WO2015191686A1 - Procédés d'administration de méthylnaltrexone - Google Patents

Procédés d'administration de méthylnaltrexone Download PDF

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Publication number
WO2015191686A1
WO2015191686A1 PCT/US2015/035063 US2015035063W WO2015191686A1 WO 2015191686 A1 WO2015191686 A1 WO 2015191686A1 US 2015035063 W US2015035063 W US 2015035063W WO 2015191686 A1 WO2015191686 A1 WO 2015191686A1
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subject
methylnaltrexone
mntx
administration
opioid
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PCT/US2015/035063
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English (en)
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William Forbes
Enoch Bortey
Pam Golden
Craig Paterson
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Salix Pharmaceuticals, Inc.
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Publication of WO2015191686A1 publication Critical patent/WO2015191686A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • Opioids are widely used in treating patients with pain. Such patients include those with advanced cancers and other terminal diseases and also those with chronic non-malignant pain and acute non-malignant pain.
  • Opioids are narcotic medications that activate opioid receptors located in the central nervous system to relieve pain. Opioids, however, also react with receptors outside of the central nervous system, resulting in side effects including constipation, nausea, vomiting, urinary retention, and severe itching. Notable are the effects of opioids in the gastrointestinal (GI) tract where these drugs inhibit gastric emptying and peristalsis in the intestines, thereby decreasing the rate of intestinal transit and producing constipation.
  • GI gastrointestinal
  • the use of opioids in treating pain is often limited due to these undesired side effects, which can be debilitating and often cause patients to refuse the use of opioid analgesics.
  • endogenous opioids and opioid receptors can also affect the gastrointestinal (GI) tract and can be involved in normal regulation of intestinal motility and mucosal transport of fluids.
  • GI gastrointestinal
  • an abnormal physiological level of endogenous opioids and/or receptor activity can also lead to bowel dysfunction.
  • patients who have undergone surgical procedures, especially surgery of the abdomen often suffer from a particular bowel dysfunction, termed post-operative ileus, that can be caused by fluctuations in natural opioid levels.
  • post partum ileus which can be caused by similar fluctuations in natural opioid levels as a result of birthing stress.
  • Gastrointestinal dysfunction associated with post-operative or post-partum ileus can typically last for 3 to 5 days, with some severe cases lasting more than a week.
  • Administration of opioids to a patient after surgery to treat pain which is now an almost universal practice, can exacerbate bowel dysfunction, thereby delaying recovery of normal bowel function, prolonging hospital stays, and increasing medical care costs.
  • Opioid receptor antagonists such as naloxone, naltrexone, and nalmefene, have been studied as a means of antagonizing the undesirable peripheral side effects of opioids.
  • these agents not only act on peripheral opioid receptors but also on opioid receptors in the central nervous system, sometimes reversing the beneficial and desired analgesic effects of opioids or causing symptoms of opioid withdrawal.
  • Preferable approaches for use in controlling opioid-induced side effects include administration of peripheral acting opioid receptor antagonists that do not readily cross the blood-brain barrier.
  • the peripheral ⁇ opioid receptor antagonist methylnaltrexone has been studied since the late 1970s. It has been used in patients to reduce opioid-induced side effects such as constipation, pruritus, nausea, and urinary retention(see, e.g., U.S. Patents 5,972,954, 5,102,887, 4,861,781, and 4,719,215; and Yuan et al, Drug and Alcohol Dependence 1998, 52, 161).
  • the dosage form of methylnaltrexone used most often in these studies has been a solution of methylnaltrexone for intravenous injection.
  • kits for treating opioid-induced constipation in a subject wherein the method decreases the risk of a cardiovascular event in a subject having opioid induced constipation, wherein the methods include administering to the subject a pharmaceutical composition containing a compound of formula (II):
  • a " is a suitable anion, and wherein the administration of the pharmaceutical composition results in a rescue free bowel movement, thereby reducing the risk of a cardiovascular event in the subject.
  • Also disclosed herein are methods of decreasing the risk of a a cardiovascular event in a subject having opioid induced constipation wherein the methods include administering to the subject a pharmaceutical composition containing a compound of formula (II), wherein A " is a suitable anion, and wherein the administration of the pharmaceutical composition reduces the risk of a cardiovascular event in the subject.
  • administration of the pharmaceutical composition results in a rescue free bowel movement and/or improved stool consistency, thereby reducing the risk of a cardiovascular event in the subject.
  • the risk of a cardiovascular event in the subject is reduced due to a reduction in straining.
  • the risk of a cardiovascular event in the subject is reduced due to the subject's ability to maintain optimal opioid pain management.
  • the cardiovascular event is at least one selected from the group of: myocardial infarction, acute myocardial infarction, cardiac arrest, cardiorespiratory arrest, congestive cardiac failure, cardiovascular disorder, coronary artery disease, cyanosis, ischemic coronary artery disorders, rate and rhythm disorders, and supraventricular arrhythmias.
  • the cardiovascular event is at least one selected from the group of: elevated pulse, stroke, changes in blood pressure, changes in systolic blood pressure and changes in diastolic blood pressure.
  • Embodiments are also directed to methods of increasing compliance with opioid treatment in a subject having opioid induced constipation, wherein the methods include administering to the subject a pharmaceutical composition containing a compound of formula (II), wherein A " is a suitable anion, and wherein the administration of the pharmaceutical composition results in a rescue free bowel movement, thereby reducing the risk of symptoms of opioid withdrawal.
  • the methods include administering to the subject a pharmaceutical composition containing a compound of formula (II), wherein A " is a suitable anion, and wherein the administration of the pharmaceutical composition results in a rescue free bowel movement, thereby reducing the risk of symptoms of opioid withdrawal.
  • Embodiments also relate to methods of treating opioid-induced constipation in a subject, wherein the methods include: administering to the subject a pharmaceutical composition containing a compound of formula (II), wherein A " comprises a suitable anion, and wherein the subject is suffering from hepatic impairment.
  • the subject has Child-Pugh Class B or Class C hepatic impairment.
  • Also provided herein are methods of treating opioid-induced constipation in a subject wherein the methods include: administering to the subject a pharmaceutical composition containing a compound of formula (II), wherein A " comprises a suitable anion, and wherein the subject is suffering from renal impairment.
  • the subject has a creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault.
  • the subject has advanced illness and is receiving palliative care. In one embodiment, the subject's response to laxative therapy has not been sufficient. In one embodiment, the subject has advanced chronic pain.
  • the subject's response to laxative therapy has not been sufficient.
  • the method increases compliance with opioid treatment in a subject having opioid induced constipation.
  • the subject thereby reduces the risk of opioid withdrawal.
  • the risk of opioid withdrawal includes risk of having one or more withdrawal symptoms.
  • the subject thereby reduces the risk of having one or more withdrawal symptoms.
  • the subject is also administered opioids.
  • the administering of the pharmaceutical composition comprising a compound of formula (II) is not followed by an adjustment of administration of the opioid in the subject.
  • the administering of the pharmaceutical composition does not lead to an adjustment of the dosage of opioid administered to the subject.
  • the administering of the pharmaceutical composition is not followed by an increase in the dosage of the opioid administered to the subject.
  • the administering of the pharmaceutical composition is not followed by an increase in pain intensity experienced by the subject.
  • PAMORA peripherally- acting mu-opioid receptor antagonists
  • a " includes an anion selected from the group consisting of: chloride, bromide, iodide, fluoride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate sulfonate, methylsulfonate, formate, carboxylate, methylsulfate or succinate salt.
  • a " includes bromide.
  • a " includes an anion selected from the group consisting of: is butyl sulfate, pentyl sulfate, hexyl sulfate, heptyl sulfate, octyl sulfate, nonyl sulfate, decyl sulfate, undecyl sulfate, dodecyl sulfate, tridecyl sulphate, tetradecyl sulfate, pentadecyl sulfate, hexadecyl sulfate, heptadecyl sulfate, octadecyl sulfate, eicosyl sulfate, docosyl sulfate, tetracosyl sulfate, hexacosyl sulfate, octacosyl sulfate, and triacontyl
  • the pharmaceutical composition further includes at least one agent selected from the group consisting of sodium bicarbonate, microcrystalline cellulose, crospovidone, polysorbate 80, edetate calcium disodium dehydrate, silicified microcrystalline cellulose, talc, colloidal silicon dioxide, magnesium stearate, and combinations thereof.
  • at least one agent selected from the group consisting of sodium bicarbonate, microcrystalline cellulose, crospovidone, polysorbate 80, edetate calcium disodium dehydrate, silicified microcrystalline cellulose, talc, colloidal silicon dioxide, magnesium stearate, and combinations thereof.
  • the pharmaceutical composition further includes at least one agent selected from the group consisting of colloidal silicone dioxide, EDTA calcium disodium dehydrate, sodium lauryl sulfate, microcrystalline cellulose, crospovidone, croscarmellose sodium, poloxamer 407, siliconized microcrystalline cellulose, stearic acid.and combinations thereof.
  • at least one agent selected from the group consisting of colloidal silicone dioxide, EDTA calcium disodium dehydrate, sodium lauryl sulfate, microcrystalline cellulose, crospovidone, croscarmellose sodium, poloxamer 407, siliconized microcrystalline cellulose, stearic acid.and combinations thereof.
  • the pharmaceutical composition dosage form is a tablet.
  • administration includes orally administering from about 150 mg to about 450 mg of methylnaltrexone, or a salt thereof. In one embodiment, administration includes orally administering about 150 mg, about 300 mg, or about 450 mg of methylnaltrexone, or a salt thereof. In one embodiment, the methylnaltrexone is administered as one or more tablets, wherein each tablet contains about 150 mg of methylnaltrexone.
