KR-20260065803-A - Composition for achieving an effective dose level of an mTOR inhibitor

Abstract

Compositions and methods for treating autoimmune, alloimmunological, inflammatory, age-related, and cancer-related pathological conditions are provided herein.

Inventors

• 클리, 트레버

Assignees

• 클리, 트레버

Dates

Publication Date

20260511

Application Date

20240830

Priority Date

20230901

Claims (20)

1. A method for treating alloimmunological, autoimmunological, inflammatory, age-related, or cancer-related pathological conditions of a subject, comprising the step of administering an mTOR inhibitor and a cytochrome p450 inhibitor to the subject.
2. A method according to claim 1, wherein the mTOR inhibitor and the cytochrome p450 inhibitor are administered simultaneously.
3. A method according to claim 1, wherein the mTOR inhibitor and the cytochrome p450 inhibitor are administered almost simultaneously but sequentially.
4. A method according to any one of claims 1 to 3, wherein the mTOR inhibitor is selected from rapamycin, everolimus, temsirolimus, lidaphorolimus, umirolimus, zotarolimus, and analogs or derivatives thereof.
5. In any one of claims 1 to 4, the cytochrome p450 inhibitor is amiodarone, chloroquine, cimetidine, clomipramine, diphenhydramine, fluoxetine, fluphenazine, haloperidol, paroxetine, perphenazine, propafenone, propoxyphen, quinacrine, quinidine, sertraline, terbinafine, thioridazine, amprenavir, clarithromycin, danazol, delavirdine, diltiazem, efavirenz, erythromycin, ethinylestradiol, fluconazole, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, quinine, ritonavir, saquinavir, synercid, troleandomycin, verapamil, Boceprevir, Telithromycin, Ceritinib, Mibepradil, Ribociclib, Tucatinib, Chloramphenicol, Posaconazole, Voriconazole, Cobicistat, Aprepitant, Ciprofloxacin, Conivabtan, Crizotinib, Rutin, Topisopam, Miconazole, Bergamotin, Cyclosporine, Donedarone, Imatinib, Berberine, Buprenorphine, Cafestol, Cilostazol, Fossaprepitant, Lomitapide, Orphenadrin, Omeprazole, Quercetin, Ranitidine, Ranolazine, Tacrolimus, Ticagrelor, Valproic Acid, Amlodipine, Azithromycin, Bergaptol, Cannabidiol, Dithiocarbamate, Mifepristone, Norfloxacin, Gestodene, Niacin, Niacinamide, Isoniazid, A method selected from zafir-lukast and analogs or derivatives thereof.
6. A method according to any one of claims 1 to 5, wherein the mTOR inhibitor is rapamycin.
7. A method according to any one of claims 1 to 6, wherein the cytochrome p450 inhibitor is ritonavir.
8. A method according to any one of claims 1 to 6, wherein the cytochrome p450 inhibitor is cobicistat.
9. A method according to any one of claims 1 to 8, wherein the mTOR inhibitor is administered in an amount of about 0.2 mg/day, about 0.6 mg/day, about 1 mg/day, about 4 mg/day, about 8 mg/day, or about 16 mg/day.
10. A method according to any one of claims 1 to 8, wherein the mTOR inhibitor is administered in an amount of about 0.2 mg/week, about 0.6 mg/week, about 1 mg/week, about 4 mg/week, about 8 mg/week, or about 16 mg/week.
11. A method according to any one of claims 1 to 8, wherein the mTOR inhibitor is administered in an amount of about 0.6 mg/week.
12. A method according to any one of claims 1 to 11, wherein the cytochrome p450 inhibitor is administered in an amount of about 0.1 mg per kg of the subject's body weight daily, about 0.5 mg per kg of the subject's body weight daily, about 1 mg per kg of the subject's body weight daily, about 2 mg per kg of the subject's body weight daily, or about 4 mg per kg of the subject's body weight daily.
13. A method according to any one of claims 1 to 11, wherein the cytochrome p450 inhibitor is administered in an amount of about 5 mg/day, about 10 mg/day, about 20 mg/day, or about 40 mg/day.
14. A method according to any one of claims 1 to 11, wherein the cytochrome p450 inhibitor is administered in an amount of about 5 mg/week, about 10 mg/week, about 20 mg/week, or about 40 mg/week.
15. A method according to any one of claims 1 to 11, wherein the cytochrome p450 inhibitor is administered in an amount of about 20 mg/week.
16. A method according to any one of claims 1 to 15, wherein the autoimmune, alloimmunological, or inflammatory pathological condition is associated with an increase in lymphocyte levels.
17. A method according to any one of claims 1 to 15, wherein the cancer-related pathological condition is associated with the mTOR complex.
18. A method according to any one of claims 1 to 15, wherein the aging-related pathological condition is associated with the mTOR complex.
19. In paragraph 16, the above-mentioned autoimmune, alloimmunological, or inflammatory pathological condition is organ transplant rejection, lupus, sclerosis, or heart failure.
20. In paragraph 17, the above cancer-related condition is breast cancer, prostate cancer, lung cancer, melanoma, bladder cancer, brain cancer, or kidney cancer.

