Methods of treatment with trandipitant

Abstract

Disclosed herein are methods of treating individuals who are experiencing or are at risk of experiencing the adverse consequences of opioid use, and treating individuals who are experiencing or are at risk of experiencing craving for opioids, and the use of the NK-1 receptor antagonist trandipitant in treating such individuals.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 682,831, filed on June 8, 2018, which is hereby incorporated by reference in its entirety. Background Art

[0003] The present application generally relates to the use of NK-1 receptor antagonists. More specifically, the present application relates to the use of the NK-1 antagonist randipitant in treating individuals who are experiencing or may experience the undesirable consequences of opioid use.

[0004] Tandipitant (i.e., 2-[1-[[3,5-bis(trifluoromethyl)phenyl]methyl]-5-(4-pyridinyl)-1H-1,2,3-triazol-4-yl]-3-pyridinyl](2-chlorophenyl)-methanone or {2-[1-(3,5-bis(trifluoromethyl)phenyl]methyl]-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone) and its pharmaceutically acceptable acid addition salts (collectively referred to herein as "tandipitant") are known to be highly potent, selective, centrally penetrant and orally active NK-1 receptor antagonists, and its free base form is described below as a compound of formula I

[0005]

[0006] Crystalline Forms IV and V of the free base form of trandipitant are disclosed in US Patent 7,381,826.

[0007] In U.S. Patent 7,320,994, it is described that the free base and pharmaceutically acceptable acid addition salt forms of trametapitant can be used to treat a number of diseases associated with tachykinin receptor activation, including addictive diseases such as alcoholism as one of a large number of named diseases and conditions. The medical use of trametapitant is further disclosed in International Patent Application Publication Nos. WO2016 / 141341A1 (itch) and WO2019 / 055225A1 (atopic dermatitis). WO 2016 / 141341A1 describes the administration of tamiflu to achieve tamiflu plasma concentration levels of 100 ng / mL or more, 125 ng / mL or more, 150 ng / mL or more, 175 ng / mL or more, 200 ng / mL or more, and 225 ng / mL or more, and oral administration of tamiflu in an immediate release solid dosage form or a controlled release dosage form, at a tamiflu administration dose of 100-400 mg / day, 100-300 mg / day, 100-200 mg / day, and 85 mg twice a day.

[0008] Known opioids include opiates known in the art (e.g., heroin and morphine) and non-opioid opioids (e.g., oxycodone, hydrocodone, and fentanyl). Similarly, the uses of opioids are known in the art, such as most notably as analgesics.

[0009] Opioids are known to have multiple forms of use, including acceptable forms of therapeutic use and misuse, including opioid abuse. These forms of opioid use in individuals are known to have the potential to evolve over time, e.g., an individual may initiate opioid treatment for one or more acceptable therapeutic uses and subsequently transition to misuse, such as abuse of opioids.

[0010] Misuse, including abuse, is known to result in one or more undesirable aspects or consequences to an individual's mental or physical health or well-being. Craving for opioids is known to be an undesirable consequence of opioid use or abuse. It may be the primary undesirable consequence of opioid use or misuse, including abuse. Craving for opioids is known to be an undesirable consequence of opioid use or abuse. It may be the primary undesirable consequence of opioid use or abuse, including abuse. Opioid abuse is also known to include inappropriate behavioral consequences, such as using opioids prescribed for another individual, using opioids at a dose or frequency different from that prescribed, and repeatedly using opioids to produce pleasure, relieve stress, or to alter or escape reality. Other known undesirable consequences of opioid use include inappropriate physical, behavioral, and psychological changes, including drowsiness, confusion, an initial feeling of euphoria followed by apathy, feelings of restlessness, involuntary and purposeless movements such as hand twisting, pacing, and uncontrolled tongue movements; cognitive and motor slowing, impaired judgment, nausea, constipation, respiratory depression, slurred speech, diminished pain relief over time and concomitant increase in pain, increased tolerance, disability, relapse, and death. Known misuse of opioids involves the use of opioid medications obtained legally by prescription, as well as the illegal acquisition and illegal use of illegal substances such as heroin.

