the drug twice a day because the risk is further reduced by lowering the Cmax and the currently estimated half-life is short.
- the medicament, pharmaceutical composition or oral preparation according to this embodiment has an average Cmax of compound A of about 23.5 ng / mL to about 1100 ng / mL when blood is collected after a single administration to a human subject. preferably reached.
- the mean Cmax of Compound A after a single dose is from about 29.8 ng/mL to about 870 ng/mL, from about 66 ng/mL to about 1100 ng/mL, from about 223 ng/mL to about 696 ng/mL, or from about 279 ng/mL More preferably, it reaches within the range of about 557 ng/mL.
- the pharmaceutical composition, pharmaceutical composition, or oral preparation according to this embodiment has an average AUC (0-12 h) of compound A of about 71.4 h ng/mL to about It is preferable to reach within the range of 3040 h ⁇ ng/mL.
- the mean Cmax of Compound A after a single dose was about 89.2 h ⁇ ng/mL to about 2430 h ⁇ ng/mL, about 105 h ⁇ ng/mL to about 2980 h ⁇ ng/mL, about 214 h ⁇ ng/mL to about More preferably, it reaches within the range of 2430 h ⁇ ng/mL, from about 606 h ⁇ ng/mL to about 2390 h ⁇ ng/mL, or from about 758 h ⁇ ng/mL to about 1920 h ⁇ ng/mL.
- AUC (0-12h) is the area under the curve plotting changes in plasma concentration over time up to 12 hours after administration.
- the average Cmax of compound A reaches within the range of about 50 ng / mL to about 2000 ng / mL. is preferred.
- the mean Cmax of Compound A after 8 consecutive days of administration is about 12.6 ng/mL to about 2140 ng/mL, about 318 ng/mL to about 2140 ng/mL, about 43.1 ng/mL to about 1150 ng/mL, or about 589 ng /mL to about 1080 ng/mL.
- the medicament, pharmaceutical composition, or oral preparation according to this embodiment has an average AUC (0-tau), ss of about 45.4 h ng/ It is preferred to reach within the range of mL to about 9550 h ⁇ ng/mL.
- the mean AUC (0-tau), ss of Compound A after repeated dosing for 8 days was about 56.7 h ⁇ ng/mL to about 7640 h ⁇ ng/mL, about 56.7 h ⁇ ng/mL to about 7640 h ⁇ ng/mL.
- AUC (0-tau),ss is the area under the plasma concentration-time curve per dosing interval at steady state.
- the average AUC (0-tau), ss of compound A is about 9000 h ng / mL or less, about It is preferably 8000 h ⁇ ng/mL or less, about 7700 h ⁇ ng/mL or less, or about 7640 h ⁇ ng/mL or less.
- the medicament or oral formulation according to this embodiment has an average AUC (0-tau),ss of about 7640 h ng/ mL or less. Gastrointestinal symptoms associated with administration of the pharmaceutical composition or oral preparation according to the present embodiment can be suppressed, and the physical and mental burden on human subjects tends to be reduced.
- the pharmaceutical or pharmaceutical composition has a mean AUC of about 7.58 h*ng/mL to about 31.3 h*ng/mL (0-12 h*ng/mL) per mg of Compound A after a single administration to a human subject. ) , preferably a daily dose administered orally twice per day.
- the pharmaceutical composition achieves a mean AUC (0-12 h) per mg of Compound A of from about 7.58 h ⁇ ng/mL to about 19.9 h ⁇ ng/mL after a single administration to a human subject. and more preferably a daily dose administered orally twice daily.
- the pharmaceutical or pharmaceutical composition achieves a mean Cmax of from about 2.79 ng/ml to about 11.3 ng/ml of Compound A per mg of Compound A after a single administration to a human subject.
- a daily dose administered orally twice per day is preferred.
- the pharmaceutical composition is administered 2 times per day at a dose to achieve a mean Cmax of from about 2.79 ng/ml to about 5.54 ng/ml per mg of Compound A after a single administration to a human subject. Even more preferred is a daily dose administered orally in single doses.
- the upper limit of 150 mg BID can be estimated from the value of 120 mg BID or 100 mg BID obtained in Examples, or by calculating the value of 1 mg as Compound A. It is also possible to consider the minimum value or maximum value obtained as individual data for the same dosage as the lower limit value or maximum value of the range, respectively, and set the range based on these values.
- a medicament, pharmaceutical composition or oral formulation according to this embodiment may be used to be administered with a 5-HT 3 receptor antagonist.
- Administration of the above pharmaceutical composition or oral formulation may cause gastrointestinal symptoms in the patient.
- preferred gastrointestinal symptoms in this embodiment are nausea and vomiting.
- Nausea or vomiting, which are gastrointestinal symptoms associated with administration of the pharmaceutical composition or oral preparation according to this embodiment, can be suppressed by administering a 5- HT3 receptor antagonist, but other antiemetic agents It is difficult to suppress.
- a 5-HT 3 receptor antagonist may be administered.
- a medicament, pharmaceutical composition or oral formulation comprising Compound A or a pharmaceutically acceptable salt thereof may be administered simultaneously or separately with the 5- HT3 receptor antagonist.
- a medicament, pharmaceutical composition or oral formulation containing Compound A or a pharmaceutically acceptable salt thereof may be a kit that separately comprises a 5-HT 3 receptor antagonist.
- administered with a 5-HT 3 receptor antagonist or “administered in combination with a 5-HT 3 receptor antagonist” refers to a pharmaceutical containing compound A or a pharmaceutically acceptable salt thereof, It means that the pharmaceutical composition or oral formulation and the 5- HT3 receptor antagonist may be administered simultaneously or separately. That is, the 5-HT 3 receptor antagonist is a compound A or a pharmaceutical composition or oral formulation containing a pharmaceutically acceptable salt thereof, the patient administered the pharmaceutical composition or oral formulation according to the present embodiment It may be administered after the appearance of gastrointestinal symptoms associated with administration, or it may be administered prophylactically before or simultaneously with the administration of the pharmaceutical composition or oral preparation.
- administered at the same time in “administered at the same time or separately” means that two subjects administered in combination are administered at the same time, or substantially at substantially the same time, simultaneously administered by the same route of administration, and simultaneously or substantially simultaneously, by different routes of administration separately administration do.
- “administered at the same time” includes the case where two subjects are administered as one formulation.
- “administered separately” of “administered at the same time or separately” means that two subjects administered in combination are administered at different times ( It means to be administered at the different times (sequential administration).
