System for improving treatment compliance of anticancer compound E7766

Abstract

A system for reducing medication errors and increasing treatment compliance in individuals suffering from cancer is reported. In embodiments, drug-drug interaction information is provided for the administration of anticancer therapy compound 1 (E7766) in potential combination with an OATP inhibitor.

Description

Detailed Description of the Invention

[0001] [Cross - Reference to Related Applications] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 869,389, filed on Jul. 1, 2019. That application is incorporated herein by reference in its entirety as if fully rewritten herein. [Background Art]

[0002] [Background] Understanding the clearance mechanism and pharmacokinetics of novel chemical substances in drug development is important to ensure safe and effective exposure of patients to new chemical substances and to prevent clinically harmful interactions that may occur due to co - administration with other drugs. Compound 1, which is the diammonium salt of E7766, is reported to be used in the treatment of cancer as shown below. For example, see U.S. Patent No. 10,246,480, which is incorporated herein by reference. [Chemical Formula]

[0003] E7766 is (1R,3R,15E,28R,29R,30R,31R,34R,36R,39S,41R)-29,41 - difluoro - 34,39 - bis(sulfanyl)-2,33,35,38,40,42 - hexaoxa - 4,6,9,11,13,18,20,22,25,27 - decaaza - 34λ 5 ,39λ 5 - diphosphaoctacyclo[28.6.4.1 3,36 .1 28,31 .0 4,8 .0 7,12 .0 19,24 .0 23,27 dotetraconta - 5,7,9,11,15,19,21,23,25 - nonaene - 34,39 - dione, also known as. If there is a conflict between this chemical name and the above - shown structure, the above - shown structure shall control. [Summary of the Invention]

[0004] [Brief Summary] For the purpose of assisting in clinical trial samples, the inventors used a preclinical model to measure the clearance of Compound 1, both alone and when potentially affected by drug-drug interactions. Without being bound by theory, based on the investigation of the inventors' compounds, the inventors concluded that this compound would have a low LogP (<1), low permeability (<1×10 -6 cm / sec), a pKa of 3-4 and a MW>600. Accordingly, according to the Extended Clearance Classification System, Compound 1 is classified as Class 3B. Compounds of that class are mainly cleared by excretion in bile or urine following active uptake.

[0005] E7766 is represented below. Compound 1, the diammonium salt of E7766, has a molecular weight of 780.7, a measured pKa of 3.41, a measured LogD of 1.31, a PSA of 200, a solubility of 150 μmol / L, a Papp value of 0.36×10 6 cm / s and is in ECCS Class 3B using the scale reported in Varma, et al., Pharm Res (2015) 32:3785-3802, which is incorporated herein by reference. In the examples reported herein, Compound 1, the diammonium salt, was used. Usually, different lots were used for different studies. [Chemical formula]

[0006] In one embodiment, a system for reducing medication errors and increasing treatment compliance in an individual suffering from cancer, the system comprising a pharmaceutical composition containing E7766 and a pharmaceutically acceptable salt thereof in a certain amount [Chemical formula] At least one container containing, and at least one cautionary statement attached to said container containing instructions of information regarding potential drug-drug interactions, wherein said information regarding drug-drug interactions indicates that the administration of the pharmaceutical composition causes potentially different effects in individuals being treated with an organic anion transporting polypeptide inhibitor than in individuals not receiving an organic anion transporting polypeptide inhibitor. A system is provided comprising said cautionary statement. In a further embodiment, the organic anion transporting polypeptide inhibitor inhibits an organic anion transporting polypeptide selected from OATP1B1, OATP1B3, and combinations of OATP1B1 and OATP1B3.

[0007] In a further embodiment, references to "OATP" are limited to OATP1B1 and / or OATP1B3 inhibitors.

[0008] In a further embodiment, the information regarding potential drug-drug interactions instructs that the organic anion transporting polypeptide inhibitor and the pharmaceutical composition should not be co-administered. In a further embodiment, the information regarding potential drug-drug interactions instructs that one or both of the organic anion transporting polypeptide inhibitor and the pharmaceutical composition should be administered at a lower dose and / or less frequently than if either were administered without the other.

[0009] In some embodiments, the dosage of the pharmaceutical composition is reduced by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. In further embodiments, the dosage of the pharmaceutical composition is reduced by 5 - 75%; 10 - 50%; or 20 - 40%. In some embodiments, the dosage of the OATP inhibitor is reduced by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. In further embodiments, the dosage of the OATP inhibitor is reduced by 5 - 75%; 10 - 50%; or 20 - 40%.

[0010] In a further embodiment of the above system, the organic anion transporting polypeptide inhibitor is selected from the group consisting of fimasartan, clarithromycin, rifampin, clopidogrel, eslicarbazepine, CP - 778875, isavuconazole, itraconazole, ombitasvir, asunaprevir, boceprevir, daclatasvir, dasabuvir, elbasvir, faldaprevir, grazoprevir, ledipasvir, ombitasvir, paritaprevir, pibrentasvir, trimethoprim, ritonavir, simeprevir, sofosbuvir, telaprevir, velpatasvir, voxilaprevir, lopinavir, pemigatinib, quercetin, tipranavir, metformin, diltiazem, sacubitril, valsartan, furosemide, gemfibrozil, eluxadoline, cyclosporine, tacrolimus, eltrombopag, grapefruit juice, ursodeoxycholic acid, Silybum marianum, emtricitabine, tenofovir, vercirnon (GSK1605786), telmisartan, epigallocatechin gallate, ezetimibe, amlodipine, obeticholic acid, omega - 3 carboxylic acids, idelalisib, baicalin, empagliflozin, elvitegravir, and cobimetinib.

[0011] A further embodiment provides a method for preventing excessive exposure to E7766 or a pharmaceutically acceptable salt thereof in a patient selected for treatment with E7766 or a pharmaceutically acceptable salt thereof, the method comprising administering E7766 or a pharmaceutically acceptable salt thereof to the patient when the patient is not also administered a drug that is an OATP1B1 or OATP1B3 inhibitor.

[0012] A further embodiment provides a method for preventing excessive exposure to E7766 or a pharmaceutically acceptable salt thereof in a patient selected for treatment with E7766 or a pharmaceutically acceptable salt thereof, the method comprising administering E7766 or a pharmaceutically acceptable salt thereof to the patient when the patient is administered a drug that is an OATP1B1 or OATP1B3 inhibitor in an amount less than the amount of the OATP1B1 or OATP1B3 inhibitor that would be administered in the absence of E7766 or a pharmaceutically acceptable salt thereof.

[0013] A further embodiment provides a method for preventing excessive exposure to E7766 or a pharmaceutically acceptable salt thereof in a patient selected for treatment with E7766 or a pharmaceutically acceptable salt thereof, the method comprising administering E7766 or a pharmaceutically acceptable salt thereof to a patient in whom a fixed amount of a drug that is an OATP1B1 or OATP1B3 inhibitor has been administered, the method comprising administering E7766 or a pharmaceutically acceptable salt thereof to the patient in an amount less than the amount of E7766 or a pharmaceutically acceptable salt thereof that would be administered in the absence of an OATP1B1 inhibitor or an OATP1B3 inhibitor.

[0014] In some embodiments, E7766 or a pharmaceutically acceptable salt thereof is administered at least 1 day after, at least 2 days after, at least 3 days after, at least 4 days after, at least 5 days after, at least 6 days after, at least 7 days after, at least 2 weeks after, at least 3 weeks after, or at least 1 month after the administration of the drug.

[0015] In embodiments of the methods described herein, the drug can be selected from the group consisting of fimasartan, clarithromycin, rifampin, clopidogrel, eslicarbazepine, CP-778875, isavuconazole, itraconazole, ombitasvir, asunaprevir, boceprevir, daclatasvir, dasabuvir, elbasvir, faldaprevir, grazoprevir, ledipasvir, ombitasvir, paritaprevir, pibrentasvir, trimethoprim, ritonavir, simeprevir, sofosbuvir, telaprevir, velpatasvir, voxilaprevir, lopinavir, pemigatinib, quercetin, tipranavir, metformin, diltiazem, sacubitril, valsartan, furosemide, gemfibrozil, elexacaftor, cyclosporine, tacrolimus, eltrombopag, grapefruit juice, ursodeoxycholic acid, Silybum marianum, emtricitabine, tenofovir, GSK1605786, telmisartan, epigallocatechin gallate, ezetimibe, amlodipine, obeticholic acid, omega-3 carboxylic acid, idelalisib, baicalein, empagliflozin, elvitegravir, and cobicistat.