  • the subject has chronic non-malignant pain. In one embodiment, the subject has had chronic non-malignant pain for at least 2 months prior to administration of the pharmaceutical composition.
  • the subject has been receiving opioid treatment prior to administration of the pharmaceutical composition. In one embodiment, the subject has been receiving opioid treatment for at least one month. In one embodiment, the subject has been receiving opioid treatment comprising at least 50 mg of oral morphine equivalents per day for at least 14 days.
  • the subject will start opioid treatment in less than 1, 2, 3 or 4 weeks.
  • the subject has had opioid induced constipation for at least 30 days.
  • the subject has experienced less than 3 rescue free bowel movements per week for at least four consecutive weeks.
  • the subject has experienced straining during bowel movements.
  • the administering results in a rescue free bowel movement within 4 hours of administration of the pharmaceutical composition. In one embodiment, the administering results in an increase of at least one rescue free bowel movement per week as compared to the number of rescue free bowel movements per week prior to administration of the pharmaceutical composition.
  • the administering results in an increase of at least 2, 3, 4 or 5 rescue free bowel movements per week.
  • the administering results in an increase of at least one rescue free bowel movement per week for each of the first 4 weeks of daily administration of the pharmaceutical composition.
  • the administering results in improved stool consistency.
  • the subject experiences at least 3 rescue free bowel movements in each of the first 4 weeks of daily administration of the pharmaceutical composition; and the subject experiences an increase of at least one rescue free bowel movement per week for at least 3 of the first 4 weeks of daily administration as compared to the number of rescue free bowel movements per week prior to administration of the pharmaceutical composition.
  • the administering comprises orally administering about 150 mg of methylnaltrexone, or a salt thereof.
  • the administering comprises orally administering about 300 mg of methylnaltrexone, or a salt thereof.
  • the administering comprises orally administering less than about 450 mg of methylnaltrexone, or a salt thereof.
  • administration of the pharmaceutical composition does not result in any clinically significant drug-drug interactions.
  • administration of the pharmaceutical composition demonstrates minimal interaction with CYP enzymes and/or drug transporters.
  • Figure 1 summarizes adverse events that occurred amongst all subjects as set forth in Example 1.
  • Figure 2 summarizes serious adverse events by system organ class that occurred amongst all subjects as set forth in Example 1.
  • Figure 3 summarizes adverse events by system organ class that occurred amongst all subjects as set forth in Example 1.
  • Figure 4 summarizes clinically significant ECG results as set forth in Example 1.
  • Figure 5 includes charts that illustrate that straining and stool consistency improved as a result of administration of methylnaltrexone during an open label study of the drug.
  • Figure 6 includes charts that illustrate the sustainability of rapid response and durability of efficacy of administration of methylnaltrexone during an open label study of the drug.
  • Figure 7 is a table summarizing mean pulse (beats per minute) and supine blood pressure (mm Hg) changes from baseline on Day 1 and Day 3 in post-operative ileus studies involving administration of methylnaltrexone.
  • Figure 8 is a table summarizing outliers for pulse and blood pressure parameters over 10 days of observation in the same post-operative ileus studies.
  • Figure 9 is a series of charts illustrating that there was no consistent, clinically meaningful changes in supine pulse or blood pressure among subjects with opioid-induced constipation and chronic non-cancer pain who were administered methylnaltrexone.
  • Figure 10 is a table illustrating the lack of metabolic effects observed over a 48-week period of time in subjects having chronic non-cancer pain and opioid-induced constipation who were administered methylnaltrexone (12 mg PRN).
  • Figure 11 is a table summarizing the comparable event rates for myocardial infarction among subjects having chronic non-cancer pain and chronic opioid use.
  • Figure 12 is a table that summarizes cardiac adverse events between placebo and treatment groups for methylnaltrexone.
  • Figure 13 is a graph that summarizes changes in the pulse of subjects one hour post dose on the first day of treatment with intravenously administered methylnaltrexone.
  • Figure 14 is a graph that summarizes changes in Systolic Blood Pressure in subjects one hour post dose on the first day of treatment with intravenously administered methylnaltrexone .
  • Figure 15 is a graph that summarizes changes in Diastolic Blood Pressure in subjects one hour post dose on the first day of treatment with intravenously administered methylnaltrexone .
  • Figure 16 is a graph is a graph that summarizes changes in pulse in subjects one hour post dose on the first day of treatment with subcutaneously administered methylnaltrexone.
  • Figure 17 is a graph that summarizes changes in Systolic Blood Pressure in subjects one hour post dose on the first day of treatment with subcutaneously administered methylnaltrexone .
  • Figure 18 is a graph that summarizes changes in Diastolic Blood Pressure in subjects one hour post dose on the first day of treatment with subcutaneously administered methylnaltrexone .
  • Figure 19 is a graph that summarized all-cause mortality in Placebo controlled study of Relistor.
  • Figure 20 is a graph that summarizes the timing of reported Myocardial Infarctions in Placebo controlled study of Relistor as compared to a placebo controlled study of Alvimopan.
  • Figure 21 is a table that summarizes the incidence of potential opioid withdrawal symptoms.
  • Figure 22 is a table that summarizes the assessment of opioid withdrawal.
  • Figure 23 is a table that summarizes the assessment of opioid withdrawal.
  • Figure 24 demonstrates the rapid and durable efficacy of Relistor.
  • Figure 25 shows in vitro inhibition of platelet aggregation in naloxone, naltrexone, methylnaltrexone and alvimopan.
  • Figure 26 summarizes pain intensity reported by patients.
  • Figure 27 is a bar chart illustrating an efficacy endpoint after a single dose of oral methylnaltrexone (two separate formulations) relative to placebo.
  • Figure 28 is a linear plot illustrating the plasma concentration time profile for methylnaltrexone following a single oral dose of methylnaltrexone in subjects.
  • Figure 29 is a linear plot illustrating the plasma concentration time profile for methylnaltrexone metabolite M2 (methylnaltrexone sulfate) following a single oral dose of methylnaltrexone in subjects.
  • Figure 30 is a linear plot illustrating the plasma concentration time profile for methylnaltrexone metabolite M4 (methyl-6a-naltrexol) following a single oral dose of methylnaltrexone in subjects.
  • Figure 31 is a linear plot illustrating the plasma concentration time profile for methylnaltrexone metabolite M5 (methyl-6b-naltrexol) following a single oral dose of methylnaltrexone in subjects.
  • Figure 32 is a logarithmic plot illustrating the plasma concentration time profile for methylnaltrexone following a single oral dose of methylnaltrexone in subjects.
  • Figure 33 is a logarithmic plot illustrating the plasma concentration time profile for methylnaltrexone metabolite M2 (methylnaltrexone sulfate) following a single oral dose of methylnaltrexone in subjects.
  • Figure 34 is a logarithmic plot illustrating the plasma concentration time profile for methylnaltrexone metabolite M4 (methyl-6a-naltrexol) following a single oral dose of methylnaltrexone in subjects.
  • Figure 35 is a logarithmic plot illustrating the plasma concentration time profile for methylnaltrexone metabolite M5 (methyl-6b-naltrexol) following a single oral dose of methylnaltrexone in subjects.
  • Figure 36 is a plot of observed and predicted methylnaltrexone pharmacokinetic parameters correlated with a single dose of 450 mg and 150 mg (respectively) oral methylnaltrexone in healthy subjects and subjects with hepatic impairment.
  • Figure 37 is a plot of observed and predicted methylnaltrexone pharmacokinetic parameters correlated with a single dose of 450 mg and 300 mg (respectively) oral methylnaltrexone in healthy subjects and subjects with renal impairment.
  • Figure 38 is a plot of the proportion of subjects who experienced laxation within four hours after administration of methylnaltrexone versus the midpoint of each C max quintile, analyzed across six studies.
  • Figure 39 is a plot showing time to laxation after administration of methylnaltrexone versus plasma MNTX C max , analyzed across six studies.
  • Figure 40 is a fit of a logistic regression model to the probability of laxation within four hours of methylnaltrexone administration for various T max values versus ln(C max ) +1 from a model development data set.
  • Embodiments are directed to methods for preventing and treating the inhibition of gastrointestinal motility, particularly constipation, that arises in the group of patients taking chronic or maintenance doses of opioids, comprising administering a therapeutically effective amount of a quaternary derivative of noroxymorphone (QDNM).
  • QDNM quaternary derivative of noroxymorphone
  • These patients include late stage cancer patients, elderly patients with osteoarthritic changes, methadone maintenance patients, neuropathic pain and chronic back pain patients. Treatment of these patients is important from a quality of life standpoint, as well as to reduce complications arising from chronic constipation, such as hemorrhoids, appetite suppression, mucosal breakdown, sepsis, colon cancer risk, and myocardial infarction.
  • the quaternary derivative of noroxymorphone is methylnaltrexone.
  • the opioid-induced side effect to be treated includes, but is not limited to, constipation and gastrointestinal motility inhibition, dysphoria, pruritus, and urinary retention.
  • R is allyl or a related radical such as chlorallyl, cyclopropyl-methyl or propargyl
  • X is the anion of an acid, especially a chloride, bromide, iodide or methylsulfate anion.
  • a method of decreasing the risk of a cardiovascular event a subject suffering from opioid-induced constipation comprising administering a composition comprising methylnaltrexone to the subject.
  • the methylnaltrexone is administered subcutaneously.
  • the methylnaltrexone is administered orally.
  • the subject is receiving opioids chronically.
  • administration of the composition results in a decrease of about one point in a bowel movement straining scale.
  • administration of the composition results in an improvement of at least one point in a stool consistency scale (e.g. Bristol Stool Scale).