- “Separately administered” also includes cases where the dosing regimens for the two subjects differ in dosing frequency or dosing duration.
- a 5-HT 3 receptor antagonist is a compound that antagonizes the 5-HT 3 receptor with serotonin (5-HT: 5-hydroxytryptamine) as a ligand.
- 5-HT 3 receptor antagonists used in combination with the medicaments, pharmaceutical compositions or oral preparations according to this embodiment include 5-HT 3 receptor antagonistic antiemetic agents.
- 5- HT3 receptor antagonistic antiemetic agents include, for example, azasetron hydrochloride, ondansetron hydrochloride hydrate, granisetron hydrochloride, palonosetron hydrochloride, dolasetron, ramosetron hydrochloride, tropisetron hydrochloride.
- Examples of 5-HT 3 receptor antagonists used in combination with the pharmaceutical composition or oral preparation of this embodiment include azasetron, ondansetron, indisetron, ramosetron, granisetron and palonosetron, or pharmaceutically acceptable salts thereof. etc.
- the 5- HT3 receptor antagonist is ondansetron hydrochloride hydrate, ramosetron hydrochloride, granisetron hydrochloride, or palonosetron hydrochloride, preferably ramosetron hydrochloride or granisetron hydrochloride. is more preferred.
- the 5- HT3 receptor antagonist is, for example, ondansetron hydrochloride hydrate.
- the 5- HT3 receptor antagonist is, for example, ramosetron hydrochloride or granisetron hydrochloride. In some other embodiments, the 5-HT 3 receptor antagonist is, for example, palonosetron hydrochloride.
- Ondansetron hydrochloride dihydrate (CAS Registry Number: 103639-04-9) is the generic name and the chemical name is ( ⁇ )-2,3-dihydro-9-methyl-3-[(2- Methylimidazol-1-yl)methyl]carbazol-4(1H)-one hydrochloride dihydrate (( ⁇ )-2,3-dihydro-9-methyl-3-[(2-methylimidazol-1-yl) methyl]carbazol-4(1H)-one monohydrochloride dihydrate) and has the following structural formula.
- Granisetron hydrochloride (CAS Registry Number: 107007-99-8) is the generic name and the chemical name is 1-methyl-N-(endo-9-methyl-9-azabicyclo[3.3.1]non-3 1-Methyl-N-(endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carbboxamide hydrochloride It is a compound of the following structural formula.
- Ramosetron hydrochloride (CAS Registry Number: 132907-72-3) is a generic name, and its chemical name is (-)-(R)-5-[(1-methyl-3-1H-indole-3- yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride ((-)-(R)-5-[(1-Methyl-1H-indol-3-yl)carbonyl]-4 ,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride) and has the following structural formula.
- Palonosetron hydrochloride (CAS Registry Number: 135729-62-3) is the generic name and the chemical name is (3aS)-2-[(3S)-quinuclidin-3-yl]-2,3,3a,4, 5,6-hexahydro-1H-benzo[de]isoquinolin-1-one hydrochloride ((3aS)-2-[(3S)-Quinuclidin-3-yl]-2,3,3a,4,5,6- hexahydro-1H-benzo[de]isoquinolin-1-one monohydrochloride) and has the following structural formula.
- This embodiment administers to a human subject a medicament, pharmaceutical composition or oral formulation containing Compound A or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. It also has an aspect of a method for treating solid tumors (solid cancer), including.
- Another embodiment of the present invention provides a method for treating 5- HT3 receptors in patients who develop gastrointestinal symptoms associated with administration of a drug, pharmaceutical composition or oral formulation containing Compound A or a pharmaceutically acceptable salt thereof.
- compositions of the present disclosure administer Compound A or a pharmaceutically acceptable salt thereof twice daily to human subjects with solid tumors at a dosage of about 10 mg to about 150 mg of Compound A per dose. and co-administering to said human subject an amount of a 5- HT3 receptor antagonist effective to suppress gastrointestinal symptoms.
- the gastrointestinal symptoms result from administration of Compound A or a pharmaceutically acceptable salt thereof to a human subject.
- Gastrointestinal symptoms when a human subject develops gastrointestinal symptoms such as nausea or vomiting following administration of a drug, pharmaceutical composition or oral preparation containing Compound A or a pharmaceutically acceptable salt thereof Gastrointestinal symptoms can be suppressed by administering a receptor antagonist.
- inhibiting means partially or completely alleviating, reversing, alleviating, abrogating, reducing the severity of and/or reducing the incidence of gastrointestinal symptoms.
- a 5-HT 3 receptor antagonist may be administered orally or parenterally.
- Dosage forms of 5-HT 3 receptor antagonists include, for example, tablets, powders, granules, syrups, capsules and oral liquids.
- Dosage forms of 5-HT 3 receptor antagonists for parenteral administration include, for example, injections, drips, suspensions, poultices, lotions, aerosols, plasters, etc.
- a 5- HT3 receptor antagonist according to the present disclosure can be formulated, for example, by methods described in the Japanese Pharmacopoeia 18th Edition (JP), the United States Pharmacopoeia (USP), or the European Pharmacopoeia (EP). can.
- Dosages for 5-HT 3 receptor antagonists range from about 0.1 mg to about 100 mg as a daily dose. In some embodiments, the dosage of 5-HT 3 receptor antagonist is from about 0.1 mg to about 16 mg as a daily dose. In some embodiments the dosage is from about 0.3 mg to about 8 mg.
- the dose varies depending on the age of the subject and the degree of symptoms. In the case of marketed ethical drugs, administration according to the dosage and administration described in the package insert can more reliably suppress gastrointestinal symptoms associated with administration of the pharmaceutical composition or oral preparation of the present disclosure. .
- ondansetron hydrochloride hydrate When ondansetron hydrochloride hydrate is administered as a 5-HT 3 receptor antagonist, for example, about 4 mg of ondansetron is administered orally or intravenously once a day. In another embodiment, when ondansetron hydrochloride hydrate is administered, for example, ondansetron is administered orally at a dosage of about 24 mg once daily, or about 8 mg twice daily. In other embodiments, for example, about 8 mg, or about 0.15 mg/kg is administered intravenously. The dosage may be adjusted appropriately depending on the age and symptoms of the subject. In addition, if the effect is insufficient, the same dose can be additionally administered.