[0016] A further embodiment is a method of preventing excessive exposure to E7766 or a pharmaceutically acceptable salt thereof in a patient selected for treatment with E7766 or a pharmaceutically acceptable salt thereof, the method comprising monitoring the exposure of the patient to E7766 or a pharmaceutically acceptable salt thereof and maintaining the exposure at a value of less than 12,800 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 9,600 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 6,400 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 3,200 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 2,400 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 2,000 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 1,750 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 1,600 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 1,200 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 800 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 600 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 300 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 150 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 75 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; maintaining the exposure at a value of less than 50 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight; or maintaining the exposure at a value of less than 25 μg of E7766 or a pharmaceutically acceptable salt thereof per 100 kg of patient body weight.In some embodiments, exposure to E7766 or a pharmaceutically acceptable salt thereof described in this paragraph is carried out in patients administered with an OATP1B1 inhibitor and / or an OATP1B3 inhibitor.

[0017] In some methods, the maintenance step includes reducing the dosage of E7766 or a pharmaceutically acceptable salt thereof. This can be reduced, for example, by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the above values.

[0018] In some methods, the exposure is monitored by quantifying the presence of E7766 or a pharmaceutically acceptable salt thereof in the blood of the patient. In some methods, the exposure is evaluated from the plasma of the patient.

[0019] A further embodiment provides a system or method as described herein, wherein the pharmaceutically acceptable salt of E7766 is the diammonium salt of E7766.

[0020] A further embodiment is a method for treating cancer in a patient selected for treatment with E7766 or a pharmaceutically acceptable salt thereof, comprising administering to the patient E7766 or a pharmaceutically acceptable salt thereof, wherein the patient has not been treated with an organic anion transporting polypeptide (OATP) inhibitor.

[0021] A further embodiment is a method for treating cancer in a patient selected for treatment with E7766 or a pharmaceutically acceptable salt thereof, which comprises the step of administering to the patient E7766 or a pharmaceutically acceptable salt thereof, wherein the patient has been previously administered an OATP inhibitor or an OATP inhibitor is still being administered, and concomitantly stopping or reducing the administration of the OATP inhibitor to eliminate related adverse events or reduce the frequency of related adverse events.

[0022] A further embodiment is a method for treating cancer in a patient selected for treatment with E7766 or a pharmaceutically acceptable salt thereof, the method comprising administering to the patient E7766 or a pharmaceutically acceptable salt thereof, wherein the patient has been previously administered, or is still being administered, an OATP inhibitor, and concomitantly discontinuing or reducing the administration of the E7766 or a pharmaceutically acceptable salt thereof to eliminate or reduce the number of related adverse events.

[0023] In some embodiments, the OATP inhibitor is selected from the group consisting of fimasartan, clarithromycin, rifampin, clopidogrel, eslicarbazepine, CP-778875, isavuconazole, itraconazole, ombitasvir, asunaprevir, boceprevir, daclatasvir, dasabuvir, elbasvir, faldaprevir, grazoprevir, glecaprevir, paritaprevir, pibrentasvir, trimethoprim, ritonavir, simeprevir, sofosbuvir, telaprevir, velpatasvir, voxilaprevir, lopinavir, pemigatinib, quercetin, tipranavir, metformin, diltiazem, sacubitril, valsartan, furosemide, gemfibrozil, eprosartan, cyclosporine, tacrolimus, eltrombopag, grapefruit juice, ursodeoxycholic acid, Silybum marianum, emtricitabine, tenofovir, GSK1605786, telmisartan, epigallocatechin gallate, ezetimibe, amlodipine, obeticholic acid, omega-3 carboxylic acids, idelalisib, baicalein, empagliflozin, elvitegravir, and cobicistat.

[0024] In some embodiments, E7766 or a pharmaceutically acceptable salt thereof is administered at least 1 day after administration of the OATP inhibitor. In some embodiments, E7766 or a pharmaceutically acceptable salt thereof is administered at least 2 days after administration of the OATP inhibitor. In some embodiments, E7766 or a pharmaceutically acceptable salt thereof is administered at least 3 days after administration of the OATP inhibitor. In some embodiments, E7766 or a pharmaceutically acceptable salt thereof is administered at least 4 days after administration of the OATP inhibitor. In some embodiments, E7766 or a pharmaceutically acceptable salt thereof is administered at least 5 days after administration of the OATP inhibitor. In some embodiments, E7766 or a pharmaceutically acceptable salt thereof is administered at least 6 days after administration of the OATP inhibitor. In some embodiments, E7766 or a pharmaceutically acceptable salt thereof is administered at least 7 days after administration of the OATP inhibitor. In some embodiments, E7766 or a pharmaceutically acceptable salt thereof is administered at least 2 weeks after administration of the OATP inhibitor. In some embodiments, E7766 or a pharmaceutically acceptable salt thereof is administered at least 3 weeks after administration of the OATP inhibitor. In some embodiments, E7766 or a pharmaceutically acceptable salt thereof is administered at least 1 month after administration of the OATP inhibitor. In some embodiments, the patient is still being administered the OATP inhibitor. In the above embodiments, the OATP inhibitor is typically OATP1B1 and / or OATP1B3.

Brief Description of the Drawings

[0025]

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Mode for Carrying Out the Invention

[0026] [Detailed Description of Embodiments] The inventors studied the pharmacokinetics and disposition of Compound 1 in in vitro systems and in vivo preclinical species. From the pharmacokinetics in bile-cannulated rats and dogs, it was found that Compound 1 was mainly excreted unchanged in bile (>80%) and to a lesser extent in urine (<20%). Uptake studies in human hepatocytes showed temperature-dependent active uptake, which could be inhibited by rifampin but not by tetraethylammonium, indicating the involvement of organic anion transporting polypeptide (OATP) in the excretion of Compound 1. Further studies using HEK293 cells overexpressing human OATP1B1 and OATP1B3 confirmed that Compound 1 was a substrate of OATP1B1 and OATP1B3.

[0027] In vitro studies in multidrug resistance-related protein 2 (MRP2)-expressing vesicles demonstrated that Compound 1 was a substrate of the bile excretion transporter MRP2. The pharmacokinetics of Compound 1 were also evaluated in humanized OATP1B1 / 1B3, Oatp1a / 1b knockout, or wild-type mice. In wild-type mice, an increase (5.4-fold) in the plasma exposure of Compound 1 was confirmed in the presence of rifampin, and the liver exposure of Compound 1 was equivalent in wild-type mice in the presence or absence of rifampin. The plasma concentration of Compound 1 increased 4.5-fold in the presence of rifampin in humanized OATP1B1 / 1B3 mice. From these preclinical results, it was predicted that OATP-mediated hepatic uptake was the rate-limiting step in the clearance of Compound 1, and from these preclinical results, it was also predicted that inhibition of OATP in clinical settings would result in a significant increase in the systemic exposure of Compound 1.

[0028] Those skilled in the art will recognize that when the substituents attached to the phosphorus atoms (P1, P2) have both single and double bonds, they are prone to tautomerization. For example, the compound can tautomerize in an equilibrium state. An example is shown below:

Chemical formula

[0029] Such tautomers should be considered to be within the scope of the claims. The structural representations of any tautomer of a given compound represent the same compound.

[0030] [Treatment method] In some embodiments, E7766 or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment. In some embodiments, the compound administered is provided as an NH4 salt, a free acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is provided as an NH4 salt. When E7766 is provided as an NH4 salt, the compound is referred to as Compound 1.

[0031] [Dosage] The optimal dosage for the treatment of cancer can be determined empirically for each individual using known methods and varies depending on various factors including the activity of the drug; the weight, general health, sex, and diet of the individual; the time and route of administration; and other medications the individual is taking. The optimal dosage can be established using routine tests and procedures well known in the art. Administration of the above compounds can be effected by any suitable route.