[0011] Opioids are known to produce physical dependence. This dependence is characterized by the onset of withdrawal symptoms, such as general pain, muscle and bone pain, chills, cramps, pupil dilation, restlessness, anxiety, insomnia and other sleep problems, nausea, diarrhea, vomiting, cold flashes, goose bumps, uncontrolled leg movements, and severe cravings while the body adjusts to the absence or loss of the opioid. Individuals who use or misuse, including abuse of opioids, can be addicted or non-addicted to opioids. Opioid addiction is known to result in an individual's inability to control the urge to use opioids despite undesirable consequences, such as negative effects on personal relationships or finances. Summary of the invention

[0012] The present invention provides a method for treating an individual with chuandipitant, and an individual who is experiencing or is at risk of experiencing the undesirable consequences of opioid use, the treatment comprising administering chuandipitant to the individual, in particular administering the following dose of chuandipitant to the individual: a dose effective to achieve a plasma concentration of at least about 100 ng / mL, about 125 ng / mL, about 150 ng / mL, about 175 ng / mL, about 200 ng / mL, or about 225 ng / mL during the treatment period, or a dose of 100-400 mg / day, 100-300 mg / day, 100-200 mg / day, 150-400 mg / day, 150-300 mg / day, 150-200 mg / day or about 170 mg / day. More specifically, a dose of 170 mg / day can be 85 mg, administered twice a day, for example, once every 12 hours.

[0013] The use of opioids may be in accordance with a treatment regimen, or may constitute a form of opioid misuse, such as in the case of opioid abuse. The individual being treated may be an opioid naive individual, or may be opioid experienced, such as an individual diagnosed with opioid use disorder (OUD). As used herein, the term "individual" refers to a human being.

[0014] Undesirable consequences of opioid use may manifest as or include a craving for the administration of opioids. Such administration of tradipitant may reduce or eliminate the craving or desire for opioids in the treated individual. In other cases, such administration of tradipitant may be preventive in nature and may be administered to an individual who is currently using opioids and is therefore at risk of experiencing undesirable consequences of such use, but has not experienced such undesirable consequences to date.

[0015] The chuandipitant used in the above-mentioned treatment regimen can be prepared in an immediate release solid dosage form or a controlled release solid dosage form, and such a preparation is prepared using a conventional method for preparing a pharmaceutical composition for oral administration. Specifically, the free base form of chuandipitant can be prepared using its crystalline form known in the art, such as crystalline form IV or crystalline form V.

[0016] These and other aspects, advantages and salient features of the invention will become apparent from the following detailed description, which, taken in conjunction with the annexed drawings, discloses various embodiments of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1-4 The results of the study described herein regarding the effects of trandipitant treatment on subjective outcomes of oxycodone administration are illustrated in graphical form. DETAILED DESCRIPTION

[0018] Various embodiments of the invention described herein include methods of treating an individual experiencing or at risk of experiencing undesirable consequences of opioid use by administering to the individual randipitant, randipitant for treating an individual experiencing undesirable consequences of opioid use, and methods of reducing an individual's need (i.e., craving) for opioids by administering randipitant.

[0019] Methods for treating individuals who experience undesirable consequences of opioid use may first include identifying the individual to be treated. Determination of individuals for whom treatment with trandipitant is indicated may be accomplished by a health care professional trained to identify individuals who experience undesirable consequences of opioid abuse. In addition, individuals may self-assess the need for intervention to address such consequences.

[0020] In some embodiments, the individual may have been an opioid naive before the opioid use associated with undesirable consequences, that is, the individual may not have a history of prescribing, administering, or self-administering opioids on a daily or regular basis. Such individuals may include, for example, individuals who are prescribed opioid analgesics by a medical provider and use such opioid analgesics for the first time and / or according to a prescribed treatment regimen, or individuals who have recently begun self-administering opioid drugs for any reason. In other embodiments, the individual may be opioid-experienced, that is, may have a history of using opioids. In further embodiments, the individual may be highly opioid-experienced, and may have a diagnosis of opioid use disorder (OUD).

[0021] The methods disclosed herein may include administering tampamp to an individual who experiences undesirable consequences of opioid use, consistent with use or misuse, including abuse. During the treatment period, the dose of tampamp administered to the individual may be effective to achieve a tampamp plasma concentration of at least about 100 ng / mL, about 125 ng / mL, about 150 ng / mL, about 175 ng / mL, about 200 ng / mL, or about 225 ng / mL.