- granisetron hydrochloride When granisetron hydrochloride is administered as a 5-HT 3 receptor antagonist, for example, about 40 ⁇ g/kg of granisetron is intravenously injected or dripped once a day. In another embodiment, when granisetron hydrochloride is administered, for example, about 1 mg or about 0.01 mg/kg of granisetron can be administered intravenously. The dosage may be adjusted according to age and symptoms, but if the symptoms are not improved, an additional dose of about 40 ⁇ g/kg can be administered once. When granisetron hydrochloride is administered as a 5-HT 3 receptor antagonist, for example, granisetron is orally administered at a dose of about 2 mg once a day, or at a dose of about 1 mg twice a day.
- granisetron hydrochloride when administered, for example, it can be administered in a patch of about 52 cm 2 containing about 34.3 mg of granisetron (transdermal system). The dosage may be adjusted appropriately according to age and symptoms.
- ramosetron hydrochloride When ramosetron hydrochloride is administered as a 5-HT 3 receptor antagonist, for example, about 0.3 mg of ramosetron hydrochloride is intravenously administered once a day. The dosage should be adjusted according to age and symptoms. In addition, if the effect is insufficient, the same dose can be additionally administered. However, it should not exceed about 0.6 mg as a daily dose.
- ramosetron hydrochloride When ramosetron hydrochloride is administered as a 5-HT 3 receptor antagonist, it may be administered orally, for example, at a dose of about 0.1 mg as ramosetron once a day. The dosage may be adjusted appropriately according to age and symptoms. The dosage may be adjusted appropriately according to age and symptoms.
- palonosetron hydrochloride When palonosetron hydrochloride is administered as a 5-HT 3 receptor antagonist, for example, about 0.75 mg of palonosetron may be intravenously administered once a day, or about 0.5 mg may be orally administered. . In another embodiment, when palonosetron hydrochloride is administered, for example, about 0.25 mg of palonosetron hydrochloride may be administered intravenously or orally. The dosage may be adjusted appropriately according to age and symptoms.
- dolasetron mesylate as a 5-HT 3 receptor antagonist
- about 1.8 mg/kg or about 100 mg may be administered orally once daily.
- the dosage may be adjusted appropriately according to age and symptoms.
- tropisetron hydrochloride When tropisetron hydrochloride is administered as a 5-HT 3 receptor antagonist, for example, it may be administered orally or intravenously at a dose of about 5 mg as tropisetron. The dosage may be adjusted appropriately according to age and symptoms.
- This embodiment is a pharmaceutical composition for treating solid tumors comprising Compound A or a pharmaceutically acceptable salt thereof, wherein Compound A or a pharmaceutically acceptable salt thereof is administered twice daily, once A dose of about 10 mg to about 150 mg of Compound A per dose is administered to a human subject in combination with an amount of a 5- HT3 receptor antagonist that suppresses gastrointestinal symptoms, wherein said gastrointestinal symptoms are associated with the administration of Compound A to the human subject. or a pharmaceutical composition for gastrointestinal symptoms associated with administration of a pharmaceutically acceptable salt thereof.
- a pharmaceutical composition for treating solid tumors comprising Compound A or a pharmaceutically acceptable salt thereof, wherein Compound A or a pharmaceutically acceptable salt thereof is administered twice daily is administered to a human subject at a dose of about 120 mg per dose of Compound A in combination with an amount of a 5-HT3 receptor antagonist that suppresses gastrointestinal symptoms, wherein said gastrointestinal symptoms are compound A or Provided is a pharmaceutical composition which is at least one selected from nausea and vomiting associated with administration of a pharmaceutically acceptable salt thereof.
- the “amount that suppresses gastrointestinal symptoms” includes, for example, a daily dose of about 0.1 mg to about 100 mg.
- the "5-HT3 receptor antagonist" herein includes, for example, at least one selected from ondansetron hydrochloride hydrate, ramosetron hydrochloride and granisetron hydrochloride.
- the "gastrointestinal symptom-suppressing amount of a 5- HT3 receptor antagonist” includes, for example: (a) ondansetron at a dose of about 4 mg once daily as ondansetron (b) granisetron hydrochloride at a dose of about 2 mg as granisetron once a day; (c) ramosetron hydrochloride at a dose of about 0.1 mg once a day as ramosetron, and the like. .
- a pharmaceutical composition for treating solid tumors comprising Compound A or a pharmaceutically acceptable salt thereof, wherein Compound A or a pharmaceutically acceptable salt thereof is administered twice daily, at a dose of about 120 mg as Compound A per dose in combination with ondansetron hydrochloride hydrate at a dose of about 4 mg once daily as ondansetron, wherein said gastrointestinal symptoms are induced in a human subject; and nausea and vomiting associated with administration of compound A of or a pharmaceutically acceptable salt thereof.
- a pharmaceutical composition for treating solid tumors comprising Compound A or a pharmaceutically acceptable salt thereof, wherein Compound A or a pharmaceutically acceptable salt thereof is administered twice daily, administered in combination with granisetron hydrochloride at a dose of about 2 mg as granisetron once daily to a human subject at a dose of about 120 mg as Compound A per dose, wherein said gastrointestinal symptoms are reduced by administration of Compound A to a human subject; or at least one selected from nausea and vomiting associated with administration of a pharmaceutically acceptable salt thereof.
- a pharmaceutical composition for treating solid tumors comprising Compound A or a pharmaceutically acceptable salt thereof, wherein Compound A or a pharmaceutically acceptable salt thereof is administered twice daily, in combination with ramosetron hydrochloride at a dose of about 0.1 mg as ramosetron once daily to a human subject at a dose of about 120 mg as Compound A per dose, wherein the gastrointestinal symptoms are provided is a pharmaceutical composition which is at least one selected from nausea and vomiting associated with administration of Compound A or a pharmaceutically acceptable salt thereof to patients.
- This study was conducted as an open-label phase 1 clinical study on Compound A.
- the study consisted of a dose escalation part evaluating the safety and tolerability of Compound A and an expansion part evaluating the safety, tolerability and preliminary efficacy of Compound A.
- Each dose in the Examples is expressed as a dose of Compound A in free form.
- Investigational drug Tablets containing compound A were used as the investigational drug.
- Compound A was synthesized according to the method of WO2016/208576.
- selection criteria (1)Patients who are histologically or cytologically diagnosed with solid cancer and meet the following criteria.
- ⁇ Dose escalation part patients with solid tumors, including patients with advanced, unresectable or recurrent colorectal cancer with no standard therapy or no other effective therapy
- ⁇ Expansion part 3rd line or later advanced, unresectable or recurrent disease patients with colorectal cancer, or patients with gastrointestinal cancer such as small bowel cancer and gastrointestinal neuroendocrine tumors after at least one regimen of systemic anticancer drug treatment after discussion and agreement with the sponsor
- Dosage Incremental part Patients with colorectal cancer are required to have a biopsy and submit archival tumor specimens (if archived)
- Extended part Patients with biopsyable disease are required to have a biopsy.