[0032] As used herein, "drug interaction" means a pharmacokinetic or pharmacodynamic effect that can occur when two or more drugs are administered simultaneously. Such effects generally do not occur when the drugs are administered alone (i.e., in the absence of other drugs). Non-limiting examples of pharmacokinetic drug interactions include, for example, changes in the absorption, distribution, metabolism, or excretion of one or both of the co-administered drugs. Non-limiting examples of pharmacodynamic drug interactions include, for example, interference (e.g., competitively or allosterically) of one drug with another at a protein (or receptor) binding site, or indirect interference through binding of a protein (or receptor) in a related biological pathway. Non-limiting examples of drug interactions include expected side effects, unexpected side effects, clinically adverse events, and contraindications, all of which can be managed during the administration of drugs potentially involved in a drug interaction.

[0033] As used herein, "pharmaceutically acceptable salt" means an acid addition salt or a base addition salt of a compound of the present disclosure. A pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not exert any overly harmful or undesirable effects on the subject to which it is administered in the circumstances of administration. Pharmaceutically acceptable salts include, but are not limited to, metal complexes and salts of both inorganic and carboxylic acids. Pharmaceutically acceptable salts include metal salts such as aluminum, calcium, iron, magnesium, manganese and complex salts. Further, pharmaceutically acceptable salts include, but are not limited to, acidic salts such as acetate, aspartate, alkylsulfonate, arylsulfonate, acetyl salt, benzenesulfonate, benzoate, bicarbonate, bisulfite, bitartrate, butyrate, calcium edetate, camsylate, carboxylate, chlorobenzoate, citrate, edetate, edisylic acid salt, estolic salt, esyl, esylate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycolylarsanyl acid salt, hexamine salt, hexylresorcinol salt, hydrabamic salt, hydrobromide, hydrochloride, hydrochloride, hydroiodide, hydroxynaphthoate, isethionate, lactate, lactobionate, maleate, malate, malonate, mandelate, methanesulfonate, methyl nitrate, methyl sulfate, mucate, muconate, napsylic acid salt, nitrate, oxalate, p-nitromethanesulfonate, pamoate, pantothenate, phosphate, monohydrogen phosphate, dihydrogen phosphate, phthalate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfonate, sulfate, tannate, tartrate, teoclic acid salt, toluenesulfonate, etc. Sodium salts and potassium salts can also be prepared.

[0034] The embodiment can be the diammonium salt of E7766. Pharmaceutically acceptable salts can be derived from amino acids such as cysteine, among others. Methods for manufacturing a compound as a salt are known to those skilled in the art (see, for example, Stahl et al., Handbook of Pharmaceutical salts: Properties, Selection, and Use, Wiley - VCH; Verlag Helvetica Chimica Acta, Zurich, 2002; Berge et al., J. Pharm. Sci. 66:1, 1977).

[0035] The "effective amount" or "therapeutically effective amount" of a therapeutic agent is an amount sufficient to provide an observable therapeutic advantage as compared to the cancer left untreated in a subject or patient.

[0036] The agents reported herein can be combined with a pharmaceutically acceptable carrier to provide the pharmaceutical formulation thereof. The specific choice of carrier and formulation will vary depending on the particular route of administration for which the composition is intended.

[0037] As used herein, "pharmaceutically acceptable carrier" means a non - toxic carrier, adjuvant, or excipient that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or excipients that can be used in the compositions of the present invention include, but are not limited to, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose - based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene glycol, and lanolin.

[0038] The compositions of the present invention are suitable for parenteral, oral, inhaled spray, topical, rectal, nasal, buccal, vaginal, intravesical, intravesical, intratumoral, or implantable reservoir administration, etc. In some embodiments, the formulation includes components of natural or non-natural origin. In some embodiments, the formulation or carrier can be provided in a sterile state. Non-limiting examples of sterile carriers include endotoxin-free water or pyrogen-free water. The composition can be administered by intravesicular, intravesical, or intratumoral administration.

[0039] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intramedullary, intraliver, intralesional, and intracranial injection or infusion techniques. In certain embodiments, the compound is administered by intravenous, oral, subcutaneous, or intramuscular administration. The injectable sterile state of the compositions of the present invention can be an aqueous or oily suspension. These suspensions can be formulated according to techniques known in the art using appropriate dispersing or wetting agents and suspending agents. The injectable sterile preparation can be an injectable sterile solution or suspension in a parenterally acceptable non-toxic diluent or solvent. Acceptable excipients and solvents that can be used are, in particular, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixed oils have conventionally been used as solvents or suspending media.

[0040] For this purpose, any non-irritating fixed oil such as synthetic mono- or diglycerides can be used. Pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially their polyoxyethylenated types of fatty acids and their glyceride derivatives, are useful in the manufacture of injectable solutions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants such as carboxymethylcellulose, or dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and suspensions. Other commonly used surfactants such as Tween and Span, and other emulsifying agents commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purpose of formulation.

[0041] For oral administration, the compound or salt can be provided in an acceptable oral dosage form such as, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, generally used carriers include lactose and corn starch. Lubricants such as magnesium stearate can also be added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient can be combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added. Furthermore, preservatives can be added. Suitable examples of pharmaceutically acceptable preservatives include, but are not limited to, various antibacterial and antifungal agents such as solvents, for example ethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternary ammonium salts, and parabens (methylparaben, ethylparaben, propylparaben, etc.).

[0042] "Immediate release" means including the conventional release in which the release of the drug starts immediately after administration. As used herein, the term "immediate release" includes dosage forms that do not intend to delay or prolong the dissolution or absorption of the drug and enable the drug to dissolve in the gastrointestinal contents. The purpose is to enable the rapid release of the drug after administration, for example, at least 80% of the drug is released within approximately 30 minutes after the start of dissolution in a dissolution test.

[0043] "Sustained release" or "extended release" includes dosage forms in which the drug release characteristics are selected over time and / or position to achieve therapeutic or convenience purposes not conferred by conventional dosage forms such as solutions or immediate release dosage forms.

[0044] The term "steady state" means that the plasma level of a given active agent has been achieved, which is maintained at subsequent doses of the active agent at a level above the minimum effective therapeutic level and below the minimum toxic plasma level of the given active agent.

[0045] As used herein, the term "dosage range" means the upper and lower limits of the acceptable variation in the amount of a specified agent. Usually, any amount of the agent within the specified range can be administered to a patient undergoing treatment.

[0046] The term "treat" or "treatment" as used herein means to alleviate, reduce or mitigate at least one symptom of a disease in a subject. For example, with respect to cancer, "treat" or "treatment" can mean to prevent the onset, delay (i.e., the period prior to the clinical signs or symptoms of the disease), and / or reduce the risk of developing or worsening the symptoms of cancer. The term "protect" or "protection" as used herein means to prevent, delay, or treat, or any of, the onset, persistence or exacerbation of the symptoms of cancer in a subject, as appropriate.

[0047] The term "subject" or "patient" is intended to include animals that can or are suffering from cancer. Examples of subjects or patients include mammals such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject is a human who has cancer, is at risk of having cancer, or may have cancer.

[0048] As used herein, "Warnings" can include, but are not limited to, documents as part of a regulatory authority-approved pharmaceutical product such as a product label or package insert. Such documents can include instructions, cautions or warnings to the patient or prescribing physician, for example, in one or more of drug interactions, clinical pharmacology, dosage and administration, warnings and precautions, contraindications, or a boxed warning section.

[0049] The term "about" or "approximately" usually means within 20%, more preferably within 10%, and most preferably within 5% of a given value or range. Alternatively, particularly in biological systems, the term "about" preferably means within approximately two factors, i.e., within about log (i.e., one order of magnitude) of a given value.

[0050] The terms "one", "a kind", "the", and the use of similar designations in the context of describing the present invention (in particular, the context of the following claims) are to be construed as including both the singular and the plural, unless otherwise specified herein or clearly inconsistent with the context. The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e., meaning "including but not limited to") unless otherwise specified. The description of a range of values herein is merely intended to serve as a shorthand for referring individually to each different value within that range, and each different value is incorporated herein as if it were individually recited herein.

[0051] Exemplary cell proliferative disorders that can be treated using one or more of the compounds disclosed herein include, but are not limited to, cancer or precancer or pre-cancerous conditions, as well as metastatic diseased tissues and organs in the body. Cell proliferative disorders include hyperplasia, metaplasia, and dysplasia.

[0052] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be used to treat or prevent cell proliferative diseases, or to treat or prevent cancer in subjects generally at high risk of developing cancer in the general population, or to identify suitable candidates for such purposes.