  • the improvement in strain or stool scale is observed for at least two weeks, at least four weeks, at least eight weeks, at least 12 weeks, at least 24 weeks or at least 48 weeks.
  • the cardiovascular event can be at least one selected from the group of: myocardial infarction, acute myocardial infarction, cardiac arrest, cardiorespiratory arrest, congestive cardiac failure, cardiovascular disorder, coronary artery disease, cyanosis, ischemic coronary artery disorders, rate and rhythm disorders, and supraventricular arrhythmias.
  • constipation refers to a condition in which a subject suffers from infrequent bowel movements or bowel movements that are painful and/or hard to pass. A subject experiencing constipation often suffers from straining during bowel movements and/or a sensation of incomplete evacuation following bowel movements.
  • constipation refers to a subject who experiences less than three (3) rescue free bowel movements (RFBMs) per week on average, wherein "rescue free bowel movement” refers to the passage and evacuation of feces, or laxation.
  • RFBMs rescue free bowel movements
  • opioid induced constipation refers to a subject who suffers from constipation resulting from opioid therapy.
  • a subject can suffer from opioid induced constipation arising from opioid therapy with alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifent
  • an "effective amount" of a composition of methylnaltrexone refers to the level required to treat or prevent one or more symptoms of opioid induced constipation. In some embodiments, an “effective amount” is at least a minimal amount of a composition of methylnaltrexone, which is sufficient for treating or preventing one or more symptoms of opioid induced constipation, as defined herein. In some embodiments, the term "effective amount,” as used in connection with an amount of methylnaltrexone, salt thereof, or composition of methylnaltrexone or salt thereof, refers to an amount of methylnaltrexone, salt thereof, or composition of methylnaltrexone or salt thereof sufficient to achieve a rescue free bowel movement in a subject.
  • maintain optimal opioid pain management includes, for example, not lowering the dose of opioid due to constipation.
  • PAMORA peripherally- acting mu-opioid receptor antagonists
  • peripherally- acting mu-opioid receptor antagonists include for example, methylnaltrexone, naloxegol, naloxegol.
  • PAMORA may also include centrally acting mu-opioid receptor antagonists that have been formulated to act only peripherally (e.g., formulated to reduce or eliminate their absorption or systemic availability.
  • treat refers to partially or completely alleviating, inhibiting, delaying onset of, reducing the incidence of, ameliorating and/or relieving opioid induced constipation, or one or more symptoms of opioid induced constipation.
  • unit dosage form refers to a physically discrete unit of a composition or formulation of methylnaltrexone, appropriate for the subject to be treated. It will be understood, however, that the total daily usage of provided formulation will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject will depend upon a variety of factors including the severity of the opioid induced constipation; nature and activity of the composition; specific formulation employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.
  • non-malignant pain refers to pain originating from a non- malignant source such as cancer.
  • subject means a mammal and includes human and animal subjects, such as domesticated animals (e.g. , horses, dogs, cats, etc.) and experimental animals (e.g. , mice, rats, dogs, chimpanzees, apes, etc.). In a particular embodiment, the subject is human.
  • domesticated animals e.g. , horses, dogs, cats, etc.
  • experimental animals e.g. , mice, rats, dogs, chimpanzees, apes, etc.
  • the subject is human.
  • uffer or “suffering” as used herein refers to one or more conditions that a patient has been diagnosed with, or is suspected to have, in particular, opioid induced constipation.
  • amphiphilic refers to the molecule's dual hydrophobic and hydrophilic properties. Typically, amphiphilic molecules have a polar, water soluble group (e.g. , a phosphate, carboxylic acid, sulfate) attached to a nonpolar, water- insoluble group (e.g., a hydrocarbon).
  • a polar, water soluble group e.g. , a phosphate, carboxylic acid, sulfate
  • nonpolar, water- insoluble group e.g., a hydrocarbon
  • amphiphilic is synonymous with amphipathic. Examples of amphiphilic molecules include sodium dodecyl (lauryl) sulfate, fatty acids, phospholipids, and bile acids. Amphiphilic molecules can be uncharged, cationic, or anionic.
  • lipophilicity refers to a compound' s ability to associate with or dissolve in a fat, lipid, oil, or non-polar solvent. Lipophilicity and hydrophobicity can be used to describe the same tendency of a molecule to dissolve in fats, oils, lipids, and non- polar solvents.
  • Relistor or “Relistor®” is used to indicate methylnaltrexone.
  • this can refer to the lack of a bowel movement or adequate relief from constipation within about 48 hours after administration of laxative therapy. In some embodiments, this can refer to the lack of a bowel movement or adequate relief from constipation within about 12 hours after administration of laxative therapy. In some embodiments, this can refer to the lack of a bowel movement or adequate relief from constipation within about 6 hours after administration of laxative therapy. In some embodiments, this can refer to the lack of a bowel movement or adequate relief from constipation within about 4 hours after administration of laxative therapy.
  • compositions comprising a compound of formula II and/or II'
  • a " is a suitable anion
  • a " is the anion of a suitable Br0nsted acid.
  • Br0nsted acids include, but are not limited to, hydrogen halides, carboxylic acids, sulfonic acids, sulfuric acid and phosphoric acid.
  • a " is chloride, bromide, iodide, fluoride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate, sulfonate, methylsulfonate, formate, carboxylate, methylsulfate or succinate salt.
  • a " is trifluoroacetate.
  • a " is bromide.
  • compositions comprising are formulated in a liquid formulation.
  • Liquid formulations and compositions of methylnaltrexone are described, for example, in International Publications No. WO 2004/091623, WO 2008/019115 and WO 2010/039851, each of which is incorporated herein by reference in its entirety.
  • the liquid formulation or composition is provided in a packaged composition that is substantially free of tungsten, as described, for example in WO 2010/039851.
  • a packaged composition that is substantially free from tungsten can be provided, comprising a unit dosage of a liquid composition comprising methylnaltrexone, a calcium chelating agent, a buffering agent and an isotonicity agent.
  • the packaged composition can comprise a unit dosage of a liquid composition that comprises methylnaltrexone bromide, edetate calcium disodium and glycine hydrochloride. In some embodiments, the packaged composition can comprise a unit dosage of a liquid composition that comprises methylnaltrexone bromide, edetate calcium disodium and glycine hydrochloride and sodium chloride.
  • the liquid formulation or composition comprises a compound of Formula II and/or II'.
  • a packaged composition can include, for example, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the liquid composition comprising methylnaltrexone has a pH of from about pH 2.0 to about pH 6.0.
  • the pH of the formulation is from about pH 2.6 to about pH 5.0.
  • the pH of the formulation is from about pH 3.0 to about pH 4.0.
  • the pH of the formulation is from about pH 3.4 to about pH 3.6.
  • the pH of the formulation is about pH 3.5.
  • the liquid composition comprising methylnaltrexone has a pH of from about pH 2.5 to about pH 6.0.
  • the packaged composition comprises methylnaltrexone in an amount from about 0.5 mg to about 200 mg, about 1 mg to about 80 mg, from about 5 mg to about 40 mg. In some embodiments, the packaged composition comprises methylnaltrexone bromide in an amount of about 8 mg, about 12 mg, about 16 mg, about 18 mg, or about 24 mg.
  • the packaged composition comprises a liquid composition comprising methylnaltrexone bromide in an amount from about 0.01 mg/mL to about 2 mg/mL, or from about 0.1 mg/mL to about 1 mg/mL in the formulation, or from about 0.2 mg/mL to about 0.8 mg/mL of the formulation.
  • a chelating agent can be present in the liquid composition an amount of from about 0.1 mg/mL to about 1 mg/mL. In some embodiments, the chelating agent is present in the liquid composition in an amount of about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL or about 1.0 mg/mL.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (also synonymous with EDTA, edetic acid, versene acid, and sequestrene), and EDTA derivatives, such as sodium EDTA, and potassium EDTA, diammonium EDTA, dipotassium EDTA, disodium EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium EDTA, HEDTA, and trisodium HEDTA, and related salts thereof.
  • EDTA derivatives such as sodium EDTA, and potassium EDTA, diammonium EDTA, dipotassium EDTA, disodium EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium EDTA, HEDTA, and trisodium HEDTA, and related salts thereof.
  • chelating agents include niacinamide and derivatives thereof and sodium desoxycholate and derivatives thereof, ethylene glycol-bis-(2-aminoethyl)-N,N,N', N'-tetraacetic acid (EGTA) and derivatives thereof, diethylenetriaminepentaacetic acid (DTPA) and derivatives thereof, N,N- bis(carboxymethyl)glycine (NTA) and derivatives thereof, nitrilotriacetic acid and derivatives thereof.
  • Additional chelating agents that are contemplated include citric acid and derivatives thereof.
  • Citric acid also is known as citric acid monohydrate. Derivatives of citric acid include anhydrous citric acid and trisodiumcitrate-dihydrate.
  • the chelating agent is at least one selected from the group consisting of EDTA, an EDTA derivative, EGTA and an EGTA derivative.
  • the chelating agent comprises EDTA disodium such as, for example, EDTA disodium hydrate.
  • a calcium salt is present in the liquid composition an amount of from about 0.1 mg/mL to about 1 mg/mL. In some embodiments, the calcium salt is present in the liquid composition in an amount of about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL or about 1.0 mg/mL.
  • Exemplary calcium salts include, but are not limited to calcium chloride, calcium acetate, calcium citrate, calcium sulfate, and the like.
  • a calcium salt chelating agent is present in the liquid composition an amount of from about 0.1 mg/mL to about 1 mg/mL. In some embodiments, the calcium salt chelating agent is present in the liquid composition in an amount of about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL or about 1.0 mg/mL.