- test again Males of reproductive potential and females of childbearing potential , Patients who do not agree to use a medically appropriate contraceptive method Note) for 90 days for men and 30 days for women after the study period and the administration of Compound A (17) Patients with a history of administration of Compound A a patient
- the dose titration part evaluated the safety and tolerability of Compound A at multiple doses using a 3+3 design.
- the starting dose of Compound A was set at 10 mg BID (twice daily).
- Dose Escalation Part Dose considered tolerable from the results of the dose escalation part or the optimal dose based on PK or PD analysis was examined in the extension part.
- DLTs are adverse events considered causally related to Compound A and are the following events that occurred during Cycle 1 (28 days). NCI CTCAE v5.0 was used to assess severity.
- Non-hematological toxicity ⁇ Grade ⁇ 4 events ⁇ Clinically Significant Grade 3 events (excluding diarrhea, nausea and vomiting that resolve to Grade 0-1 within 7 days with appropriate treatment) ⁇ Grade 3 osteoporosis ⁇ Among Grade 2 or higher bone fragility fractures, events without a history of trauma or events due to falls from a height below height ⁇ Fasting serum type I collagen cross
- Table 1 shows the background of the administration subjects. Most subjects (82.1%) had an ECOG (Eastern Cooperative Oncology Group) performance status of 0. Subjects with mutations in NRAS, KRAS, APC, CTNNB1 were also included. Note that Table 1 does not include the background of subjects administered Compound A at a dosage of 120 mg BID.
- Administration method [early period of administration] In the pre-dose period, informed consent was obtained from subjects and baseline assessments were performed to confirm eligibility screening and disease status. After screening, patients who met all inclusion criteria and did not meet any exclusion criteria were enrolled as subjects for treatment. Baseline evaluations are performed from 3 days before administration of Compound A to immediately before administration, and the disease state is confirmed before transitioning to the dosing phase.
- administering period In the administration period, compound A (oral formulation containing compound A) is administered to the administration subject with 28 days as one cycle. Subjects continued to receive Compound A until disease progression, intolerable side effects, subject withdrawal, consent withdrawal, or sponsor termination of the study. 28 days of administration is defined as one cycle, and notation such as "C1D28" indicates the number of cycles and the number of days in the cycle, for example, "C1D28" means the 28th day of cycle 1 (first cycle). . Subjects were hospitalized until C1D28, and were examined and tested at C1D15, and were allowed to leave the hospital if the investigator or subinvestigator determined that there were no medical problems based on the results. In addition, if the administration was to be continued after the examination and examination at the time of C2D1, written consent for continuation was obtained before the administration at the time of C2D1.
- Compound A tablets containing Compound A are used and repeatedly administered orally twice a day (BID). Food was fasted 2 hours before and 1 hour after administration. The tablets were taken with water, and whenever possible, they were taken at the prescribed time, but when it was difficult to do so, they were taken at least 8 hours after the previous administration.
- the tolerability analysis was performed on the DLT analysis target population (subjects who received the study drug as planned in Cycle 1 in the dose escalation part, and those who did not observe DLT regardless of compliance with Compound A administration). Other safety analyzes were performed using the safety analysis set (subjects who received at least one dose of the study drug. This includes all safety evaluations (excluding DLT evaluations). ) was performed using the analysis target population).
- Laboratory test values include hematological tests (red blood cell count, hemoglobin, hematocrit value, platelet count, white blood cell count, white blood cell differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils) coagulation test: INR), blood biochemical tests (liver function tests (AST, ALT, ALP, GGT, total bilirubin, direct bilirubin), renal function tests (BUN, creatinine), other tests (blood sugar, albumin, cholesterol, LDH, total Protein, uric acid, amylase, lipase, Na, K, Cl, Ca, phosphorus, Mg Virus test: HBs antigen a, HBs antibody a, HBc antibody a, HCV antibody a, HIV antibody a, HBV DNAb, ⁇ -CTXc, 25 Hydroxyvitamin Dd), urinalysis (pH, protein, sugar, ketone bodies, occult blood, specific gravity)) were measured.
- Tables 8 and 9 show side effects occurring after administration of Compound A, ie, treatment-emergent adverse events (TEAEs) causally related to Compound A.
- TEAEs treatment-emergent adverse events
- the figures in parentheses are the percentage of subjects in whom adverse events were observed for all 28 administration subjects listed in Table 1.
- a high rate of nausea and vomiting was found to be observed at all doses from 10 mg BID to 160 mg BID.
- Tables 8 and 9 do not include data from subjects administered with a dosage of 120 mg BID.
- Antiemetics include domperidone (5-HT 1A receptor antagonist, Nauzelin tablets), metoclopramide (peripheral D2 receptor antagonist, metoclopramide tablets), ramosetron hydrochloride (5- HT3 receptor antagonist, Nazea tablets ), granisetron (5- HT3 receptor antagonist, Kytril tablets), etc. were used.
- the highest value for AUC (0-tau),ss at C1D8 was 7640 h ⁇ ng/mL in subjects who were able to suppress vomiting after administration of a 5-HT 3 receptor antagonist.
- the lowest value for AUC (0-tau),ss at C1D8 was 9060 h ⁇ ng/mL in subjects in whom vomiting could not be suppressed by administration of a 5-HT 3 receptor antagonist.
- AUC (0-tau) When AUC (0-tau), ss at the time of C1D8 is 7640 h ng/mL or less, administration of 5-HT 3 receptor antagonist accompanied by administration of compound A or a pharmaceutically acceptable salt thereof It was predicted that gastrointestinal symptoms could be suppressed.
- AUC (0-tau) ss at the time of C1D8 is 9060 h ng/mL or more, even if a 5-HT 3 receptor antagonist is administered, administration of compound A or a pharmaceutically acceptable salt thereof It was predicted that the accompanying gastrointestinal symptoms, ie nausea or vomiting, could not be controlled. That is, at 160 mg BID, administration of a 5-HT 3 receptor antagonist was highly likely not to suppress gastrointestinal symptoms associated with administration of compound A or its pharmaceutically acceptable salt. Therefore, the recommended dose was determined to be less than 160 mg BID. The recommended amount is about 80 mg to about 120 mg, and 100 mg BID or 120 mg BID was considered particularly preferable.