[0053] [Pharmaceutical Formulations and Routes of Administration] Pharmaceutical formulations comprising E7766 or a pharmaceutically acceptable salt thereof for the treatment of cancer are provided herein. The pharmaceutical formulations may further comprise a carrier or excipient, a stabilizer, a flavoring agent, and / or a coloring agent.

[0054] E7766 or a pharmaceutically acceptable salt thereof can be administered using various routes of administration known to those skilled in the art. Routes of administration include oral administration, intratumoral administration, intravesical administration, and intravesical instillation. In certain embodiments, a pharmaceutical formulation comprising the compound or a pharmaceutically acceptable salt thereof can be orally ingested in the form of a liquid, syrup, tablet, capsule, powder, sprinkle, chewable tablet, or dissolvable disk. Alternatively, the pharmaceutical formulations of the present invention can be administered intravenously or transdermally. Other routes of administration are known to those skilled in the art (see, e.g., Remington’s Pharmaceutical Sciences, Gennaro A.R., Ed., 20th Edition, Mack Publishing Co., Easton, Pa.).

[0055] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is formulated as a paste, jelly, or suspension. For example, the drug is dissolved, encapsulated, or suspended in the form of drug particles, microencapsulated particles, or drug-polymer particles in a gelatinous solution or semi-solid. The advantage of an oral jelly formulation is that it is easy to administer the drug to patients who have difficulty swallowing tablets, capsules, or pills. In certain embodiments, the compound is completely mixed and suspended in a suitable medium to form a paste or gel. Additional agents can be optionally mixed to impart flavor upon oral administration. Peanut butter or strawberry flavored alginates, and sweeteners are examples of many suitable flavoring agents. In various embodiments, the paste or jelly can also be formulated with suitable binders or excipients known in the art for topical administration.

[0056] Methods for manufacturing sustained-release formulations in the form of tablets, capsules, or pills are known in the art. In some embodiments, the sustained-release formulation is manufactured by coating the active ingredient of the drug with a polymer, preferably a water-insoluble polymer. For example, water-insoluble polymers used in the pharmaceutical field as sustained-release coating agents, enteric coating agents, or gastric coating agents can be mentioned. Examples of water-insoluble polymers include ethyl cellulose, purified shellac, shellac, aminoalkyl methacrylate copolymer RS, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl-cellulose, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer E, or polyvinyl acetal diethylaminoacetate.

[0057] The type, degree of distribution, and molecular weight of the water-insoluble polymer can vary depending on the solubility of the active ingredient in water or alcohol, the desired level of sustained release, etc. The water-insoluble polymer can be used alone or in combination. Hydrogenated oil, stearic acid, or cetyl alcohol can be further incorporated as coating aids, and medium-chain triglycerides, triacetin, triethyl citrate, or cetyl alcohol can be incorporated as plasticizers.

[0058] In some embodiments, the sustained-release formulation is a matrix-type tablet or granule. The active ingredient can be coated with up to three different types of polymers. These three different types of polymers can include: 1) water-insoluble polymers such as ethyl cellulose; 2) pH-independent gelling polymers such as hydroxypropyl methylcellulose; and 3) pH-dependent gelling polymers such as sodium alginate. Using these three different types of polymers together can reduce the drug release rate.

[0059] [Intratumoral Administration and Dosage Regimen] In an embodiment of intratumoral administration, E7766 or a pharmaceutically acceptable salt thereof is administered to a patient in a plurality of cycles, each cycle lasting 3 weeks. E7766 or a pharmaceutically acceptable salt thereof is administered on days 1, 8, and 15 in an induction cycle (cycle 1); and on day 1 of each subsequent maintenance cycle (cycle 2 and later). The total dose administered at each time point can be 25 μg, 50 μg, 75 μg, 150 μg, 300 μg, 600 μg, 1200 μg, or 1750 μg. The dose administered is within one of the following dosage ranges: 75-1750 μg, 75-1200 μg, 75-600 μg, 75-300 μg, 75-150 μg, 150-1750 μg, 150-1200 μg, 150-600 μg, 150-300 μg, 300-1750 μg, 300-1200 μg, 300-600 μg, 1200-1750 μg, 75-200 μg, 75-150 μg, or 100-150 μg.

[0060] In one embodiment, E7766 or a pharmaceutically acceptable salt thereof is provided as a solid or concentrated solution and is diluted to a final volume of 1 mL with normal saline for intratumoral administration.

[0061] In one embodiment, E7766 or a pharmaceutically acceptable salt thereof is provided for intratumoral administration for the treatment of breast cancer (such as triple-negative breast cancer (TNBC)), colon cancer, colorectal cancer, glioma, head and neck squamous cell carcinoma, liver cancer, lymphoma, melanoma, prostate cancer, pancreatic cancer, kidney cancer, or other solid tumors.

[0062] [Intrathecal or Intravesical Administration and Dosage Schedule] In an embodiment of intrathecal administration, or an embodiment of intravesical administration, E7766 or a pharmaceutically acceptable salt thereof is first administered to a patient in an induction cycle (cycle 1) lasting 6 weeks. In the induction cycle, E7766 or a pharmaceutically acceptable salt thereof is administered on days 1, 8, 15, 22, 29, and 36. Subsequent maintenance cycles (cycle 2 and later) are initiated as identified in Table 1 below.

[0063]

Table 1

[0064] The total dose administered at each time point can be 600 μg, 800 μg, 1,600 μg, 2,000 μg, 2,400 μg, 3,200 μg, 6,400 μg, 9,600 μg, or 12,800 μg. The dose administered is within one of the following dosage ranges: 800 - 12,800 μg; 800 - 9,600 μg; 800 - 6,400 μg; 800 - 3,200 μg; 800 - 2,400 μg; 800 - 2,000 μg; 800 - 1,600 μg; 1,600 - 12,800 μg; 1,600 - 9,600 μg; 1,600 - 6,400 μg; 1,600 - 3,200 μg; 1,600 - 2,400 μg; 1,600 - 2,000 μg; 2,000 - 12,800 μg; 2,000 - 9,600 μg; 2,000 - 6,400 μg; 2,000 - 3,200 μg; 2,000 - 2,400 μg; 2,400 - 12,800 μg; 2,400 - 9,600 μg; 2,400 - 6,400 μg; 2,400 - 3,200; 3,200 - 12,800 μg; 3,200 - 9,600 μg; 3,200 - 6,400 μg; 6,400 - 12,800 μg; 6,400 - 9,600 μg; or 9,600 - 12,800 μg. In other embodiments, E7766 or a pharmaceutically acceptable salt thereof is provided as a solid or concentrated solution and is diluted to a final volume of 25 mL with normal saline for intracellular administration. In other embodiments, E7766 or a pharmaceutically acceptable salt thereof is provided as a solid or concentrated solution and is diluted to a final volume of 25 mL with normal saline for intravesical administration.

[0065] In one embodiment, E7766 or a pharmaceutically acceptable salt thereof is provided for intracellular administration for the treatment of cancer (muscle-invasive and non-muscle-invasive bladder cancer (NMIBC, such as bacillus Calmette-Guérin (BGC)-therapy refractory NMIBC), transitional cell carcinoma of the bladder, carcinoma in situ (CIS), Ta or T1 papillary disease with or without CIS, and urinary bladder neoplasms). In one embodiment, E7766 or a pharmaceutically acceptable salt thereof is provided for intravesical administration for the treatment of cancer (muscle-invasive and non-muscle-invasive bladder cancer (NMIBC, such as bacillus Calmette-Guérin (BGC)-therapy refractory NMIBC), transitional cell carcinoma of the bladder, carcinoma in situ (CIS), Ta or T1 papillary disease with or without CIS, and urinary bladder neoplasms).

[0066] [Dosage form: Release characteristics] Sustained-release formulations can achieve a certain degree of sustained-action. However, the exposure and / or bioavailability of the active ingredient can vary based on various factors such as, for example, the absorption window, the carrier or excipient used in the formulation, the mode of delivery of the formulation, and / or the transit time of the active ingredient through the patient's gastrointestinal tract.

[0067] The therapy can include at least one sustained-release portion that performs a sustained-release function and one immediate-release portion that performs an immediate-release function. In certain embodiments, when the therapy is in a single dosage form, it can be a tablet formed from a mixture of sustained-release granules that make up the sustained-release portion and immediate-release granules that make up the immediate-release portion, a capsule formulation obtained by filling a capsule with the sustained-release granules and the immediate-release granules, or in the form of a nucleated tablet where an outer layer that makes up the immediate-release portion is formed on an inner core that makes up the sustained-release portion. However, there is no limitation to the above embodiments.

