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EP-3730140-B1 - TRADIPITANT FOR USE IN TREATING NAUSEA OR VOMITING

EP3730140B1EP 3730140 B1EP3730140 B1EP 3730140B1EP-3730140-B1

Inventors

  • POLYMEROPOULOS, MIHAEL, H
  • LICAMELE, LOUIS WILLIAM

Dates

Publication Date
20260506
Application Date
20160304

Claims (15)

  1. Tradipitant for use in treating a disorder selected from nausea, and vomiting in an individual, such use comprising: oral administration to the individual of tradipitant in a solid immediate release form comprising one or more pharmaceutically acceptable excipients, and tradipitant at a dose of 100-400 mg/day.
  2. Tradipitant for use according to claim 1, wherein the dose of tradipitant is 150-400 mg once daily (qd).
  3. Tradipitant for use according to claim 2, wherein the dose of tradipitant is 150-300 mg qd.
  4. Tradipitant for use according to claim 3, wherein the dose of tradipitant is 150-200 mg qd.
  5. Tradipitant for use according to claim 1, wherein the dose of tradipitant is 170 mg/day.
  6. Tradipitant for use according to claim 5, wherein the dose of tradipitant is administered as 85 mg twice daily (bid).
  7. Tradipitant for use according to claim 1, wherein the dose of 100-400 mg/day of tradipitant is administered as 50 to 200 mg twice daily (bid).
  8. Tradipitant for use according to claim 7, wherein the dose of tradipitant is 100-300 mg/day, administered as 50-150 mg bid.
  9. Tradipitant for use according to claim 8, wherein the dose of tradipitant is 100-200 mg/day, administered as 50-100 mg bid.
  10. Tradipitant for use according to any of claims 1-9, wherein the solid immediate release form is a capsule or a tablet.
  11. Tradipitant for use according to any of claims 1-10, wherein the disorder is nausea.
  12. Tradipitant for use according to any of claims 1-10, wherein the disorder is vomiting.
  13. Tradipitant for use according to any of claims 1-12, wherein the dose of tradipitant is sufficient to achieve and maintain a tradipitant plasma concentration in the individual of 175 ng/mL or greater throughout a duration of treatment.
  14. Tradipitant for use according to claim 13, wherein the effective plasma concentration of tradipitant is about 200 ng/mL or greater.
  15. Tradipitant for use according to claim 1, wherein the effective plasma concentration of tradipitant is about 225 ng/mL or greater.

Description

BACKGROUND The NK-1R is expressed throughout different tissues of the body, with major activity found in neuronal tissue. SP and NK-1R interactions in neuronal tissue regulate neurogenic inflammation locally and the pain perception pathway through the central nervous system. Other tissues, including endothelial cells and immune cells, have also exhibited SP and NK-1R activity. The activation of NK-1R by the natural ligand SP is involved in numerous physiological processes, including the perception of pain, behavioral stressors, cravings, and the processes of nausea and vomiting. An inappropriate over-expression of SP either in nervous tissue or peripherally could result in pathological conditions such as substance dependence, anxiety, nausea/vomiting, and pruritus. An NK-1R antagonist may possess the ability to reduce this over-stimulation of the NK-1R, and as a result address the underlying pathophysiology of the symptoms in these conditions. Tradipitant is a neurokinin-1 receptor antagonist formerly known as VLY-686, having the chemical names 2-[1-[[3,5-bis(trifluoromethyl)phenyl]methyl]-5-(4-pyridinyl)-1H-1,2,3-triazol-4-yl]-3-pyridinyl](2-chlorophenyl)-methanone and {2-[1-(3,5-Bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone, and the following chemical structure: Tradipitant is disclosed in US Pat. 7,320,994, and contains six main structural components: the 3,5-bis-trifluoromethylphenyl moiety, two pyridine rings, the triazol ring, the chlorophenyl ring and the methanone. Crystalline Forms IV and V of tradipitant are disclosed in US Pat. 7,381,826. A process for synthesizing tradipitant is disclosed in US Pat. 8,772,496. BRIEF DESCRIPTION OF THE INVENTION A first aspect of the disclosure provides a method of administering tradipitant to a patient in need thereof which comprises internally administering to the patient tradipitant in an amount and at a frequency of administration sufficient to achieve and to maintain a plasma concentration of > 100 ng/mL. A second aspect of the disclosure provides a method of administering tradipitant to a patient in need thereof which comprises internally administering an effective amount of tradipitant to the patient. The effective amount may be, e.g., 100 to 400 mg/day, 100 to 300 mg/day, or 100 to 200 mg/day. The effective amount may be administered twice daily, i.e., 50 to 200 mg bid, 50 to 150 mg bid, 50 to 100 mg bid, or about 85 mg bid. A third aspect of the disclosure provides a use of tradipitant for the treatment of a disorder selected from nausea, and vomiting by internally administering to a patient suffering from a disorder selected from nausea or vomiting by internally administering to the patient tradipitant in an amount and at a frequency of administration sufficient to achieve and to maintain a plasma concentration of > 100 ng/mL, i.e., an effective amount of tradipitant. A fourth aspect of the disclosure provides a use of tradipitant for the preparation of a medicament for the treatment of a disorder selected from nausea or vomiting by internally administering to the patient tradipitant in an amount and at a frequency of administration sufficient to achieve and to maintain a plasma concentration of > 100 ng/mL, i.e., an effective amount, e.g., an amount of 85 mg bid, 85 mg qd, 100 mg qd, or other dosing regimen. In further aspects of the invention, the dose can be 85 to 170 mg/day. This may be, e.g., 85 mg bid, 85 mg qd, 100 mg qd, or 100 mg bid. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 provides a scatter plot of serum levels of tradipitant, showing concentration weight vs. visit time.FIG. 2 provides a scatter plot of VAS change vs. concentration-weight of tradipitant (Spearman correlation P-value = 0.0204). DETAILED DESCRIPTION OF THE DISCLOSURE The invention is defined in the appended claims. Any references in the description to methods of treatment refer to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy. Although embodiments of the invention are illustrated relative to specific dosing regimens, e.g., 100 mg qd, 85 mg bid, and 85 mg qd, it is understood that the teachings are equally applicable to other dosing regimens, e.g., 100 to 400 mg/day, 100 to 300 mg/day, 100 to 200 mg/day, or about 85-170 mg/day, which may be administered as, e.g., 50 to 200 mg bid, 50 to 150 mg bid, 50 to 100 mg bid, or about 85 mg bid. As used herein, the term "patient" refers to a mammal that is afflicted with one or more disorders ameliorated by administration of tradipitant. Guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of mammals within the scope of the meaning of the term. It will be understood that the most preferred patient is a human. It is also recognized that one skilled in the art may affect the disorders by treating a patient presently afflicted with the diso