- FIG. 1 and 2 are graphs showing the relationship between Cmax (Cmax, ss) or AUC (AUC (0-tau), ss ) and vomiting flag for each subject at the time of C1D8.
- Vomiting flags are as described in Table 10.
- emesis flag 3 was initially treated with an antiemetic drug other than a 5-HT 3 receptor antagonist, but vomiting could not be suppressed, and when switched to a 5-HT 3 receptor antagonist, it was suppressed. means.
- Table 13 shows the incidence of nausea or vomiting as an adverse event causally related to compound A in 8 cases of 120 mg BID.
- Ramosetron hydrochloride or granisetron hydrochloride were administered to four subjects who complained of vomiting during Cycle 1.
- Granisetron hydrochloride was administered to 3 of the 4 subjects who complained of vomiting to prevent gastrointestinal symptoms (nausea and vomiting) associated with the administration of Compound A.
- the recommended clinical dose is about 80 mg to about 120 mg, with 100 mg BID or 120 mg BID being particularly preferred, and 120 mg BID being most preferred.
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Abstract
Description
[1]
式(I)で表される(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩を含む、固形腫瘍治療用医薬組成物であって、
(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩の投与量が、1日2回、1回あたり(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドとして約10mgから約150mgの投与量で、消化器症状を抑制するのに有効な量の5-HT3受容体アンタゴニストとヒト対象に併用投与され、
前記消化器症状は、ヒト対象への(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩の投与に起因する消化器症状である、医薬組成物。
前記消化器症状が、悪心及び嘔吐から選ばれる少なくとも1つである、[1]に記載の医薬組成物。
[3]
(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩が、1回あたり(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドとして約120mgの投与量で投与される、[1]または[2]に記載の医薬組成物。
[4]
前記5-HT3受容体アンタゴニストと同時にまたは別々に併用投与される、[1]から[3]のいずれか一項に記載の医薬組成物。
[5]
前記5-HT3受容体アンタゴニストが、アザセトロン、オンダンセトロン、インジセトロン、ラモセトロン、グラニセトロンおよびパロノセトロンからなる群から選ばれる少なくとも1つまたはその薬剤学的に許容される塩である、[1]から[4]のいずれか一項に記載の医薬組成物。
[6]
1日用量として、約0.1mg~約100mgの投与量の前記5-HT3受容体アンタゴニストと併用投与される、[1]から[5]のいずれか一項に記載の医薬組成物。
[7]
前記5-HT3受容体アンタゴニストが、ラモセトロン塩酸塩及びグラニセトロン塩酸塩から選ばれる少なくとも1つである、[1]から[6]のいずれか一項に記載の医薬組成物。
[8]
前記5-HT3受容体アンタゴニストが、オンダンセトロン塩酸塩水和物である、[1]から[6]のいずれか一項に記載の医薬組成物。
[9]
前記5-HT3受容体アンタゴニストが、パロノセトロン塩酸塩である、[1]から[6]のいずれか一項に記載の医薬組成物。
[10]
前記5-HT3受容体アンタゴニストがグラニセトロン塩酸塩であり、1日1回、グラニセトロンとして約2mgの投与量で併用投与される、[1]から[7]のいずれか一項に記載の医薬組成物。
[11]
前記5-HT3受容体アンタゴニストがラモセトロン塩酸塩であり、1日1回、ラモセトロンとして約0.1mgの投与量で投与される、[1]から[7]のいずれか一項に記載の医薬組成物。
[12]
(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩が(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドである、[1]から[11]のいずれか一項に記載の医薬組成物。
[13]
固形腫瘍を治療するために使用される、式(I)で表される(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩であって、
(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩の投与量が、1日2回、1回あたり(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドとして約10mgから約150mgの投与量で、消化器症状を抑制するのに有効な量の5-HT3受容体アンタゴニストとヒト対象に併用投与され、
前記消化器症状は、ヒト対象への(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩の投与に伴う消化器症状である、(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩。
固形腫瘍治療用医薬組成物を製造するための、式(I)で表される(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩の使用であって、
(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩の投与量が、1日2回、1回あたり(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドとして約10mgから約150mgの投与量で、消化器症状を抑制するのに有効な量の5-HT3受容体アンタゴニストとヒト対象に併用投与され、
前記消化器症状は、ヒト対象への(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩の投与に起因する消化器症状である、使用。
固形腫瘍を治療する方法であって、