[0068] Furthermore, there are no particular restrictions on the state of drug encapsulation in the composition or in the immediate-release portion or sustained-release portion; the compound can be uniformly dispersed in the composition, the immediate-release portion or the sustained-release portion, or can be contained only in one portion of the composition, the immediate-release portion or the sustained-release portion, or can be contained such that a concentration gradient exists.

[0069] The sustained-release portion in the composition according to the present invention may contain at least one non-pH-dependent polymer substance or pH-dependent polymer substance in order to control drug release.

[0070] The non-pH-dependent polymer substance used herein may include polymer substances generally found in the gastrointestinal tract, specifically those whose charge state hardly changes under pH conditions of pH 1 to 8. This means a polymer having no functional groups whose charge state changes according to pH, such as basic functional groups such as amino groups or acidic functional groups such as carboxylic acid groups. Note that non-pH-dependent polymer substances are included to impart a sustained-release function to the composition according to the present invention, but may also be included for other purposes. Furthermore, the non-pH-dependent polymer substance used in the present invention may be water-insoluble, or may swell in water or dissolve in water to form a gel.

[0071] Examples of water-insoluble non-pH-dependent polymer substances include, but are not limited to, cellulose ethers, cellulose esters, and methacrylic acid-acrylic acid copolymers (trade name Eudragit, manufactured by Rohm GmbH & Co. KG, Darmstadt, Germany). Examples include, but are not limited to, cellulose alkyl ethers such as ethyl cellulose (trade name Ethocel, manufactured by Dow Chemical Company, USA), ethyl methyl cellulose, ethyl propyl cellulose or isopropyl cellulose, and butyl cellulose, cellulose aralkyl ethers such as benzyl cellulose, cellulose cyanoalkyl ethers such as cyanoethyl cellulose, cellulose organic acid esters such as cellulose acetate butyrate, cellulose acetate, cellulose propionate or cellulose butyrate, and cellulose acetate propionate, ethyl acrylate-methyl methacrylate copolymers (trade name Eudragit NE, manufactured by Rohm GmbH & Co. KG, Darmstadt, Germany), and aminoalkyl methacrylate copolymers RS (trade names Eudragit RL, Eudragit RS).

[0072] There is no particular limitation on the average particle size of the water-insoluble polymer used in the present invention. Generally, the lower the average particle size, the better the performance. The average particle size is preferably 0.1 to 100 μm, more preferably 1 to 50 μm, particularly preferably 3 to 15 μm, and most preferably 5 to 15 μm. Further, examples of the water-soluble or water-swellable non-pH-dependent polymer substances include, but are not limited to, polyethylene oxide (trade name Polyox, manufactured by Dow Chemical, molecular weight 100,000 to 7,000,000), low-substituted hydroxypropyl cellulose (trade name L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd., Japan), hydroxypropyl cellulose (trade name HPC, manufactured by Nippon Soda Co., Ltd., Japan), hydroxypropyl methylcellulose (trade names Metolose 60SH, 65SH, 90SH, manufactured by Shin-Etsu Chemical Co., Ltd. (Japan)), and methylcellulose (trade name Metolose SM, manufactured by Shin-Etsu Chemical Co., Ltd. (Japan)).

[0073] In some embodiments, a single non-pH-dependent polymer substance may be included in the composition, or a plurality of non-pH-dependent polymer substances may be included. When used in the embodiments described herein, the non-pH-dependent polymer substance may be a water-insoluble polymer substance, more preferably ethyl cellulose, an ethyl acrylate-methyl methacrylate copolymer (trade name Eudragit NE), or an aminoalkyl methacrylate copolymer RS (trade names Eudragit RL, Eudragit RS). One of ethyl cellulose and aminoalkyl methacrylate copolymer RS is particularly preferred. Ethyl cellulose is most preferred. There is no particular limitation on the amount of the non-pH-dependent polymer substance contained in the composition: this amount can be appropriately adjusted according to the purpose such as the control of sustained drug release.

[0074] The pH-dependent polymer substance that can be used in the embodiments described in this specification can be a polymer substance that is commonly found in the gastrointestinal tract and, specifically, whose charge state changes under pH conditions of pH 1 to 8. This means a polymer substance having a functional group whose charge state changes according to pH, such as a basic functional group like an amino group or an acidic functional group like a carboxylic acid group. The pH-dependent functional group of the pH-dependent polymer substance is preferably an acidic functional group, and the pH-dependent polymer substance most preferably has a carboxylic acid group.

[0075] The pH-dependent polymer substance used in the present invention can be water-insoluble or can swell or dissolve in water to form a gel. Examples of the pH-dependent polymer substance used in the present invention include, but are not limited to, enteric polymer substances. Examples of enteric polymer substances include, but are not limited to, methacrylic acid-methyl methacrylate copolymer (Eudragit L100, Eudragit S100, manufactured by Rohm GmbH&Co.KG, Darmstadt, Germany), methacrylic acid-ethyl acrylate copolymer (Eudragit L100-55, Eudragit L30D-55, manufactured by Rohm GmbH&Co.KG, Darmstadt, Germany), hydroxypropylmethylcellulose phthalate (HP-55, HP-50, manufactured by Shin-Etsu Chemical Co., Ltd. (Japan)), hydroxypropylmethylcellulose acetate succinate (AQOAT, manufactured by Shin-Etsu Chemical Co., Ltd. (Japan)), carboxymethylethylcellulose (CMEC, manufactured by Freund Corporation, Japan), and cellulose acetate phthalate.

[0076] Examples of pH-dependent polymer substances that swell or dissolve in water to form a gel include, but are not limited to, alginic acid, pectin, carboxyvinyl polymer, and carboxymethyl cellulose. In the present invention, a single pH-dependent polymer substance may be included in the composition, or a plurality of pH-dependent polymer substances may be included. The pH-dependent polymer substance used in the present invention is preferably an enteric polymer substance, more preferably a methacrylic acid-ethyl acrylate copolymer, a methacrylic acid-methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate, and particularly preferably a methacrylic acid-ethyl acrylate copolymer.

[0077] When using a pH-dependent polymer substance in the process of manufacturing the composition according to the present invention, commercially available products in powder type, granule type, or suspension type in which the pH-dependent polymer substance is previously dispersed in a solvent can be used as they are, or such commercially available products can be dispersed in water or an organic solvent and used. The lower the particle size of the pH-dependent polymer substance, the better the performance, and the pH-dependent polymer substance is preferably in powder type. In the case of a methacrylic acid-ethyl acrylate copolymer, an example is Eudragit L100-55. There is no particular limitation on the average particle size of the pH-dependent polymer substance used in the present invention, but the average particle size is preferably 0.05 to 100 μm, more preferably 0.05 to 70 μm, and most preferably 0.05 to 50 μm. Further, for example, in the case of an enteric polymer substance, there is no particular limitation on the amount of the pH-dependent polymer substance, but it is generally 0.1 to 90 parts by weight, preferably 1 to 70 parts by weight, more preferably 5 to 60 parts by weight, and particularly preferably 10 to 50 parts by weight based on 100 parts by weight of the composition.

[0078] The therapy according to the embodiments described in this specification may further contain, as necessary, any of various additives such as diluents, lubricants, binders, disintegrants, and various pharmacologically acceptable carriers such as preservatives, colorants, sweeteners, plasticizers, film coating agents, etc. Examples of diluents include, but are not limited to, lactose, mannitol, dibasic calcium phosphate, starch, pregelatinized starch, crystalline cellulose, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, etc. Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, etc. Examples of binders include, but are not limited to, hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, etc. Examples of disintegrants include, but are not limited to, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, etc.

[0079] Examples of preservatives include, but are not limited to, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. Preferred examples of colorants include, but are not limited to, water-insoluble lake pigments, natural pigments (e.g., β-carotene, chlorophyll, red ferric oxide), yellow ferric oxide, red ferric oxide, black ferric oxide, etc. Preferred examples of sweeteners include, but are not limited to, sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, etc. Examples of plasticizers include, but are not limited to, glycerol fatty acid esters, triethyl citrate, propylene glycol, polyethylene glycol, etc. Examples of film coating agents include, but are not limited to, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, etc.