[0022] As used herein, the modifier "about" used in connection with an amount (e.g., "about 175 ng / mL or more") is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular amount). The concentrations of trandipitant referred to herein refer to the concentration of the free base form of trandipitant.

[0023] In further embodiments, during the treatment period, tautomer can be administered at a dose effective to achieve and maintain a tautomer plasma concentration of at least about 100 ng / mL, about 125 ng / mL, about 150 ng / mL, about 175 ng / mL, about 200 ng / mL, or about 225 ng / mL.

[0024] The plasma concentration levels disclosed herein can be achieved by orally administering vendipitant, such as Form IV or Form V (or a pharmaceutically acceptable acid addition salt thereof), once daily at a higher dose of an immediate release solid dosage form, at a lower dose of an immediate release dosage form with improved bioavailability, in a controlled release dosage form, or by orally administering vendipitant multiple times a day (e.g., twice or more a day) at a lower dose in an immediate release or controlled release dosage form.

[0025] The pharmaceutically acceptable acid addition salts of chuandipitant include salts formed with a variety of organic and inorganic acids, and include physiologically acceptable salts commonly used in pharmaceutical chemistry. These salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19 (1977), which are known to those skilled in the art. Typical inorganic acids used to form such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, hypophosphorous acid, metaphosphoric acid, pyrophosphoric acid, etc. Salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, can also be used.

[0026] In the embodiments disclosed herein, the individual can be administered Chamdipitant in an effective dose or effective amount, and the effective dose or effective amount used herein refers to a dose or amount that is effective for treating the symptoms, symptoms or consequences of the use of opioids described herein. In various embodiments, the effective dose of Chamdipitant can be, for example, 100-400 mg / day, 100-300 mg / day, 100-200 mg / day, 150-400 mg / day, 150-300 mg / day, 150-200 mg / day or about 170 mg / day. The milligram amount of Chamdipitant mentioned here refers to its free base form. The above ranges are inclusive and can be independently combined, so that, for example, the range of "100-400 mg / day" includes its endpoints. The disclosed ranges can be further combined to include intermediate ranges, such as 100-150 mg / day, 150-170 mg / day, 170-200 mg / day, etc. In addition, in embodiments where trandipitant is administered at a dose of about 170 mg / day, it may be more particularly administered at a dose of 85 mg twice a day (bid), or more particularly administered at 85 mg every 12 hours (Q12H). With respect to dosing, "bid" or twice daily dosing generally refers to dosing once in the morning and once in the evening, generally separated by no less than about 8 hours or more than about 16 hours, such as 10 to 14 hours or 12 hours ("Q12H").

[0027] It should be understood that effective plasma concentrations can also be achieved using different doses and / or different formulations, including but not limited to controlled release formulations. Regardless of the specific formulation, and whether the individual is administered vampitant at a dose specified by the amount of vampitant or a plasma concentration level produced and / or maintained by the dose, vampitant can produce a significantly reduced experience of the undesirable consequences of using opioids, such as the desire or craving for opioids. This in turn provides a useful tool for treating opioid misuse, including opioid abuse and / or addiction.

[0028] It is also recognized that one skilled in the art can influence an individual's experience of the undesirable consequences of opioid use by treating an individual currently suffering from the undesirable consequences of opioid use with an effective amount of trandipitant or by prophylactically treating an individual who uses opioids but has not yet experienced the undesirable consequences. Such individuals for whom prophylactic treatment is indicated can be said to be at risk for experiencing the undesirable consequences of opioid use, including opioid misuse, such as abuse. Because individuals who continue to use opioids are at risk and may experience undesirable consequences during such continued use, any such individuals who continue to use opioids (including those who abuse opioids) can be treated prophylactically.

[0029] Thus, for purposes of the present invention, the terms "treat" and "treatment" are intended to include any process in which there may be a slowing, interruption, prevention, control or cessation of the undesirable consequences of opioid use. Thus, while the term includes preventive treatment of the undesirable consequences of opioid use, it does not necessarily mean complete prevention or complete elimination of the undesirable consequences.