式(I)で表される(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩を、1日2回、1回あたり(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドとして約10mgから約150mgの投与量で、固形腫瘍を持つヒト対象に投与すること、および
消化器症状を抑制するのに有効な量の5-HT3受容体アンタゴニストを前記ヒト対象に併用投与することを含み、
前記消化器症状は、ヒト対象への(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩の投与に起因する消化器症状である、方法。
ヒト対象に(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩を投与する方法であって、
式(I)で表される(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩を、1日2回、1回あたり(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドとして約10mgから約150mgの投与量で、固形腫瘍を持つヒト対象に投与すること、および
消化器症状を抑制するのに有効な量の5-HT3受容体アンタゴニストを前記ヒト対象に併用投与することを含み、
前記消化器症状は、ヒト対象への(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩の投与に起因する消化器症状である、方法。
消化器症状を抑制しながら固形腫瘍を治療する方法であって、
式(I)で表される(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩を、1日2回、1回あたり(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドとして約10mgから約150mgの投与量で、固形腫瘍を持つヒト対象に投与すること、および
消化器症状を抑制するのに有効な量の5-HT3受容体アンタゴニストを前記ヒト対象に併用投与することを含み、
前記消化器症状は、ヒト対象への(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩の投与に起因する消化器症状である、方法。
固形腫瘍の治療方法であって、
ヒト対象の消化器症状を抑制するために5-HT3受容体アンタゴニストを選択し、
固形腫瘍の治療のために、ヒト対象に(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩を、5-HT3受容体アンタゴニストと併用投与し、
消化器症状はヒト対象への(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩の投与に起因する消化器症状であり、
ヒト対象の消化器症状は抑制されている、方法。
[P1]
下記式(I)で表される(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドである化合物Aまたはその薬剤学的に許容される塩が、化合物Aとして1回あたり約10mgから約150mgの投与量で、ヒト対象に対して、1日あたり2回経口投与されるように用いられる医薬。
前記医薬が、ヒト対象への単回の投与後、化合物Aの1mg当たり約7.58h・ng/mL~約31.3h・ng/mLの平均AUC(0-12h)を達成する、前記[P1]に記載の医薬。
[P3]
前記医薬が、ヒト対象への単回の投与後、約71.4h・ng/mL~約3040h・ng/mLの平均AUC(0-12h)を達成する、前記[P1]または[P2]に記載の医薬。
[P4]
前記医薬が、ヒト対象への単回の投与後、化合物Aの1mg当たり約2.79ng/ml~約11.3ng/mlの平均Cmaxを達成する、前記[P1]~[P3]に記載の医薬。
[P5]
前記医薬が、ヒト対象への単回の投与後、約23.5ng/ml~約1100ng/mlの平均Cmaxを達成する、前記[P1]~[P4]のいずれか一項に記載の医薬。
[P6]
前記医薬が、ヒト対象への8日間の反復投与後において、AUC(0-tau),ssが約7700h・ng/mL以下である、前記[P1]~[P5]のいずれか一項に記載の医薬。
[P7]
前記[P1]~[P6]のいずれか一項に記載の医薬の投与に伴う消化器症状を抑制する5-HT3受容体アンタゴニストとともに投与されるように用いられる、前記[P1]~[P6]のいずれか一項に記載の医薬。
[P8]
前記消化器症状が、悪心及び嘔吐から選ばれる少なくとも1つである、前記[P7]記載の医薬。
[P9]
前記5-HT3受容体アンタゴニストが、1日用量として、約0.3mg~約8mgの投与量で投与される前記[P7]または[P8]に記載の医薬。
[P10]
固形がんの治療のために用いられる、前記[P1]~[P9]のいずれか一項に記載の医薬。
[P11]
固形がんが消化器癌、消化管内分泌腫瘍、子宮癌、悪性黒色腫、又は肺癌である、前記[P10]に記載の医薬。
[P12]
前記5-HT3受容体アンタゴニストが、オンダンセトロン塩酸塩水和物、グラニセトロン塩酸塩、パロノセトロン塩酸塩、ドラセトロン、ラモセトロン塩酸塩、トロピセトロン塩酸塩からなる群から選択される前記[P9]記載の医薬。
[P13]
下記式(I)で表される(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドである化合物Aまたはその薬剤学的に許容される塩が、化合物Aとして1回あたり約10mgから約150mgの投与量で、ヒト対象に対して、1日あたり2回経口投与することを含む、固形がんの治療方法。
前記ヒト対象が、前記化合物Aまたはその薬剤学的に許容される塩の投与に伴う消化器症状を発現するとき、前記化合物Aまたはその薬剤学的に許容される塩とともに5-HT3受容体アンタゴニストを投与することを含む、前記[P13]記載の治療方法。
本明細書に記載される本発明がより十分に理解され得るように、以下の定義が本開示のために提供される。
AUC:血漿濃度時間曲線下面積
AUC(0-tau):0時間から最終定量可能濃度の時間までの血漿中濃度時間曲線下面積
AUC(0-inf):0時間から無限大時間までの血漿中濃度時間曲線下面積
CL/F:血管外(例えば、経口)投与後の見かけの全身クリアランス
Cmax:最大観察濃度
t1/2:最終排出半減期
tmax:薬物投与後最大(ピーク)濃度に達するまでの時間
Cmax,ss:定常状態における最高血漿中濃度
tmax,ss:定常状態における最高血漿中濃度到達時間
AUC(0-tau),ss:定常状態における投与間隔ごとの血漿中濃度-時間曲線下面積
Rac(AUC):単回投与の後のAUC(0-tau),ssおよびAUC(0-tau)から算出した蓄積係数
Rac(Cmax):単回投与の後のCmax,ssおよびCmaxから算出した蓄積係数
Effective t1/2 (h):有効消失半減期
Vz/F:終末相の見かけの分布容積
%CV: 平方根(exp[対数変換データのSD**2]-1)*100
本明細書で使用される場合、「1つ(a)」、「1つ(an)」および「その(the)」などの単語の単数形は、文脈が別段明確に指示していなければ、その対応する複数の参照を含む。
1つの実施形態において、本発明は、化合物Aまたはその薬剤学的に許容される塩が、化合物Aとして1回あたり約10mgから約150mgの投与量で、ヒト対象に対して、1日あたり2回経口投与されるように用いられる医薬を提供する。