[0080] [Manufacturing Method] To manufacture the embodiments described in this specification, a single conventional method or a combination of conventional methods can be used. For example, when manufacturing drug-containing granules as sustained release or immediate release, granulation is the main operation, but this may be combined with other operations such as mixing, drying, sieving, and classification. As granulation methods, for example, a wet granulation method in which a binder and a solvent are added to the powder and granulation is performed, a dry granulation method in which the powder is compressed and granulation is performed, a melt granulation method in which a binder that melts when heated is added and heating and granulation are performed, etc. can be used.

[0081] Furthermore, according to granulation, a mixed granulation method using a star mixer, a screw mixer, etc., a high-speed mixed granulation method using a Henschel mixer, a Super mixer, etc., an extrusion granulation method using a cylindrical granulator, a rotary granulator, a screw extrusion granulator, a pellet mill type granulator, etc., a wet high-shear granulation method, a fluidized bed granulation method, a compression granulation method, a pulverization granulation method, or a spray granulation method can be used. After granulation, drying using a dryer, a fluidized bed, etc., cracking and sieving can be performed to obtain granules or fine particles for use. Furthermore, when preparing the composition according to the present invention, a granulation solvent can be used. Such a granulation solvent is not particularly limited, but can be either water or various organic solvents, for example, water, lower alcohols such as methanol or ethanol, ketones such as acetone or methyl ethyl ketone, methylene chloride, or a mixture thereof.

[0082] Regarding the sustained-release granules included in the embodiments, at least one drug is mixed together with at least one of a non-pH-dependent polymer substance and a pH-dependent polymer substance, and a diluent and a binder are added as necessary, and granulation is performed to obtain a granular substance. The obtained granular substance is dried using a shelf dryer, a fluidized bed dryer, etc., and sieving is performed using a mill or an oscillator to obtain sustained-release granules. As an alternative, as a method for manufacturing the sustained-release granules in the present invention, at least one drug, at least one selected from a non-pH-dependent polymer substance and a pH-dependent polymer substance, and a diluent and a binder as necessary are added, and while mixing, compression molding is performed using a dry compactor such as a roller compactor or a slug tablet machine, and then granulation can be performed by cracking down to an appropriate size. The granular substance produced using such a granulator can be used as it is as granules or fine granules according to the present invention, or can be further cracked and sieved using a powder mill, a rotary granulator, a rotor speed mill, etc. to obtain sustained-release granules. Immediate-release granules can also be manufactured in the same manner as the sustained-release granules.

[0083] Using a single conventional method, or a combination of conventional methods, compression-molded products can be manufactured as drug-containing sustained-release portions or immediate-release portions, or as the compositions described herein. For example, at least one drug, at least one selected from a non-pH-dependent polymer substance and a pH-dependent polymer substance, a diluent such as mannitol or lactose, a binder such as polyvinylpyrrolidone or crystalline cellulose, a disintegrant such as sodium carboxymethylcellulose or crospovidone, and a lubricant such as magnesium stearate or talc are used, and tableting is performed using a normal method, whereby a compression-molded product can be obtained. In this case, tableting is the main operation in the manufacturing method of the compression-molded product, but this can be combined with other operations such as mixing, drying, sugar coating formation, and coating.

[0084] Examples of tablet-forming methods include, but are not limited to, direct compression molding in which at least one drug and a pharmaceutically acceptable additive are mixed with each other and then the mixture is directly compression-molded into tablets using a tableting machine, and dry granule compression or wet granule compression in which the sustained-release granules or immediate-release granules according to the present invention are compression-molded after adding a lubricant or a disintegrant as necessary. There are no particular restrictions on the tableting machine used for compression molding; for example, a single-punch tableting machine, a rotary tableting machine, or a press-coating tableting machine can be used.

[0085] The drug-containing sustained-release granules or immediate-release granules, or compression-molded products according to the embodiments herein can be used as such in the form of granules or tablets as a composition, but can also be processed further to produce a composition. For example, the compression-molded product or granules can be provided in the form of a film using a film-based material such as ethyl cellulose, casein, methyl cellulose, hydroxypropyl methyl cellulose, methacrylic acid copolymer L, cellulose acetate phthalate, shellac, etc., or in the form of a sugar-coated tablet using a sugar-coating solution containing sucrose, sugar alcohol, gum arabic powder, talc, etc., and thus film-coated tablets or sugar-coated tablets are produced. One solvent in this coating technique can be purified water, but organic solvents such as alcohol, ketone, ether, or chlorinated hydrocarbon, or a mixture thereof can also be used. For example, ethanol, acetone, methylene chloride, etc. can also be used as organic solvents. Further, as the coating device, a device commonly used in coating techniques for drug production can be used, examples of which include a spray coating device in which coating is performed by spraying a coating solution or the like, and a rotary fluidized bed granulator for layering.

[0086] When manufacturing a capsule formulation, a capsule formulation can be produced by using an automatic capsule filling machine to fill the sustained-release granules or immediate-release granules, or mini-tablets described above into hard gelatin capsules or HPMC capsules. As an alternative method, in the case of a formulation for administration from a tube or a dry syrup agent that is used by mixing with water or the like when ingested, the sustained-release granules or immediate-release granules described above can be mixed with a thickening agent or a dispersing agent in order to disperse these granules, and then the mixture is produced into granules or tablets. Furthermore, a liquid or jelly can be produced using water and a substance selected from a dispersing agent, an emulsifying agent, a thickening agent, a preservative, a pH adjuster, a sweetening agent, a flavoring agent, an aroma, etc. However, there is no limitation to the above regarding other manufacturing methods.

[0087] As reported in more detail below, from mechanistic in vivo and in vitro experiments, 1) the rate-determining step in the systemic clearance of Compound 1; 2) the relative contribution of transporters involved in the uptake and biliary clearance of Compound 1; and 3) the potential drug-drug interaction associated with OATP1B1 / 1B3 in humans were determined.

[0088] The pharmacokinetics and predisposing factors of Compound 1 were studied in vivo in bile-cannulated rats and dogs, and OATP1B1 / 1B3 humanized mice. Transfected cell lines and vesicles were used to perform transporter phenotyping of Compound 1. The biliary excretion and uptake clearance of Compound 1 were also determined in sandwich-cultured human hepatocytes. In silico modeling, particularly simCYP™, was also used for physiologically based pharmacokinetic (PBPK) modeling and clinical drug-drug interaction (DDI) prediction. PBPK modeling was applied to evaluate the potential drug-drug interaction with OATP inhibitors in the clinic.

[0089] Based on the studies reported in this specification, E7766 or a pharmaceutically acceptable salt thereof, particularly Compound 1, may cause potential drug-drug interactions with OATP inhibitors. These OATP inhibitors can be OATP1B1 inhibitors and / or OATP1B3 inhibitors. By co-administering an OATP inhibitor with E7766 or a pharmaceutically acceptable salt thereof, the dosage and dosing schedule of the administration of E7766 or a pharmaceutically acceptable salt thereof, and / or the administration of the OATP inhibitor can be changed, or attention can be paid to the co-administration completely.

[0090] Examples of OATP inhibitors that may have potential drug-drug interactions with E7766 or its pharmaceutically acceptable salts include, but are not limited to, fimasartan, clarithromycin, rifampin, clopidogrel, eslicarbazepine, CP-778875, isavuconazole, itraconazole, ombitasvir, asunaprevir, boceprevir, daclatasvir, dasabuvir, elbasvir, faldaprevir, grazoprevir, ledipasvir, ombitasvir, paritaprevir, pibrentasvir, trimethoprim, ritonavir, simeprevir, sofosbuvir, telaprevir, velpatasvir, voxilaprevir, lopinavir, peficitinib, quercetin, tipranavir, metformin, diltiazem, sacubitril, valsartan, furosemide, gemfibrozil, elexacaftor, cyclosporine, tacrolimus, eltrombopag, grapefruit juice, ursodeoxycholic acid, milk thistle (Silybum marianum), emtricitabine, tenofovir, belsirnon (GSK1605786), telmisartan, epigallocatechin gallate, ezetimibe, amlodipine, obeticholic acid, omega-3 carboxylic acids, idelalisib, baicalin, empagliflozin, elvitegravir, and cobicistat. OATP inhibitors are generally reported in Karlgren, et al., Classification of Inhibitors of Hepatic Organic Anion Transporting Polypeptides (OATPs): Influence of Protein Expression on Drug-Drug Interactions, J Med Chem, 2012 May 24;55(10):4740-4763, which is incorporated herein by reference.