Description

Composition for achieving an effective dose level of an mTOR inhibitor The present disclosure provides a method of administering an mTOR inhibitor (e.g., sirolimus, also known as rapamycin) in combination with a cytochrome p450 enzyme inhibitor (e.g., ritonavir) to achieve blood levels correlated with effective inhibition of the mTOR complex and limitation of adverse effects. In some embodiments, the methods and compositions described herein are useful for alleviating, slowing, or preventing the onset of autoimmune, alloimmunological, inflammatory, cancer-related, or age-related pathologies. Cross-reference regarding related applications This application claims priority and the benefit thereof to U.S. Application No. 63/580,027 filed on September 1, 2023, the entire contents of which are incorporated herein by reference. mTOR inhibitors are used as therapeutic agents for various alloimmunological, autoimmunological, inflammatory, and cancer-related conditions. They have also been shown to be promising as therapeutic agents for age-related conditions (Reference [Wilkinson et al. 2012]). However, their use is limited by the frequency of associated adverse effects as well as the required dosing frequency for patients (Reference [Sofrianadou et al., 2011]). mTOR inhibitors are frequently used as treatments for conditions related to the immune system, including, for example, rapamycin for kidney transplantation (Knechtle et al., 2003) or everolimus to prevent rejection during liver transplantation (Levy et al., 2006). However, these treatments are limited by the adverse effects associated with mTOR inhibitors. For example, rapamycin is associated with dyslipidemia (Kassike et al., 2008), while everolimus is associated with diabetes (Ohyama et al., 2022). Because mTOR inhibitors have a narrow therapeutic index, this means that the blood levels of the mTOR inhibitor required to be effective for a given disease are close to the blood levels associated with overdose and adverse effects. Furthermore, when mTOR inhibitors are administered to patients, the 'therapeutic dose' is often monitored, which implies that the patient's blood levels of the mTOR inhibitor need to be monitored through laboratory testing. For example, rapamycin is typically administered to adults at a dose of 2 mg once daily to reach an effective concentration while avoiding adverse effects. The applicant has surprisingly discovered that the administration of an mTOR inhibitor (e.g., rapamycin) in combination with a cytochrome p450 inhibitor (e.g., ritonavir) provides more effective and consistent treatment at lower doses of the mTOR inhibitor. The synergistic effect of the provided combination therapy enables less frequent administration, lower dosages, and reduced pharmacokinetic variability for subjects receiving the mTOR inhibitor (e.g., rapamycin). mTOR inhibitors are currently known to be metabolized via cytochrome p450 enzymes. Without being bound by theory, the present disclosure includes the insight that when cytochrome p450 inhibitors are co-administered with mTOR inhibitors, dose levels associated with efficacy in the treatment of specific diseases, such as blood levels of 5–15 ng/mL associated with the safe and effective use of rapamycin in the treatment of vascular disorders, can be more consistently achieved (Reference [Nadal et al., 2016]). In some embodiments, the present disclosure provides a method for treating a disease, disorder, or pathological condition, comprising the step of administering to a subject an mTOR inhibitor or a pharmaceutically acceptable salt thereof and a cytochrome p450 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method for achieving a target dose level of an mTOR inhibitor, comprising the step of administering an mTOR inhibitor or a pharmaceutically acceptable salt thereof, and a cytochrome p450 inhibitor or a pharmaceutically acceptable salt thereof to a target or biological sample. In some embodiments, the present disclosure provides a method for preventing adverse effects associated with the metabolism of an mTOR inhibitor, comprising the steps of: contacting mTOR with an mTOR inhibitor or a pharmaceutically acceptable salt thereof; and contacting cytochrome p450 with a cytochrome p450 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the mTOR inhibitor is selected from the group consisting of rapamycin (also known as sirolimus), everolimus, temsirolimus, lidaporolimus, umirolimus, zotarolimus, and analogs or derivatives thereof. In some embodiments, the mTOR inhibitor is rapamycin. In some embodiments, the mTOR inhibitor is administered orally at a dose of about 0.6 mg daily. In some embodiments, the cytochrome p450 inhibitor is amiodarone, chloroquine, cimetidine, clomipramine, diphenhydramine, fluoxetine, fluphenazine, haloperidol, paroxetine, perphenazine, propafenone, propoxyphen, quinacrine, quinidine, se