グラニセトロンとして、約1mgもしくは約0.01mg/kgを静脈内投与することができる。なお、年齢、症状により適宜増減するが、症状が改善されない場合には、約40μg/kgを1回追加投与できる。5-HT3受容体アンタゴニストとして、グラニセトロン塩酸塩を投与する場合、例えば、グラニセトロンとして1日1回、約2mgの投与量、もしくは1日2回、1回あたり約1mgの投与量で経口投与してもよい。その他の実施形態として、グラニセトロン塩酸塩を投与する場合、例えばグラニセトロンとして約34.3mgを含む約52cm2のパッチ(経皮吸収システム)にて投与することができる。投与量は、年齢、症状により適宜増減してもよい。
治験薬として、化合物Aを含有する錠剤を使用した。化合物Aは国際公開第2016/208576号の方法に従って合成した。
以下の選択基準(1)~(15)を全て満たし、かつ、除外基準(1)~(17)のいずれにも該当しない被験者を、化合物Aの投与対象とした。
〔選択基準〕
(1)組織学的又は細胞学的に固形がんと診断された以下に該当する患者。
・用量漸増パート:標準治療のない又は他に有効な治療のない進行、切除不能又は再発の大腸癌患者を含む固形がん患者
・拡張パート:3次治療若しくはそれ以降の進行,切除不能又は再発の大腸癌患者,若しくは治験依頼者と議論・合意の上,少なくとも全身性の抗がん剤治療を1レジメン施行後の小腸癌及び消化管神経内分泌腫瘍のような消化器癌患者
(2)用量漸増パート:大腸癌患者は生検の実施と保存腫瘍検体の提出(保存されている場合)を必須とする
拡張パート:生検可能な病変を有する患者は生検の実施を必須とする。生検不能な病変を有する患者は治験依頼者と相談・合意の上,生検を実施せずに登録可能とする。保存腫瘍検体の提出(保存されている場合)は必須とする
(3)化合物Aの投与後12週間以上の生存が見込まれる
(4)ECOG-PS 0~1である
(5)・用量漸増パート:同意取得時点で20歳以上の日本人
・拡張パート:同意取得時点で20歳以上の患者
(6)がんに対する前治療による有害事象(脱毛、Grade2の末梢神経障害を除く)がGrade0~1まで(腎/骨髄/肝機能は選択基準を満たすまで)回復している患者
(7)化合物Aの投与前に前治療から以下の期間経過している患者
a)化学療法及び放射線療法を受けてから3週間以上経過している患者
b)抗体による治療を受けてから4週間以上経過している患者
c)治験薬又は治験用の医療機器を使用してから4週間以上経過している患者
d)輸血、血小板輸血又はG-CSF製剤による処置を受けてから2週間以上経過している患者
(8)適切な腎機能を有する(すなわち、血清クレアチニン<2.0mg/dL、又はCockcroft-Gault法によるクレアチニンクリアランス≧40mL/minである。)
(9)適切な骨髄機能を有する(すなわち、好中球数≧1500/mm3、血小板数≧100000/mm3、かつヘモグロビン≧9.0g/dLである)
(10)適切な肝機能を有する(すなわち、凝固能として国際標準比(INR)≦1.5、総ビリルビン≦1.5×基準値上限(ULN)、かつアルカリホスファターゼ(ALP),アラニンアミノトランスフェラーゼ(ALT)及びアスパラギン酸アミノトランスフェラーゼ(AST)≦3×ULN(肝転移を有する場合は≦5×ULN)である)
(11)適切な血清無機質を有する(すなわち、カルシウム(アルブミン補正):基準値範囲内、補正カルシウム濃度(mg/dL)=実測カルシウム濃度(mg/dL)+4-血清アルブミン濃度(g/dL)、カリウム濃度が基準値下限値以上である、かつマグネシウムが基準値下限値以上である)
(12)文書同意及び治験実施計画の遵守が可能な患者
(13)RECIST 1.1における測定可能病変を少なくとも1つ有する患者
(14)25-ヒドロキシビタミンDが10ng/mL未満である場合、各医療機関のガイドライン又は治験責任医師若しくは治験分担医師の臨床的な判断によりビタミンDの継続的な摂取に同意する患者
(15)用量漸増パート:腫瘍以外の皮膚組織の生検に同意している患者
拡張パート:各用量において少なくとも5例の患者は腫瘍以外の皮膚組織の生検に同意する患者
以下の基準のいずれかに該当する被験者は,本治験の対象から除外する。
(1)以下の心疾患のいずれかに該当する患者
・ニューヨーク心臓協会(NYHA)の分類でクラスII以上の心不全を有する患者
・不安定な虚血性心疾患(化合物Aの投与開始前6ヵ月以内の心筋梗塞、硝酸薬が週2回以上必要な狭心症)を有する患者
・QTcF>480msecのQT間隔延長が見られる患者
・左心駆出率(LVEF)<50%である患者
(2)化合物A投与前21日以内に大手術を受けた患者
(3)化合物A又は賦形剤の成分に忍容性が無いと判明している患者
(4)ヒト免疫不全ウイルス(HIV)陽性と判明している患者
(5)全身治療を要する活動性の感染症と判明している患者
(6)髄膜がん腫症の患者
(7)以下を摂取した患者
・化合物Aの投与開始前4週間以内に、チトクロームP450(CYP)3Aを強力に誘導する又はCYP3Aの基質でありかつ治療域が狭い薬剤、サプリメントを摂取した患者
・化合物Aの投与開始前2週間以内に、CYP3Aを強力に阻害する薬剤又は食物を摂取した患者
(8)化合物Aの投与開始前2週間以内に,全身ステロイド又は局所ステロイドによる免疫抑制療法(プレドニゾン10mg/日を超える又は当量)を受けている患者、あるいはこれらの療法を受ける予定の患者
(9)脳又は硬膜下転移を有する患者。ただし、化合物Aの投与開始4週間前に局所の治療が完了し副腎皮質ホルモンの投与を中止している患者は除く。化合物Aの投与開始前4週間は、徴候(例えば放射線検査上)又は症状が安定していなければならない
(10)肺のリンパ管症を有し、積極的な治療(酸素吸入を含む)を要するような呼吸不全状態にある患者
(11)経口摂取不能、消化管の吸収不良又は治験責任医師若しくは治験分担医師により化合物Aの吸収に影響を与える可能性があると判断されるその他の身体状態(悪心、下痢,嘔吐等)を示す患者
(12)以下の骨疾患又は骨の状態に該当する患者
・DXAスキャンによるTスコアが-2.5未満の骨粗鬆症
・空腹時血清中β-CTX>1000pg/mL
・骨軟化症
・ビスホスフォネート製剤で治療が必要と判断される高カルシウム血症
・化合物Aの投与開始前6ヵ月以内の骨折歴
・外科的処置を要する状態
・骨転移に対して,ビスホスフォネート製剤やデノスマブで治療していない(放射線治療をした病変を除く。)
(13)試験の評価に影響すると治験責任医師又は治験分担医師が判断したあらゆる状態
(14)化合物Aの投与開始前24ヵ月以内に活動性の悪性腫瘍を有する患者(原疾患,完全に処置された非浸潤性メラノーマ、皮膚の基底細胞癌/扁平上皮癌、非浸潤性子宮頚部癌/膀胱癌及び早期胃癌/大腸癌は除く)
(15)女性の場合には、スクリーニング時又はベースライン時に授乳中である、あるいは妊娠している患者(ヒト絨毛性ゴナドトロピン[hCG]又はヒト絨毛性ゴナドトロピンβサブユニット[β-hCG]尿中検査で陽性が確認された患者)。ただし、授乳中の方は治験参加にあたり授乳を中断される場合、本試験への参加が可能と判断する。スクリーニング時に陰性であっても、化合物Aの投与開始前7日以内に実施していない場合には、再度検査を実施すること
(16)生殖能力のある男性及び妊娠する可能性のある女性の場合、本人及びパートナーが試験期間及び化合物Aの投与終了後、男性は90日、女性は30日まで医学的に適切な避妊方法注)を用いることに同意しない患者
(17)化合物Aの投与歴のある患者
用量漸減パートでは、3+3デザインを用いて複数の用量で化合物Aの安全性と忍容性を評価した。化合物Aの開始用量は、10mgBID(1日2回)に設定した。