  • Common calcium salt chelating agents include, but are not limited to calcium ethylenediaminetetra acetic acid (EDTA) and calcium salt EDTA derivatives, calcium ethylene glycol-bis-(2-aminoethyl)-N,N,N', N'-tetraacetic acid (EGTA) and calcium salt EGTA derivatives, calcium diethylenetriaminepentaacetic acid (DTPA) and calcium salt DTPA derivatives, calcium N,N-bis(carboxymethyl)glycine (NTA) and calcium salt NTA derivatives, and calcium citrate and derivatives thereof.
  • EDTA calcium ethylenediaminetetra acetic acid
  • EGTA calcium ethylene glycol-bis-(2-aminoethyl)-N,N,N', N'-tetraacetic acid
  • DTPA calcium diethylenetriaminepentaacetic acid
  • NTA N,N-bis(carboxymethyl)glycine
  • the calcium salt chelating agent is at least one selected from the group of calcium EDTA, a calcium salt EDTA derivative, calcium EGTA and a calcium salt EGTA derivative.
  • the calcium salt chelating agent comprises calcium EDTA disodium such as, for example, calcium EDTA disodium hydrate.
  • an isotonic agent is present in the liquid composition.
  • Common isotonic agents include agents selected from the group consisting of sodium chloride, mannitol, lactose, dextrose (hydrous or anhydrous), sucrose, glycerol, and sorbitol, and solutions thereof.
  • a stabilizing agent is present in the liquid composition in an amount of from about 0.01 mg/mL to about 2 mg/mL, or from about 0.05 mg/mL to about 1 mg/mL, or from about 0.1 mg/mL to about 0.8 mg/mL.
  • the stabilizing agent can be present in an amount of about 0.10 mg/mL, about 0.15 mg/mL, about 0.2 mg/mL, about 0.25 mg/mL, about 0.3 mg/mL, about 0.35 mg/mL, about 0.4 mg/mL, about 0.45 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL or about 0.8 mg/mL.
  • Exemplary stabilizing agents include glycine, benzoic acid, citric, glycolic, lactic, malic, and maleic acid.
  • the liquid formulation comprises glycine.
  • the glycine comprises glycine-HCl.
  • methylnaltrexone for intravenous or intramuscular administration, methylnaltrexone (from, e.g., Mallinckrod Pharmaceuticals, St. Louis, Mo.) can be formulated with saline or other physiologically acceptable carriers.
  • methylnaltrexone can be formulated with a sugar and cellulose mix or other pharmacologically acceptable carriers known in the art.
  • the methods presented herein involve administration of oral compositions of methylnaltrexone comprising ion pairs of methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient.
  • the composition for use in the methods presented herein can be a salt of methylnaltrexone of the formula:
  • methylnaltrexone is the cation of the salt, and A " is an anion of an amphiphilic pharmaceutically acceptable excipient, as described in International Publication No. WO2011/112816, the entire contents of which are hereby incorporated by reference herein.
  • the methylnaltrexone is (R)-N-methylnaltrexone, a peripherally acting ⁇ opioid receptor antagonist, as shown in the formula above. It will be understood that the (R)-N-methylnaltrexone cation and the anion of the amphiphilic pharmaceutically acceptable excipient can exist in the composition as an ion pair or can exist as separate salts paired with other counter ions such as bromide and sodium, or mixtures thereof.
  • the methods presented herein involve administration of oral compositions of methylnaltrexone comprising methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient.
  • the composition for use in the methods presented herein can be a compound of methylnaltrexone of the formula:
  • a " comprises a suitable anion.
  • a " comprises an anion of an amphiphilic pharmaceutically acceptable excipient, as described in International Publication No. WO2011/112816, the entire contents of which are hereby incorporated by reference herein.
  • the methylnaltrexone is (R)-N-methylnaltrexone, a peripherally acting ⁇ opioid receptor antagonist, as shown in the formula above. It will be understood that the (R)-N-methylnaltrexone cation and the anion of the amphiphilic pharmaceutically acceptable excipient can exist in the composition as an ion pair or can exist as separate salts paired with other counter ions such as bromide and sodium, or mixtures thereof.
  • compositions for oral administration further include an anion of an amphiphilic pharmaceutically acceptable excipient (A ).
  • A amphiphilic pharmaceutically acceptable excipient increases the lipophilicity of the composition thereby allowing for increased transport through the unstirred diffusion layer in the GI tract, resulting in increased permeation through biological membranes.
  • the excipient increases the lipophilicity of the drug.
  • the amphiphilic pharmaceutically acceptable excipient can include a sulfate, sulfonate, nitrate, nitrite, phosphate, or phosphonate moiety.
  • the pharmaceutically acceptable excipient comprises an (-OSO 3 ) group.
  • the anion is butyl sulfate, pentyl sulfate, hexyl sulfate, heptyl sulfate, octyl sulfate, nonyl sulfate, decyl sulfate, undecyl sulfate, dodecyl sulfate, tridecyl sulphate, tetradecyl sulfate, pentadecyl sulfate, hexadecyl sulfate, heptadecyl sulfate, octadecyl sulfate, eicosyl sulfate, docosyl sulfate, tetracosyl sulfate, hexacosyl sulfate, octacosyl sulfate, and triacontyl sulphate.
  • a " is the anion of a Br0nsted acid.
  • Br0nsted acids include hydrogen halides, carboxylic acids, sulfonic acids, sulfuric acid, and phosphoric acid.
  • a " is chloride, bromide, iodide, fluoride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate sulfonate, methylsulfonate, formate, carboxylate, methylsulfate or succinate salt.
  • a " is trifluoroacetate.
  • the methylnaltrexone in the composition can have multiple anions (e.g., bromide and dodecyl (lauryl) sulfate) associating therewith.
  • multiple anions e.g., bromide and dodecyl (lauryl) sulfate
  • a " is bromide, such that the compositions, and formulations thereof, comprise (R)-N-methylnaltrexone bromide.
  • (R)-N-methylnaltrexone bromide which is also known as "MNTX” and is described in international PCT patent application publication number, WO2006/12789, which is incorporated herein by reference.
  • the chemical name for (R)-N-methylnaltrexone bromide is (R)-N-(cyclopropylmethyl) noroxymorphone methobromide.
  • (R)-N-methylnaltrexone bromide has the molecular formula C 2 iH 26 N0 4 Br and a molecular weight of 436.36 g/mol.
  • (R)-N-methylnaltrexone bromide has the following structure:
  • (R)-N-methylnaltrexone bromide where the compound is in the (R) configuration with respect to the quaternary nitrogen.
  • at least about 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or 99.95% of the compound is in the (R) configuration with respect to nitrogen.
  • Methods for determining the amount of (R)-N-methylnaltrexone bromide, present in a sample as compared to the amount of ( ⁇ -N-methylnaltrexone bromide present in that same sample are described in detail in WO2006/127899, which is incorporated herein by reference.
  • the methylnaltrexone contains 0.15%, 0.10%, or less (S)-N- methylnaltrexone bromide.
  • a " is an acidic amphiphilic pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient has a pK a of about 3 or less.
  • the pharmaceutically acceptable excipient has a pK a of about 2 or less.
  • the pharmaceutically acceptable excipient has a pK a between about 1 and about 2.
  • the pharmaceutically acceptable excipient has a pK a of about 1 or less.
  • the compositions for oral administration are tablet formulations.
  • the compositions for oral administration are capsule formulations. Methylnaltrexone for use in such compositions and formulations can be in any of a variety of forms.
  • forms of methylnaltrexone suitable for use in the inventive compositions and formulations include pharmaceutically acceptable salts, prodrugs, polymorphs (i.e., crystal forms), co-crystals, hydrates, solvates, and the like. Any form of methylnaltrexone can be used in the compositions or formulations, but the form should allow for ion pairing with the amphiphilic pharmaceutically acceptable excipient.
  • the methylnaltrexone ion pair is a salt that is solid at room temperature.
  • the composition is a pharmaceutical composition.
  • formulations for oral administration comprise methylnaltrexone, an amphiphilic pharmaceutically acceptable excipient as described above, and a disintegrant, and further, optionally, comprise one or more other components, such as, for example, binders, carriers, chelating agents, antioxidants, fillers, lubricants, wetting agents, or combinations thereof, as set forth in International Publication No. WO2011/112816, the entire contents of which are hereby incorporated by reference herein.
  • the composition for example, pharmaceutical composition, for oral administration comprises methylnaltrexone bromide and sodium dodecyl (lauryl) sulfate (also known as SDS or SLS).
  • the composition further includes sodium bicarbonate as a disintegrant. Additional excipients, as set forth above, can be incorporated, including, but not limited to, at least one of microcrystalline cellulose, crospovidone, polysorbate 80, edetate calcium disodium dehydrate, silicified microcrystalline cellulose, talc, colloidal silicon dioxide and magnesium stearate.
  • the composition for oral administration comprises each of methylnaltrexone bromide, sodium lauryl sulfate, sodium bicarbonate, microcrystalline cellulose, crospovidone, polysorbate 80, edetate calcium disodium dehydrate, silicified microcrystalline cellulose, talc, colloidal silicon dioxide and magnesium stearate.
  • compositions and formulations thereof for use as described herein can be generated as set forth, for example, in U.S. Patent Publication No. 2012/0190702; U.S. Patent No. 8,552,025; U.S. Patent Publication No. 2008/0070975; U.S. Patent No. 8,420,663; and International Publication No. WO2011/112816, each of which is incorporated herein by reference in its entirety. Additionally, compositions, and formulations thereof, can be generated as described in Examples 2-4 herein.