[0091] A system is disclosed that provides information about the potential drug-drug interaction between E7766 or a pharmaceutically acceptable salt thereof and at least one OATP inhibitor. By making this information available simultaneously with E7766 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing E7766 or a pharmaceutically acceptable salt thereof, potential drug-drug interactions (including possible clinical adverse events) can be managed. The management can be carried out, for example, by changing the dosage, type, or schedule of the OATP inhibitor and / or E7766 or a pharmaceutically acceptable salt thereof, or by discontinuing the administration of either E7766 or a pharmaceutically acceptable salt thereof or the OATP inhibitor.

[0092] In some embodiments, the management of potential drug-drug interactions is carried out by reducing the amount of the OATP inhibitor administered and / or the number of administrations of the OATP inhibitor. In some embodiments, the management of potential drug-drug interactions is carried out by reducing the amount of E7766 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing E7766 or a pharmaceutically acceptable salt thereof, and / or by reducing the number of administrations of E7766 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing E7766 or a pharmaceutically acceptable salt thereof.

[0093] To be more fully understood of the embodiments described herein, the following examples are presented. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting.

[0094] [Examples] [Methods and Materials] Compound 1 was formulated in sterile phosphate buffered saline (PBS) for rat and dog studies and in 0.5% 0.1N HCl, 5% DMSO, 10% EtOH, 84.5% saline for WT and humanized mouse studies. Rifampin was formulated in 0.5% 0.1N HCl, 5% DMSO, 10% EtOH, 84.5% saline. Blank urine and bile, and plasma containing sodium heparin as an anticoagulant were purchased from BioreclamationIVT (Westbury, NY).

[0095] Mass spectrometry and HPLC conditions for the analysis of Compound 1 in biological matrices are shown below.

[0096] [Table 2]

[0097] [Example 1: Pharmacokinetics in Rats and Dogs] Male bile-cannulated beagle dogs or SD rats (n = 3) were administered a single intravenous (IV) dose of Compound 1. Plasma, urine and bile samples were collected from dogs and blood, urine, bile and fecal samples were collected from rats up to 48 hours after dosing. Blood samples were maintained on wet ice after collection until centrifuged to separate plasma. Urine samples were collected into collection tubes on wet ice at 0 - 4, 4 - 8, 8 - 24, and 24 - 48 hour intervals after dosing. Bile samples were collected into collection tubes cooled by ice packs at 0 - 4, 4 - 8, 8 - 24, and 24 - 48 hour intervals after dosing. Rat fecal samples were collected at 0 - 24 hour intervals. All samples were transferred to appropriately labeled tubes and stored at -70°C until undetermined transport to the biological analysis facility. All samples were analyzed using LC-MS / MS and pharmacokinetic parameters of Compound 1 were determined using non-compartmental analysis with Phoenix WinNonlin.

[0098] Table 2 shows the percentage of the administered dose excreted (%Ae) in bile, urine, or feces of bile-duct cannulated rats or dogs after intravenous administration of 1 mg / kg or 0.075 mg / kg, respectively. Data are shown as mean ± SD. NC means not collected.

[0099]

Table 3

[0100] [Example 2: Pharmacokinetics in Knockout, Humanized, and Wild-Type Mice] Age-matched Oatp1a / 1b cluster-knockout, OATP1B1- or OATP1B3-knockin mice humanized on an Oatp1a / 1b-knockout background, and male wild-type FVB mice were purchased from Taconic Biosciences (Hudson, New York, USA). Mice were 8–10 weeks old (22–34 g) at the time of the study. Compound 1 was administered at a dose of 0.5 mg / kg by coadministration with either vehicle or rifampin (30 mg / kg). Blood and liver samples were collected at 0.083, 0.25, 0.5, 1, 1.5, 3, and 6 h. Plasma was isolated from blood samples by centrifugation. All samples were stored at -80 °C until biological analysis.

[0101] Compound 1 was administered to WT, humanized, and KO mice by intravenous injection. Blood, urine, and feces were collected from the animals over 6 h. Blood spots were collected and spotted onto FTA™ DMPK-BDBS cards (GE Healthcare, Life Sciences, Whatman™) within the appropriate sample circles. The pharmacokinetics of Compound 1 in WT animals after coadministration with rifampin were also evaluated. Liver samples were also collected from WT animals and frozen until analysis. All samples were analyzed using LC-MS / MS, and the pharmacokinetic parameters of Compound 1 were determined using non-compartmental analysis with Phoenix WinNonlin.

[0102] [In Vivo PK of Compound 1 in Oatp1b2 Knockout and OATP1B Humanized Mice] Figures 2A - 2C show the in vivo PK profiles and excretion of Compound 1 with and without co - administration of the Oatp / OATP inhibitor rifampin in different mouse models. Figure 2A shows the PK profile of Compound 1 and co - administration with rifampin in wild - type mice. Figure 2B shows the PK profile of Compound 1 and co - administration with rifampin in OATP1B humanized mice. Figure 2C shows the excretion of Compound 1 into urine and feces for the mice in Figures 2A and 2B.

[0103] Based on these results, the inventors noted that co - administration of Compound 1 with the Oatp / OATP inhibitor rifampin decreased biliary excretion by 66 - 79% while increasing the systemic exposure of Compound 1 by 4.5 - fold. This indicates that transporter - mediated uptake is rate - limiting for the clearance and disposition of Compound 1.

[0104] From the further summary shown in Figure 5, it can be seen that the AUC (area under the curve, or bioavailability) of Compound 1 in the liver after IV administration in wild - type mice did not change significantly after co - administration with rifampin. The Kp (liver / plasma) value of Compound 1 decreased to 1 / 5 in the presence of rifampin. The C max of Compound 1 increased by approximately 2 - fold in the presence of rifampin.

[0105] [Example 3: Evaluation of Uptake and Biliary Excretion Using Sandwich - Cultured Human Hepatocyte Assay] In one donor, sandwich-cultured human hepatocytes (SCHH) prepared from JEL were used to evaluate the hepatic uptake and hepatobiliary disposition of Compound 1. For the evaluation of hepatic uptake, Compound 1 was incubated for 1, 5, and 10 minutes, the solution was collected, and frozen at -80 °C until the process of biological analysis. Then, the wells were washed three times with ice-cold plus (+) buffer and frozen at -80 °C until processed for biological analysis. The B-CLEAR® technology was utilized to evaluate the biliary excretion of Compound 1 in SCHH. Briefly, the cell medium was removed, and the hepatocytes were washed twice with warm plus (+) or minus (-) buffer to maintain or disrupt the tight junctions, respectively. The wash solution was removed and replaced with fresh plus (+) buffer or minus (-) buffer. The hepatocytes were conditioned at 37 °C for 10 minutes. The conditioning solution was removed and replaced with the dosing solution of Compound 1. After incubation for 20 minutes, the solution was taken and frozen at -80 °C until the process of biological analysis. Then the wells were washed three times with ice-cold plus (+) buffer. The plate was frozen at -80 °C until processed for biological analysis. The biliary excretion index (BEI) was calculated according to the following equation:

Equation

[0106] After incubation at 4 °C, the hepatic uptake of Compound 1 decreased significantly to <7.7% at 37 °C. These results suggested that the hepatic uptake of Compound 1 was mainly mediated by an active uptake mechanism. The hepatic uptake of Compound 1 was approximately dose-proportional at dose levels of 0.3 - 1 μM after 1 - 5 minutes of exposure. However, this dose-proportionality was lost at a concentration of 10 μM, suggesting that hepatic uptake saturates at concentrations >1 μM. The biliary excretion index (BEI) of Compound 1 ranged from 70.9 - 86.2% over the concentration range evaluated, indicating a high biliary efflux of this compound. The results are shown in Figures 4A and 4B.