DLTは化合物Aと因果関係があると考えられる有害事象であり、サイクル1(28日間)で発現した以下の事象である。重症度の評価にはNCI CTCAE v5.0を用いた。
(a)血液毒性
・G-CSF投与を含む適切な治療を行っても8日以上継続するGrade4の好中球減少症
・Grade3~4の発熱性好中球減少症
・Grade4の血小板減少症
・Grade3の血小板減少症で出血を伴う、8日以上継続する又は血小板輸血を要する事象
・Grade4の貧血
・Grade3の貧血で赤血球輸血を要する事象
(b)非血液毒性
・Grade4以上の事象
・臨床的に意義のあるGrade3の事象(適切な治療により7日以内にGrade0~1に回復する下痢、悪心及び嘔吐を除く)
・Grade3の骨粗鬆症
・Grade2以上の骨脆弱性骨折のうち,外傷歴のない事象又は身長以下の高さからの転倒による事象
・空腹時血清中I型コラーゲン架橋C-テロペプチド-β異性体(β-CTX)の増加がベースラインから2倍より大きく、その値が1000pg/mL以上であり、かつビスホスフォネート製剤やデノスマブ投与にもかかわらず4週間以内にベースラインまで回復が認められない場合
・臨床的に意義のあるGrade3~4の臨床検査値異常
・治験責任医師又は治験分担医師により忍容性なしと判断される事象により、化合物Aの投与を8日間以上休止した場合
*2 DLTではないGrade2、Grade3又はそれ以上の有害事象
〔投与前期〕
投与前期には、投与対象者の同意を取得し、適格性確認のためのスクリーニングと疾患状態を確認するためのベースラインの評価を実施した。スクリーニング終了後、選択基準を全て満たし、除外基準のいずれにも抵触しない患者を投与対象者として登録した。ベースラインの評価は、化合物Aの投与3日前から投与直前までに実施し、疾患状態を確認してから投与期へ移行する。
投与期では、28日を1サイクルとして化合物A(化合物Aを含有する経口製剤)を投与対象者に投与する。被験者は病勢の進行、忍容性のない副作用の発現、投与対象者の中止希望、同意撤回又は治験依頼者による治験中止が生じるまで、化合物Aの投与を継続した。28日間の投与を1サイクルとし、「C1D28」等の表記は、サイクルの回数と当該サイクル中の日数を示し、例えば、「C1D28」はサイクル1(第1サイクル)の第28日目を意味する。投与対象者はC1D28の時点まで入院し、C1D15の時点で診察及び検査を実施し、その結果から治験責任医師又は治験分担医師が医学的に問題ないと判断した場合は退院を許可した。また、C2D1の時点の診察及び検査終了後に投与を継続する場合は、C2D1の時点の投薬前までに継続に対する文書同意を取得した。
(1)薬物動態
用量漸増パートにおいては、表5に記載のスケジュールにしたがい、投与対象者から血液を採取し、化合物Aの薬物動態を評価した。拡張パートにおいては、C1D1及びC1D8における1回目の投与前、化合物Aの経口投与の0.5、1、2時間後、及びC2D1における1回目の投与前に投与対象者から血液を採取し、化合物Aの薬物動態を評価した。C1D1(第1サイクルの第1日目)のデータが単回投与の結果に該当し、C1D8(第1サイクルの第8日目)のデータが1日あたり2回の用量で8日間の反復投与した後の結果に該当する。
忍容性の解析は、DLT解析対象集団(用量漸増パートにおいてサイクル1で治験薬が予定通り投与された被験者の集団及び化合物Aの投与の遵守によらずDLTが認められた集団)を用いて実施し、その他の安全性の解析は、安全性解析対象集団(治験薬が1回以上投与された被験者の集団とする。これは全ての安全性評価(DLT評価を除く)の解析対象集団)を用いて実施した。
忍容性の評価において、サイクル1期間中に有害事象として多く観察された化合物Aの投与に伴う消化器症状のうち、悪心又は嘔吐を抑制する方法を検討した。消化器症状である悪心又は嘔吐が見られた投与対象者について、種々の制吐剤が投与された結果を検討し、悪心又は嘔吐の発生を抑制できるかを調べた。制吐剤としては、ドンペリドン(5-HT1A受容体拮抗剤、ナウゼリン錠)、メトクロプラミド(末梢性D2受容体拮抗剤、メトクロプラミド錠)、ラモセトロン塩酸塩(5-HT3受容体アンタゴニスト、ナゼア錠)、グラニセトロン(5-HT3受容体アンタゴニスト、カイトリル錠)等が使用された。
Claims (10)
- 式(I)で表される(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩を含む、固形腫瘍治療用医薬組成物であって、
(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩が、1日2回、1回あたり(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドとして約10mgから約150mgの投与量で、消化器症状を抑制するのに有効な量の5-HT3受容体アンタゴニストと、ヒト対象に併用投与され、
前記消化器症状は、ヒト対象への(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩の投与に起因する消化器症状である、医薬組成物。
- 前記消化器症状が、悪心及び嘔吐から選ばれる少なくとも1つである、請求項1に記載の医薬組成物。
- (6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩が、1回あたり(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドとして約120mgの投与量で投与される、請求項1または2に記載の医薬組成物。
- 前記5-HT3受容体アンタゴニストと同時にまたは別々に併用投与される、請求項1から3のいずれか一項に記載の医薬組成物。
- 前記5-HT3受容体アンタゴニストが、アザセトロン、オンダンセトロン、インジセトロン、ラモセトロン、グラニセトロンおよびパロノセトロンからなる群から選ばれる少なくとも1つまたはその薬剤学的に許容される塩である、請求項1から4のいずれか一項に記載の医薬組成物。
- 1日用量として、約0.1mg~約100mgの投与量の前記5-HT3受容体アンタゴニストと併用投与される、請求項1から5のいずれか一項に記載の医薬組成物。
- 前記5-HT3受容体アンタゴニストが、ラモセトロン塩酸塩及びグラニセトロン塩酸塩から選ばれる少なくとも1つである、請求項1から6のいずれか一項に記載の医薬組成物。
- 前記5-HT3受容体アンタゴニストがグラニセトロン塩酸塩であり、1日1回、グラニセトロンとして約2mgの投与量で併用投与される、請求項1から7のいずれか一項に記載の医薬組成物。
- 前記5-HT3受容体アンタゴニストがラモセトロン塩酸塩であり、1日1回、ラモセトロンとして約0.1mgの投与量で投与される、請求項1から7のいずれか一項に記載の医薬組成物。
- (6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドまたはその薬剤学的に許容される塩が(6S,9aS)-N-ベンジル-8-({6-[3-(4-エチルピペラジン-1-イル)アゼチジン-1-イル]ピリジン-2-イル}メチル)-6-(2-フルオロ-4-ヒドロキシベンジル)-4,7-ジオキソ-2-(プロプ-2-エン-1-イル)ヘキサヒドロ-2H-ピラジノ[2,1-c][1,2,4]トリアジン-1(6H)-カルボキサミドである、請求項1から9のいずれか一項に記載の医薬組成物。
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EP4364742A1 (en) | 2024-05-08 |
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