  • the particular mode of administration of the opioid antagonist generally speaking, can be conducted using any mode of administration that is medically acceptable, e.g., any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects.
  • Such modes of administration include oral, rectal, sublingual, intramuscular, infusion, intravenous, intracavity or subcutaneous.
  • Direct injection could also be used for local delivery.
  • Oral or subcutaneous administration can be suitable for prophylactic or long term treatment because of the convenience of the patient as well as the dosing schedule.
  • the opioid antagonists can be administered as an enterically coated tablet or capsule. In some embodiments, the opioid antagonist is administered by a slow infusion method or by a time-release or controlled-release method or as a lyophilized powder.
  • the compounds and compositions as disclosed herein are provided in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions or preparations. Such preparations can routinely contain salts, buffering agents, preservatives, and optionally other therapeutic ingredients.
  • the salts are typically pharmaceutically acceptable salts, but non-pharmaceutically acceptable salts can conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention.
  • Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, p- toluenesulfonic, tartaric, citric, methanesulfonic, formic, succinic, naphthalene-2-sulfonic, pamoic, 3-hydroxy-2-naphthalenecarboxylic, and benzene sulfonic.
  • Suitable buffering agents include, but are not limited to, acetic acid and salts thereof (1-2% WN); citric acid and salts thereof (1-3% WN); boric acid and salts thereof (0.5-2.5% WN); and phosphoric acid and salts thereof (0.8-2% WN).
  • Suitable preservatives include, but are not limited to, benzalkonium chloride (0.003- 0.03% WN); chlorobutanol (0.3-0.9% WIN); parabens (0,01-0.25% WN) and thimerosal (0.004-0.02% WN).
  • a pharmaceutical composition of the peripheral opioid antagonist can also contain one or more pharmaceutically acceptable excipients, such as lubricants, diluents, binders, carriers, and disintegrants.
  • auxiliary agents can include, e.g., stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, coloring, flavoring and/or aromatic active compounds.
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • suitable pharmaceutically acceptable carriers, diluents, solvents or vehicles include, ,but are not limited to, water, salt (buffer) solutions, alcohols, gum arabic, mineral and vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, vegetable oils, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like.
  • the dosage form of the analogs can be in the form of, for example, tablets, capsules, powders, suppositories, or lozenges. If a liquid carrier is used, exemplary forms such as soft gelatin capsules, syrups or liquid suspensions, emulsions or solutions can be the dosage form.
  • injectable, sterile solutions preferably nonaqueous or aqueous solutions, as well as dispersions, suspensions, emulsions, or implants, including suppositories.
  • Ampoules are often convenient unit dosages.
  • injectable depot forms can also be suitable and can be made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled.
  • Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
  • a syrup, elixir, or the like can be used wherein a sweetened vehicle is employed.
  • Other delivery systems can include, for example, time-release, delayed-release or sustained-release delivery systems. Such systems can avoid repeated administrations of the compounds of the invention, increasing convenience to the patient and the physician and maintain sustained plasma levels of compounds.
  • Many types of controlled-release delivery system are available and known to those of ordinary skill in the art.
  • Sustained- or controlled- release compositions can be formulated, e.g., as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, and the like.
  • sustained-release matrix is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid-base hydrolysis or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids.
  • a sustained-release matrix can be desirably chosen from biocompatible materials such as liposomes, polymer-based system such as polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid), polyanhydrides, poly (ortho )esters, polysaccharides, polyamino acids, hyaluronic acid, collagen, chondroitin sulfate, polynucleotides, polyvinyl propylene, polyvinyl pyrrolidone, and silicone; nonpolymer system such as carboxylic acids, fatty acids, phospholipids, amino acids, lipids such as sterols, hydrogel release system; silastic system; peptide-based system; implants and the like.
  • biocompatible materials such as liposomes
  • polymer-based system such as polylactides (polylactic acid), polyglycolide (polymer of glycolic acid
  • a long-term sustained-release implant can be suitable for treatment of chronic conditions.
  • the implant can be constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and optionally for from about 30 to 60 days.
  • Long-term sustained-release implants are well-known to those of ordinary skill in the art and include some of the release system described above.
  • aqueous formulations can include chelating agent, a buffering agent, an anti-oxidant and, optionally, an isotonicity agent, preferably pH adjusted to between 3.0 and 3.5.
  • Preferred such formulations that are stable to autoclaving and long term storage are described, for example, in U.S. Patent No. 8,552,025, the disclosure of which is incorporated herein by reference in its entirety.
  • compounds of the invention are administered in a dosing regimen which provides a continuous dosing regimen of the compound to a subject, e.g., a regimen that maintains minimum plasma levels of the opioid antagonist, and preferably eliminates the spikes and troughs of a drug level with conventional regimens.
  • a continuous dose can be achieved by administering the compound to a subject on a daily basis using any of the delivery methods disclosed herein.
  • the continuous dose can be achieved using continuous infusion to the subject, or via a mechanism that facilitates the release of the compound over time, for example, a sustained release formulation.
  • compounds of the invention are continuously released to the subject in amounts sufficient to maintain a concentration of the compound in the plasma of the subject effective to reduce or inhibit opioid-induced side effects.
  • the compounds and compositions as disclosed herein, whether provided alone or in combination with other therapeutic agents, are provided in a therapeutically effective amount. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts.
  • the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • Those of ordinary skill in the art can readily determine effective doses and co-administration regimens (as described herein) as determined by good medical practice and the clinical condition of the individual patient.
  • the opioid antagonists are co-administered with the opioid.
  • co-administration is meant to refer to a combination therapy by any administration route in which two or more agents are administered to a patient or subject. Co-administration of agents can also be referred to as combination therapy or combination treatment.
  • the agents can be in the same dosage formulations or separate formulations. For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents can be administered concurrently, or they each can be administered at separately staggered times.
  • the agents can be administered simultaneously or sequentially (e.g., one agent can directly follow administration of the other or the agents can be give episodically, e.g., one can be given at one time followed by the other at a later time, e.g., within a week), as long as they are given in a manner sufficient to allow both agents to achieve effective concentrations in the body.
  • the agents can also be administered by different routes, e.g., one agent can be administered intravenously while a second agent is administered intramuscularly, intravenously or orally.
  • the coadministration of the opioid antagonist compound in accordance with the present invention with an opioid is suitably considered a combined pharmaceutical preparation which contains an opioid antagonist and a opioid agent, the preparation being adapted for the administration of the peripheral opioid antagonist on a daily or intermittent basis, and the administration of opioid agent on a daily or intermittent basis.
  • the opioid antagonists can be administered prior to, concomitant with, or after administration of the opioids.
  • Co- administrable agents also can be formulated as an admixture, as, for example, in a single formulation or single tablet. These formulations can be parenteral or oral, such as the formulations described, e.g., in U.S. Pat. Nos. 6,277,384; 6,261,599; 5,958,452 and International Publication No. WO 98/25613, each of which is incorporated herein by reference in its entirety.
  • the compounds and compositions disclosed herein are useful in antagonizing undesirable side effects of opioid analgesic therapy (e.g., gastrointestinal effects (e.g., delayed gastric emptying, altered GI tract motility), etc.). Furthermore, a provided compound or composition can be used as to treat subjects having disease states that are ameliorated by binding ⁇ opioid receptors, or in any treatment wherein temporary suppression of the ⁇ opioid receptor system is desired (e.g., ileus, etc.).
  • opioid analgesic therapy e.g., gastrointestinal effects (e.g., delayed gastric emptying, altered GI tract motility), etc.
  • a provided compound or composition can be used as to treat subjects having disease states that are ameliorated by binding ⁇ opioid receptors, or in any treatment wherein temporary suppression of the ⁇ opioid receptor system is desired (e.g., ileus, etc.).
  • administration of the compounds and compositions disclosed herein can be advantageous for treatment, prevention, amelioration, delay or reduction of side effects of opioid use, such as, for example, gastrointestinal dysfunction (e.g., inhibition of intestinal motility, constipation, GI sphincter constriction, nausea, emesis (vomiting), biliary spasm, opioid bowel dysfunction, colic, dysphoria, pruritus, urinary retention, depression of respiration, papillary constriction, cardiovascular effects, chest wall rigidity and cough suppression, depression of stress response, and immune suppression associated with use of narcotic analgesia, etc, or combinations thereof.
  • gastrointestinal dysfunction e.g., inhibition of intestinal motility, constipation, GI sphincter constriction, nausea, emesis (vomiting), biliary spasm, opioid bowel dysfunction, colic, dysphoria, pruritus, urinary retention, depression of respiration, papillary constriction, cardiovascular effects, chest wall rigidity and cough suppression
  • Use of a provided compound or composition as disclosed herein can thus be beneficial from a quality of life standpoint for subjects receiving opioids, as well as to reduce complications arising from chronic constipation, such as hemorrhoids, appetite suppression, mucosal breakdown, sepsis, colon cancer risk, and myocardial infarction.
  • a provided compound or composition as disclosed herein is useful for administration to a subject receiving acute opioid administration. In some embodiments, a provided compound or composition is useful for administration to subjects suffering from postoperative gastrointestinal dysfunction.
  • a provided compound or composition as disclosed herein is useful for administration to subjects receiving chronic opioid administration (e.g., terminally ill patients receiving opioid therapy such as an AIDS patient, a cancer patient, a cardiovascular patient; subjects receiving chronic opioid therapy for pain management; subjects receiving opioid therapy for maintenance of opioid withdrawal).
  • the subject is a subject using opioid for chronic pain management.
  • the subject is a terminally ill patient.
  • the subject is a person receiving opioid withdrawal maintenance therapy.