[0107] [Example 4: In vitro Hepatobiliary Transporter Phenotyping - Evaluation of Transport in Overexpressed Cells or Vesicles] TransportoCells™ (Corning, New York, USA) expressing OATP2B1, NTCP, and HEK293-FT cells stably transfected with a vector containing OATP1B1 cDNA or OATP1B3 cDNA, or an empty vector, were grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum and 2 mmol / L sodium butyrate (for NTCP only) in a humidified incubator at 37 °C and 5% CO2. Cells were harvested at 90% confluence and then seeded onto poly-D-lysine-coated 24-well plates 24 hours prior to the transporter assay. The cells were washed twice and preincubated with 200 μL of prewarmed Krebs-Henseleit buffer. After preincubation, the cells were incubated with compound 1 at 3 μmol / L or 10 μmol / L in the presence or absence of 100 μmol / L of an inhibitor (rifamycin SV for OATP2B1, troglitazone for NTCP, rifamycin for OATP1B1 and OATP1B3). The transport reaction was terminated by aspirating the buffer from the wells at the designated time points. After washing three times with 200 μL of ice-cold Krebs-Henseleit buffer, the cells were lysed and the resulting cell lysates were analyzed by LC-MS / MS.

[0108] Concentration-dependent uptake of compound 1 via OATP1B1 and OATP1B3 was performed at concentrations ranging from 0.25 to 100 μmol / L under linear uptake. All experiments were performed in triplicates.

[0109] To study the interaction of Compound 1 with hepatic efflux (ABC) transporters, TransportoCells™ membrane vesicles expressing BCRP, BSEP, MRP2, and control vector vesicles were pre-incubated with vesicle uptake buffer (47 mmol / L MOPs-Tris, 65 mmol / L KCl, 7 mmol / L MgCl2, pH 7.4 for BCRP; 47 mmol / L MOPs-Tris, 2.5 mmol / L GSH, 65 mmol / L KCl, 7 mmol / L MgCl2, pH 7.4 for MRP2; and 10 mmol / L HEPES-Tris, 100 mmol / L KNO3, 12.5 mmol / L Mg(NO3)2, and 50 mmol / L sucrose, pH 7.4 for BSEP) at 37 °C for 10 minutes. Transport was initiated by adding pre-warmed 25 mmol / L MgATP, 3 μmol / L Compound 1 in the presence or absence of inhibitors (3 μmol / L Novobioncin for BCRP, 100 μmol / L MK-571 for MRP2, and 20 μmol / L ketoconazole for BSEP). Transport was terminated at the indicated time points by adding 200 μL of ice-cold vesicle uptake buffer. The entire contents were then rapidly filtered using a MultiScreen HTS vacuum manifold, followed by five washes and filtration. The plate was completely dried and then placed on a 96-well receiver plate. 50 μL of elution solution (containing internal standard in 75% methanol) was added to each assay well, followed by centrifugation at 2000 rpm for 5 minutes. This dissolution-and-centrifugation procedure was repeated once more to maximize extraction of the compound. Samples obtained from the two centrifugations were combined and analyzed by LC-MS / MS. All experiments were performed in triplicate.

[0110] Figures 1A to 1D show the results of the in vitro hepatobiliary transporter phenotyping study of Compound 1. Figure 1(A) shows the uptake of Compound 1 evaluated in SLC transporter-expressing HEK293 cells; Figure 1(B) shows the uptake of Compound 1 evaluated in ABC transporter-expressing membrane vesicles; Figure 1(C) shows the kinetic plot fitting and Michaelis-Menten parameters of OATP1B1-mediated uptake of Compound 1; Figure (D) shows the kinetic plot fitting and Michaelis-Menten parameters of OATP1B3-mediated uptake of Compound 1. From the results shown in Figures 1A to 1D, it is suggested that SLC transporters OATP1B1 and OATP1B3, and ABC transporter MRP2 are responsible for the hepatic uptake and subsequent bile efflux of Compound 1.

[0111] [Example 5: PBPK Modeling to Predict OATP1B-Mediated Drug-Drug Interactions of Compound 1 in Clinics] PBPK modeling was performed using Simcyp (trademark) in silico bottom-up PBPK modeling. It was suggested from the PBPK modeling that changes in systemic and hepatic exposure may occur when Compound 1 is co-administered with an inhibitor of OATP1B. Furthermore, due to the dominant contribution of OATP1B3 rather than OATP1B1 to the hepatobiliary clearance of Compound 1, the hepatobiliary clearance of Compound 1 is unlikely to undergo PK changes due to polymorphisms in PATP1B1.

[0112] Figure 4A shows the average ratio (ft%) of Compound 1 transported to the liver. Figure 3B shows the average values of the liver concentrations of Compound 1 with and without interaction with rifampin over time. Figure 3C shows the average values of the systemic concentrations of Compound 1 in plasma with and without interaction with rifampin over time. Figure 4D shows the average values of the sinusoidal capillary uptake clearances of Compound 1 with and without interaction with rifampin over time. Simcyp (trademark) software version 17.0.0 was used. The Simcyp (trademark) parameters are shown in Table 3 below.

[0113]

Table 4

[0114]

Table 5

[0115] [Summary] Pharmacokinetic studies in rats with bile duct cannulation showed that Compound 1 was mainly excreted unchanged in bile (>80%) and excreted in urine in small amounts (<20%). Studies using sandwich-cultured human hepatocytes showed excretion into bile pockets following temperature-dependent active uptake. Further in vitro studies confirmed that Compound 1 is a substrate of human OATP1B1, OATP1B3, and the efflux transporter MRP2. The plasma exposure of Compound 1 increased 4.5-fold in humanized OATP1B1 / 1B3 mice in the presence of rifampin. Phenotyping studies showed a dominant contribution of OATP1B3 compared to OATP1B1 to the hepatobiliary clearance of Compound 1. Therefore, changes in systemic exposure due to polymorphisms in OATP1B1 are unlikely to occur. PBPK modeling and simulations demonstrated that systemic exposure to Compound 1 could potentially increase two-fold when co-administered with an inhibitor of OATP1B1 / 1B3.

Claims

1. An anticancer agent containing E7766 or a pharmaceutically acceptable salt thereof, which is used for administration to a patient administered with an OATP inhibitor. Subsequently, the administration of the OATP inhibitor is discontinued or reduced, or the administration of the anticancer agent is reduced to eliminate related adverse events or reduce the frequency of related adverse events. The OATP inhibitor inhibits an organic anion transporting polypeptide selected from OATP1B1, OATP1B3, and a combination of OATP1B1 and OATP1B3. Anticancer agent. [Chemical Formula 1]

2. The OATP inhibitor is selected from the group consisting of fimasartan, clarithromycin, rifampin, clopidogrel, asunaprevir, boceprevir, daclatasvir, dasabuvir, elbasvir, faldaprevir, glecaprevir, grazoprevir, ledipasvir, paritaprevir, pibrentasvir, ritonavir, simeprevir, telaprevir, velpatasvir, voxilaprevir, lopinavir, quercetin, tipranavir, sacubitril, valsartan, gemfibrozil, eprosartan, cyclosporine, tacrolimus, eltrombopag, grapefruit juice, ursodeoxycholic acid, milk thistle (Silybum marianum), epigallocatechin gallate, ezetimibe, idelalisib, and cobimetinib. The anticancer agent according to claim 1.

3. It is used such that the anticancer agent is administered at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, or 1 month after the administration of the OATP inhibitor. The anticancer agent according to claim 1 or 2.

4. The patient is still being administered the OATP inhibitor. The anticancer agent according to any one of claims 1 to 3.

5. The dosage of the OATP inhibitor is reduced by 5-75%, 10-50%, 20-40%, or 30%. The anticancer agent according to claim 4.

6. The dosage of E7766 or a pharmaceutically acceptable salt thereof is reduced. The anticancer agent according to any one of claims 1 to 5.

7. The dosage of E7766 or a pharmaceutically acceptable salt thereof is reduced by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. The anticancer agent according to claim 6. ​ **Claim 8**: The anti-cancer agent according to any one of claims 1 to 7, wherein the exposure to E7766 or a salt thereof acceptable as a drug is maintained at a value of less than 12,800 μg, less than 9,600 μg, less than 6,400 μg, less than 3,200 μg, less than 2,400 μg, less than 2,000 μg, less than 1,750 μg, less than 1,600 μg, less than 1,200 μg, less than 800 μg, less than 600 μg, less than 300 μg, less than 150 μg, less than 75 μg, less than 50 μg, or less than 25 μg per 100 kg of patient body weight. **Claim 9** The anti-cancer agent according to claim 8, wherein the exposure is evaluated from the plasma of the patient. **Claim 10** The anti-cancer agent according to any one of claims 1 to 9, wherein the salt of E7766 acceptable as a drug is the diammonium salt of E7766.

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