[0030] It will be understood by those skilled in the art that additional embodiments may be selected by combining the above embodiments or by referring to the following examples.

[0031] Example

[0032] The approximately 6-week double-blind inpatient study using a within-subject crossover design examined the effects of maintenance on oxycodone response with trandipitant compared with placebo. Study subjects included healthy adults who reported a history of regular illicit opioid misuse and intranasal opioid use without physical dependence. Participant characteristics are provided in Table 1 below.

[0033]

[0034] Subjects were administered placebo or tampitan (85 mg, oral (po), twice daily) on days 3-17 of the study, a washout period was given on days 18-23, and then placebo or tampitan (85 mg, po, twice daily) was administered on days 24-39 of the study. In this study, tampitan / placebo administration was balanced among subjects. On days 3, 18, 24, and 39 of the study, subjects participated in the stimulation phase (Day 1 and steady state), in which they received 0, 5, 10, or 20 mg intranasal (IN) oxycodone at 1 hour intervals, after which the effect of tampitan on human analgesia was evaluated. On days 2, 8, 11, 15, 29, 32, and 36 of the study, subjects participated in the sample phase, in which 0, 15, or 30 mg of intranasal oxycodone was administered to the subjects, after which the effect of tampitan on the subject evaluation outcomes was evaluated. Such subject-assessed outcomes included responses to questions including, "How much do you like the drug," "What good effects does the drug have," "Do you feel any drug effects," and "How much do you desire opioids right now?" In addition, on study days 9, 12, 16, 30, 33, and 37, subjects participated in an opt-in period in which the effect of trandipitant on oxycodone self-administration was assessed.

[0035] result

[0036] Figure 1-4Results regarding subjective outcomes are presented graphically. Oxycodone produced significant and dose-dependent increases in peak ratings of drug, good effect, and overall drug effect (p>0.001; * indicates significant difference from 0 mg). Although no significant effect of oxycodone dose was observed on trough scores of opioid craving, there was a significant effect of the tradipitant condition (p<0.05), whereby craving, i.e., decreased during tradipitant maintenance compared to placebo maintenance ( Figure 4 ). Figure 1-3 Further illustrated, at some opioid doses, such as 15 mg intranasal oxycodone, trandipitant reduced perceptions of how much the opioid was liked, how good the drug worked, and how powerful the drug felt.

[0037] Thus, it was found that maintenance with tampitan can reduce the craving for opioid drugs, and at certain doses can reduce the pleasure and drug seeking sensations. In particular, maintenance with tampitan significantly (p<0.05) reduced the need for opioid drugs compared to placebo.

Claims

1. Use of trandipitant in the preparation of a medicament for reducing an individual's need for an opioid drug comprising oxycodone or hydrocodone, the use comprising: The individual is administered a dose of 150-400 mg / day of trandipitant.

2. The use of claim 1, wherein the opioid drug comprises hydrocodone.

3. The use of claim 1, wherein the opioid drug comprises oxycodone.

4. The use according to any one of claims 1 to 3, wherein after said administration, said dose is effective to achieve and maintain a plasma concentration of 150 ng / mL or more of trandipitant during the treatment period.

5. The use as claimed in claim 4, wherein the plasma concentration is above 175 ng / mL.

6. The use according to claim 5, wherein the plasma concentration is above 200 ng / mL.

7. The use according to claim 6, wherein the plasma concentration is above 225 ng / mL.

8. The use according to any one of claims 1 to 3, wherein the dosage is 150-300 mg / day.

9. The use according to claim 8, wherein the dosage is 150-200 mg / day.

10. The use according to claim 9, wherein the dosage is 170 mg / day.

11. The use according to claim 10, wherein the dosage is 85 mg, twice a day.

12. The use according to claim 11, wherein the dose is 85 mg, once every 12 hours.

13. The use of any one of claims 1-3, wherein the subject is an opioid-experienced subject.

14. The use of any one of claims 1-3, wherein the individual is diagnosed with opioid use disorder (OUD).

15. The use of any one of claims 1-3, wherein the individual being treated is experiencing cravings for opioid drug administration.

16. The use of any one of claims 1-3, wherein the individual being treated is at risk of experiencing cravings for opioid drug administration.

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