  • Chronic opioid administration can refer to, or can be characterized by, the need for substantially higher levels of opioid to produce the therapeutic benefit as a result of prior opioid use.
  • Chronic opioid administration can include, for example, daily opioid treatment for a week or more, or intermittent opioid use for at least two weeks.
  • a provided compound or composition as disclosed herein can be useful in treating, reducing, inhibiting, or preventing the effects of opioid use including, e.g., aberrant migration or proliferation of endothelial cells (e.g., vascular endothelial cells), increased angiogenesis, and increase in lethal factor production from opportunistic infectious agents (e.g., Pseudomonas aeruginosa).
  • endothelial cells e.g., vascular endothelial cells
  • angiogenesis e.g., vascular endothelial cells
  • lethal factor production e.g., Pseudomonas aeruginosa
  • Additional advantageous uses of a provided compound or composition include treatment of opioid-induced immune suppression, inhibition of angiogenesis, inhibition of vascular proliferation, treatment of pain, treatment of inflammatory conditions such as inflammatory bowel syndrome, treatment of infectious diseases and diseases of the musculokeletal system such as osteoporosis, arthritis, osteitis, periostitis, myopathies, and treatment of autoimmune diseases.
  • a provided compound or composition as disclosed herein can be used in methods for preventing, inhibiting, reducing, delaying, diminishing or treating gastrointestinal dysfunction, including, but not limited to, irritable bowel syndrome, opioid- induced bowel dysfunction, colitis, post-operative or postpartum ileus, nausea and/or vomiting, decreased gastric motility and emptying, inhibition of the stomach, and small and/or large intestinal propulsion, increased amplitude of non-propulsive segmental contractions, constriction of sphincter of Oddi, increased anal sphincter tone, impaired reflex relaxation with rectal distention, diminished gastric, biliary, pancreatic or intestinal secretions, increased absorption of water from bowel contents, gastro-esophageal reflux, gastroparesis, cramping, bloating, abdominal or epigastric pam and discomfort, constipation, idiopathic constipation, post-operative gastrointestinal dysfunction following abdominal surgery (e.g., colectomy (e.g., right hemi
  • Provided forms of a provided compound or composition as disclosed herein are also useful in treatment of conditions including cancers involving angiogenesis, immune suppression, sickle cell anemia, vascular wounds, and retinopathy, treatment of inflammation associated disorders (e.g., irritable bowel syndrome), immune suppression, chronic inflammation.
  • conditions including cancers involving angiogenesis, immune suppression, sickle cell anemia, vascular wounds, and retinopathy, treatment of inflammation associated disorders (e.g., irritable bowel syndrome), immune suppression, chronic inflammation.
  • veterinary applications e.g., treatment of domestic animals, e.g. horse, dogs, cats, etc.
  • a provided compound or composition are provided.
  • equine gastrointestinal motility such as colic and constipation
  • Resulting pain suffered by the horse with colic can result in a death-inducing shock, while a long-term case of constipation can also cause a horse's death.
  • Treatment of equines with peripheral opioid receptor antagonists has been described, e.g., in U.S. Patent Publication No. 20050124657 published January 20, 2005.
  • a provided compound or composition and unit dose forms are useful in preparation of medicaments, including, but not limited to medicaments useful in the treatment of side effects of opioid use (e.g., gastrointestinal side effects (e.g., inhibition of intestinal motility, 01 sphincter constriction, constipation) nausea, emesis, vomiting, dysphoria, pruritus, etc.) or a combination thereof.
  • side effects of opioid use e.g., gastrointestinal side effects (e.g., inhibition of intestinal motility, 01 sphincter constriction, constipation) nausea, emesis, vomiting, dysphoria, pruritus, etc.) or a combination thereof.
  • Compounds of the present invention are useful for preparations of medicaments, useful in treatment of patients receiving acute opioid therapy (e.g., patients suffering from post-operative gastrointestinal dysfunction receiving acute opioid administration) or subjects using opioids chronically (e.g., terminally ill patients receiving opioid therapy such as an AIDS patient, a cancer patient, a cardiovascular patient; subjects receiving chronic opioid therapy for pain management; or subjects receiving opioid therapy for maintenance of opioid withdrawal).
  • acute opioid therapy e.g., patients suffering from post-operative gastrointestinal dysfunction receiving acute opioid administration
  • opioids chronically e.g., terminally ill patients receiving opioid therapy such as an AIDS patient, a cancer patient, a cardiovascular patient; subjects receiving chronic opioid therapy for pain management; or subjects receiving opioid therapy for maintenance of opioid withdrawal.
  • preparation of medicaments useful in the treatment of pain treatment of inflammatory conditions such as inflammatory bowel syndrome, treatment of infectious diseases, treatment of diseases of the musculokeletal system such as osteoporosis, arthritis, osteitis, periostitis, myopathies, treatment of autoimmune diseases and immune suppression, therapy of post-operative gastrointestinal dysfunction following abdominal surgery (e.g., colectomy (e.g., right hemicolectomy, left hemicolectomy, transverse hemicolectomy, colectomy take down, low anterior resection), idiopathic constipation, and ileus (e.g., post-operative ileus, post-partum ileus), and treatment of disorders such as cancers involving angiogenesiss, chronic inflammation and/or chronic pain, sickle cell anemia, vascular wounds, and retinopathy.
  • disorders such as cancers involving angiogenesiss, chronic inflammation and/or chronic pain, sickle cell anemia, vascular wounds, and retinopathy.
  • Embodiments disclosed herein may be of therapeutic value in opioid antagonist treatment for patients who have tumors.
  • tumors include, but are not limited to adrenal cortical carcinoma, tumors of the bladder: squamous cell carcinoma, urothelial carcinomas; tumors of the bone: adamantinoma, aneurysmal bone cysts, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, fibrous dysplasia of the bone, giant cell tumour, osteochondroma, osteosarcoma; breast tumors: secretory ductal carcinoma, chordoma; colon tumors: colorectal adenocarcinoma; eye tumors: posterior uveal melanoma, fibrogenesis imperfecta ossium, head and neck squamous ceil carcinoma; kidney tumors: chromophobe renal cell carcinoma, clear cell renal cell carcinoma, nephroblastoma (Wilms tumor), kidney:
  • a subject suffering from opioid induced constipation refers to a subject who suffers from constipation resulting from opioid activity, for example, exogenous opioid therapy or endogenous opioid activity.
  • Constipation refers to a condition in which a subject suffers from infrequent bowel movements or bowel movements that are painful and/or hard to pass. A subject experiencing constipation often suffers from hard or lumpy stools, straining during bowel movements and/or a sensation of incomplete evacuation following bowel movements.
  • constipation refers to a subject who experiences less than three (3) rescue free bowel movements (RFBMs) per week on average, for example, over the course of the last four consecutive weeks, wherein "rescue free bowel movement” refers to the passage and evacuation of feces, or laxation.
  • RFBMs rescue free bowel movements
  • Subjects taking opioids routinely stop taking their opioid medications due to constipation, thus there is a need in the art for a method to reduce OIC.
  • the methods described herein improve a subject's compliance with opioid treatment.
  • Increasing or improving compliance with opioid treatment includes, for example, a subject continuing on opioid treatment due to increased bowel movements due to methylnaltrexone administration.
  • Subjects experience less pain due to compliance with opioid treatment and thus do not experience withdrawal symptoms.
  • Opioid withdrawal symptoms include, for example, dysphoric mood, nausea or vomiting, muscle aches, lacrimation or rhinorrhea, pupillary dilation, piloerection, or sweating, diarrhea, yawning, fever, and insomnia. Decreasing opioid withdrawal leads to fewer hospitalizations.
  • the subject does not have a history of chronic constipation prior to the initiation of opioid therapy.
  • the subject at the time of the screening, is on an opioid therapeutic regimen and has been on such regimen for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 65, 70, 75, 80 85, 90, 95 or 100 days.
  • the subject has been taking opioids for at least one month.
  • the subject at the time of the screening, will begin an opioid therapeutic regimen at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 65, 70, 75, 80 85, 90, 95 or 100 days after the screening.
  • the subject at the time of the screening, will have discontinued opioid therapeutic regimen less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 65, 70, 75, 80 85, 90, 95 or 100 days prior to the screening.
  • the subject can be on an opioid regimen for a variety of purposes.
  • the subject can be a cancer or surgical patient, an immunosuppressed or immunocompromised patient (including HIV infected patient), a patient with advanced medical illness, a terminally ill patient, a patient with neuropathies, a patient with rheumatoid arthritis, a patient with osteoarthritis, a patient with chronic back pain, a patient with spinal cord injury, a patient with chronic abdominal pain, a patient with chronic pancreatic pain, a patient with pelvic perineal pain, a patient with fibromyalgia, a patient with chronic fatigue syndrome, a patient with migraine or tension headaches, a patient on hemodialysis, or a patient with sickle cell anemia.
  • the subject is receiving opioids for alleviation of pain.
  • the subject is receiving opioids for alleviation of chronic non- malignant pain.
  • non-malignant pain refers to pain originating from a non-malignant source such as cancer.
  • non-malignant pain includes to back pain, cervical pain, neck pain, fibromyalgia, low extremity pain, hip pain, migraines, headaches, neuropathic pain, or osteoarthritis.
  • chronic refers to a condition that persists for an extended period of time.
  • chronic can refer to a condition that lasts at least 1, 2, 3 or 4 weeks.
  • chronic can refer to a condition that lasts at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30 or 36 months.
  • the subject is receiving opioids for alleviation of chronic non-malignant pain that has persisted for at least 2 months.
  • the subject can be on opioid therapy including, but not limited to, alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, ethylmorphine, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, nicomorphine, opium, oxycodone, oxymorphone, papaveretum, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and/ or tram
  • opioid therapy
  • Opioids are typically administered at a morphine equivalent dosage of: 0.005 to 0.15 mg/kg body weight for intrathecal administration; 0.05 to 1.0 mg/kg body weight for intravenous administration; 0.05 to 1.0 mg/kg body weight for intramuscular administration; 0.05 to 1.0 mg/kg body weight/hour for transmucosal administration.
  • morphine equivalent dosage is meant representative doses of other opioids which equal one milligram of morphine, for example 10 mg meperidine, 1 mg methadone, and 80 ⁇ g fentanyl.
  • the subject is receiving a daily dose of at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 or 300 mg of oral morphine equivalents.
  • the subject is receiving at least 50 mg of oral morphine equivalents. Calculation of oral morphine equivalents is well known in the art. Table A provides a morphine oral equivalence table for known opioids. Table A: Morphine Oral Equivalence Table
  • the subject's opioid therapeutic regimen can be by any mode of administration.
  • the subject can be taking opioids orally, transdermally, intravenously, or subcutaneously.
  • oral doses of the opioid antagonists will range from about 0.01 to about 80 mg/kg body weight per day. In some embodiments, the oral dose of opioid antagonists range from about 1 to 20 mg/kg body weight.
  • the amount of opioid antagonist that is orally administered ranges from about 1 mg to about 1 g. In some embodiments, the amount of opioid antagonist that is orally administered ranges from about 10 mg to about 600 mg. In some embodiments, the amount of opioid antagonist that is orally administered ranges from about 75 mg to about 900 mg.
  • the amount of opioid antagonist that is orally administered is about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg, or any amount included therein.
  • the opioid antagonist can be administered once a day, twice a day, three times a day, four times a day or five times day, or as needed.
  • parenteral administration including intravenous and subcutaneous administration, will range from about 0.001 to about 5 mg/kg body weight.
  • doses administered intravenously or subcutaneously range from about 0.05 to about 0.5 mg/kg body weight.
  • doses administered intravenously or subcutaneously range from about 0.075 to about 0.6 mg/kg body weight.
  • doses administered intravenously or subcutaneously range from about 0.05 to about 0.3 mg/kg body weight.
  • doses administered intravenously are about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg or about 0.5 mg/kg body weight, or any amount that is included therein.
  • the doses administered intravenously can be administered on a continuous basis.
  • the intravenous doses can be administered every 6 hours, every 12 hours, or every 24 hours for a period of from about 5 to 15 days, or from about 7 to 10 days.
  • the intravenous doses are administered for about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days or about 15 days.
  • doses administered subcutaneously are about 0.005 mg/kg, about 0.01 mg/kg, about 0.015 mg/kg, about 0.025 mg/kg, about 0.05 mg/kg, about 0.075 mg/kg, about 0.1 mg/kg, about 0.15 mg/kg, about 0.2 mg/kg, about 0.25 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg or about 0.45 mg/kg body weight, or any amount that is included therein.
  • the subcutaneous dose can be administered every day or every other day. In some embodiments, the subcutaneous dose is not administered more than once in a 24-hour period. In some embodiments, the subcutaneous dose is administered on an as needed basis. In some embodiments, the subcutaneous dose is administered at least once per week.
  • Dosages can be adjusted appropriately to achieve desired drug levels, local or systemic, depending on the mode of administration.
  • the dosage for oral administration of the opioid antagonists in an enteric ally coated formulation can be from about 10 to 30% of the non-coated oral dose.
  • even higher doses or effectively higher dosages by a different, more localized delivery route
  • Multiple doses per day can be administered to achieve appropriate systemic levels of compounds. Appropriate system levels can be determined by, for example, measurement of the patient's plasma level of the drug using routine HPLC methods known to these of skill in the art.
  • methylnaltrexone is administered at a dosage of: 0.001 to 1.0 mg/kg body weight for intravenous administration; 0.001 to 1.0 mg/kg body weight for intramuscular administration; 0.001 to 1.0 mg/kg body weight for transmucosal administration and 0.1 to 40.0 mg/kg body weight for oral administration.
  • the administration of the methylnaltrexone can be commenced prior to administration of the opioid to prevent opioid-induced side effects, including constipation.
  • administration of methylnaltrexone commences about 5 minutes for parenteral MNTX administration and 20 minutes for enteral MNTX administration prior to administration of opioids in order to prevent these opioid-induced side effects. While the prevention of symptoms is preferred, in some patients, such as those chronically on opioids, prevention is not possible.
  • methylnaltrexone administration can also be commenced after the administration of the opioid or after the onset of opioid induced symptoms as a treatment for those symptoms.
  • Methylnaltrexone is rapidly absorbed after oral administration from the stomach and bowel. Initial plasma levels of the drug are seen within 5-10 minutes of the administration of non-enteric coated compound. Addition of an enteric coating which prevents gastric absorption is associated with lower plasma levels of the methylnaltrexone.
  • methylnaltrexone is used as an example of a particularly effective QDNM. It is apparent that other QDNMs can be used as desired, and appropriate dosage can readily be determined empirically by those of skill in the art to account for e.g., variable affinity of the QDNM for opiate receptors, different formulations, etc.
  • compositions and formulations can be administered to a patient as required to provide an effective amount of methylnaltrexone.
  • an "effective amount" of a compound or pharmaceutically acceptable composition can achieve a desired therapeutic and/or prophylactic effect.
  • an "effective amount” is at least a minimal amount of a compound, or composition containing a compound, which is sufficient for treating or preventing one or more symptoms of opioid induced constipation, as defined herein.
  • the term "effective amount,” as used in connection with an amount of methylnaltrexone, salt thereof, or composition of methylnaltrexone or salt thereof, refers to an amount of methylnaltrexone, salt thereof, or composition of methylnaltrexone or salt thereof sufficient to achieve a rescue free or spontaneous bowel movement in a subject.
  • the compositions as described herein are sufficient to achieve a rescue free bowel movement in a subject within about 24 hours, within about 12 hours, within about 8 hours, within about 5 hours, within about 4 hours, within about 3 hours, within about 2 hours, or within about 1 hours of administration to said patient. In a particular embodiment, the compositions as described herein are sufficient to achieve a rescue free bowel movement within about 4 hours of administration to the patient. In some embodiments, the compositions as described herein are sufficient to achieve a rescue free bowel movement within about 4 hours of administration to the patient for at least 100%, 99%, at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, or at least 50% of all doses administered.
  • compositions as described herein are sufficient to achieve a rescue free bowel movement within four hours during the first 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks of dosing. In some embodiments, the compositions as described herein are sufficient to achieve a rescue free bowel movement within about 4 hours of administration to the patient for all doses administered during first four weeks of dosing.
  • compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements experienced by a subject by at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements experienced by a subject by at least 1.
  • the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements experienced by a subject by at least 2.
  • the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements experienced by a subject by at least 3.
  • the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements experienced by a subject during the first 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks of dosing. In a particular embodiment, the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements experienced by a subject by at least 1 during the first 4 weeks of dosing. In another particular embodiment, the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements by at least one to at least 3 a week. In yet a further embodiment, the compositions as described herein are sufficient to increase the weekly number of rescue free bowel movements by at least one to at least 3 a week for at least 3 of the first 4 weeks following administration.
  • compositions presented herein can be further assessed using various assessment tools available to those skilled in the art to assess treatment of constipation.
  • the efficacy of the compositions of methylnaltrexone is assessed by Patient Assessment of Constipation (PAC) questionnaires.
  • the PAC consists of two complementary questionnaires: the PAC-Symptoms (SYM) and the PAC-Quality of Life (QoL) questionnaires.
  • the PAC-SYM is a 12 item survey that measures the severity of constipation symptoms across three domains: stool symptoms, rectal symptoms and abdominal symptoms.
  • the PAC-SYM scale has been used primarily to evaluate chronic constipation. The PAC-SYM scale is further described in Frank et al. Scand J Gastroenterol (1999) 34(9):870-877 and Slappendel et al.
  • the PAC-QoL is a 28-item survey that measures constipation-specific quality of life across four domains: worries and concerns, physical discomfort, psychosocial discomfort, and satisfaction.
  • the PAC-QoL scale is further described in Marquis et al. SJG (2005) 40:540-551, the entire contents of which are incorporated by reference herein.
  • the efficacy of the compositions as described herein can be assessed by the European Quality of Life-5 Dimensions (EQ-5D) analysis.
  • the EQ-5D is a 5-item standardized instrument for use as a measure of patient reported outcome (PRO). Applicable to a wide range of health conditions and treatments, the instrument provides a simple descriptive profile and a single index value for health status.
  • the EQ-5D instrument is further described in Dolan P. Medical Care (1997) 35:1095-1108, Rabin R. Ann. Med. (2001) 33(5):537-543 and Shaw et al. Medical Care (2005) 43:203-220, the entire contents of each of which are incorporated by reference herein.
  • the efficacy of the compositions as described herein is assessed by the Work Productivity and Activity Impairment General Health V2.0 (WPALGH) questionnaire.
  • the WPALGH is a 6-item questionnaire to quantify lost time from work and loss in productivity for health problems.
  • the WPALGH yields 4 types of scores: absenteeism (work time missed), "presenteeism” (impairment at work/reduced on-the- job effectiveness), work productivity loss (overall work impairment/absenteeism plus presenteeism), and activity impairment.
  • the WPALGH questionnaire is further described in Reilly et al. PharmacoEconomics (1993) 4(5):353-365, the entire contents of which are incorporated by reference herein.
  • the efficacy of the compositions as described herein can be assessed by the Global Clinical Impression of Change (GCIC) scale.
  • GCIC Global Clinical Impression of Change
  • the GCIC is a 7 point rating scale designed to assess subject's and clinician's impression of the subject's change in bowel status while on study drug. The scale ranges from 1 (Much Worse) to 7 (Much Better). This scale was completed by the subject and clinician at the end of daily dosing and End of Treatment.
  • the patient or subject is subcutaneously administered a composition of methylnaltrexone about once a day. In some embodiments, the patient or subject is subcutaneously administered a composition of methylnaltrexone about once every other day. In some embodiments, the patient or subject is subcutaneously administered a composition of methylnaltrexone on an as-needed basis. In some embodiments, the patient or subject is subcutaneously administered a composition of methylnaltrexone on an as-needed basis and at least once per week.
  • the subject is subcutaneously administered from about 6 mg to about 15 mg of methylnaltrexone, or a salt thereof, daily or every other day. In some embodiments, the subject is subcutaneously administered from about 8 mg to about 12 mg of methylnaltrexone, or a salt thereof, daily or every other day.
  • the subject can be administered about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 10.25 mg, about 10.5 mg, about 10.75 mg, about 11 mg, about 11.25 mg, about 11.5 mg about 11.75 mg, about 12 mg, about 12.25 mg, about 12.5 mg, about 12.75 mg, about 13 mg, about 13.25 mg, about 13.5 mg, about 13.75 mg, about 14 mg, about 14.25 mg, about 14.5 mg, about 14.75 mg, about 15 mg, or any other amount included therein, of methylnaltrexone, or salt thereof, daily or every other day.
  • the subject is subcutaneously administered about 8 mg of methylnaltrexone, or a salt thereof, daily or every other day. In some embodiments, the subject is subcutaneously administered about 12 mg of methylnaltrexone, or a salt thereof, daily or every other day. In some embodiments, the subject is subcutaneously administered 8 mg or 12 mg of methylnaltrexone, or a salt thereof, every other day, as needed, but not more frequently than once in a 24-hour period.
  • the subject is subcutaneously administered methylnaltrexone or a salt thereof, at a dose of between about 0.05 mg/kg to about 0.45 mg/kg body weight daily or every other day. In some embodiments, the subject is subcutaneously administered methylnaltrexone or a salt thereof, at a dose of between about 0.10 mg/kg to about 0.30 mg/kg body weight daily or every other day.
  • the subject can be administered methylnaltrexone, or a salt thereof, at a dose of about 0.05 mg/kg, about 0.10 mg/kg, about 0.15 mg/kg, about 0.20 mg/kg, about 0.25 mg/kg, about 0.30 mg/kg, about 0.35 mg/kg, about 0.40 mg/kg, about 0.45 mg/kg body weight, or any amount included therein, daily or every other day.
  • the subject is administered methylnaltrexone, or a salt thereof, at a dose of about 0.15 mg/kg body weight daily or every other day.
  • the subject is subcutaneously administered methylnaltrexone, or a salt thereof, methylnaltrexone or a salt thereof, at a dose of between about 0.05 mg/kg to about 0.45 mg/kg body weight every other day, as needed, but not more frequently than once in a 24-hour period. In some embodiments, the subject is subcutaneously administered methylnaltrexone, or a salt thereof, methylnaltrexone or a salt thereof, at a dose of between about 0.10 mg/kg to about 0.30 mg/kg body weight every other day, as needed, but not more frequently than once in a 24-hour period. In some embodiments, the subject is subcutaneously administered methylnaltrexone, or a salt thereof, at a dose of 0.15 mg/kg body weight every other day, as needed, but not more frequently than once in a 24-hour period.
  • the patient or subject is orally administered a composition of methylnaltrexone at least once a day. In some embodiments, the patient or subject is administered an oral composition of methylnaltrexone at least once, twice, three, four or five times a day. In some embodiments, the patient or subject is administered an oral composition of methylnaltrexone three times a day.
  • the subject is orally administered from about 150 mg to about 450 mg of methylnaltrexone, or a salt thereof, per day. In some embodiments, the subject is orally administered from about 150 mg to about 300 mg of methylnaltrexone, or a salt thereof, per day. In some embodiments, the subject is administered an oral dose of methylnaltrexone in the form of a tablet or capsule. In various embodiments, the subject is orally administered 150 mg of methylnaltrexone, or a salt thereof, daily. For example, the subject can be administered a tablet comprising 150 mg of methylnaltrexone or a salt thereof, daily.
  • the subject is orally administered 300 mg of methylnaltrexone or a salt thereof, daily.
  • the subject can be administered two tablets, each comprising 150 mg of methylnaltrexone or a salt thereof, daily.
  • the subject is orally administered 450 mg of methylnaltrexone or a salt thereof, daily.
  • the subject can be administered three tablets, each comprising 150 mg of methylnaltrexone or a salt thereof, daily.
  • exemplary adverse events induced by the administering oral methylnaltrexone include, but are not limited to, atrial flutter, faecaloma, impaired gastric emptying, chest pain, drug withdrawal syndrome, non- cardiac chest pain, hypersensitivity, bronchitis, cellulitis, infectious enterocolitis, gastroenteritis, influenza, osteomyelitis, pneumonia, urinary tract infection, dehydration, inadequate control of diabetes mellitus, diabetic ketoacidosis, hyperkalaemia, lumbar spinal stenosis, depression, suicidal tendencies, dyspnoea, pleurisy, pulmonary embolism, skin ulcer, knee arthoplasty, and spinal fusion surgery.
  • a composition comprising methylnaltrexone is administered subcutaneously.
  • the methylnaltrexone is administered orally.
  • the subject is receiving opioids chronically.
  • administration of the composition results in a decrease of about one point in a bowel movement straining scale.
  • administration of the composition results in an improvement of at least one point in a stool consistency scale (e.g. Bristol Stool Scale).
  • the improvement in strain or stool scale is observed for at least two weeks, at least four weeks, at least eight weeks, at least 12 weeks, at least 24 weeks or at least 48 weeks.
  • the cardiovascular event can be at least one selected from the group of: myocardial infarction, acute myocardial infarction, cardiac arrest, cardiorespiratory arrest, congestive cardiac failure, cardiovascular disorder, coronary artery disease, cyanosis, ischemic coronary artery disorders, rate and rhythm disorders, and supraventricular arrhythmias.
  • Embodiments are also directed to methods of treating a subject with oral formulations of methylnaltrexone described herein that decrease the occurrence of adverse events in comparison to the frequency of adverse events observed with previous oral methylnaltrexone formulations, for example, enterically coated oral formulations of methylnaltrexone or other oral formulations of methylnaltrexone not including an anion of an amphiphilic pharmaceutically acceptable excipient, in particular, sodium dodecyl (lauryl) sulfate.
  • an amphiphilic pharmaceutically acceptable excipient in particular, sodium dodecyl (lauryl) sulfate.
  • Example 1 demonstrate that the methods of administering the oral formulations of methylnaltrexone described herein are safer than the methods of administering previously described oral formulations of methylnaltrexone, for example, enterically coated oral formulations of methylnaltrexone or other oral formulations of methylnaltrexone that do not include an anion of an amphiphilic pharmaceutically acceptable excipient, in particular, sodium dodecyl (lauryl) sulfate.
  • an amphiphilic pharmaceutically acceptable excipient in particular, sodium dodecyl (lauryl) sulfate.
  • Embodiments are also directed to methods of treating a subject with oral formulations of methylnaltrexone, wherein the subject suffers from renal impairment.
  • the subject is administered a dose of methylnaltrexone that is less than the amount that is delivered to a subject who does not suffer from renal impairment.
  • the subject can be administered a dose of methylnaltrexone, or salt thereof, that is less than about 450 mg per day.
  • the subject is administered a dose of methylnaltrexone, or salt thereof, of about 300 mg per day.
  • the subject is administered a dose of methylnaltrexone, or salt thereof, of about 150 mg per day.
  • Embodiments are also directed to methods of treating a subject with oral formulations of methylnaltrexone, wherein the subject suffers from hepatic impairment.
  • the subject suffers from moderate to severe hepatic impairment (Child-Pugh B or Child-Pugh C).
  • the subject is administered a dose of methylnaltrexone that is less than the amount that is delivered to a subject who does not suffer from hepatic impairment.
  • the subject can be administered a dose of methylnaltrexone, or salt thereof, that is less than about 450 mg per day.
  • the subject is administered a dose of methylnaltrexone, or salt thereof, of about 300 mg per day.
  • the subject is administered a dose of methylnaltrexone, or salt thereof, of about 150 mg per day.
  • Embodiments are also directed to methods of treating a subject with oral formulations of methylnaltrexone, wherein administration of the oral formulation does not cause any drug- drug interactions.
  • administration of the oral formulation is considered to have a cleaner safety profile than that of another formulation comprising an opioid antagonist.
  • administration of the oral formulation can be administered concurrently with a composition that includes a CYP450 isozyme substrate.
  • Embodiments also relate to methods of predicting a clinical response to administration of methylnaltrexone, wherein the methods include administering an a composition comprising methylnaltrexone to a subject and analyzing the subject's plasma MNTX concentration, wherein a measurement of C max > 100 ng/mL indicates that the subject is a responder.
  • the clinical response is a laxation response within about four hours of administration of methylnaltrexone.
  • prediction of the clinical response indicates a likely response regardless of the route of administration of methylnaltrexone.
  • a clinical response based on measurement of C max after subcutaneous administration of methylnaltrexone is an indication that clinical response will occur in the subject after administration of methylnaltrexone by a non-subcutaneous route.
  • OM Oral Methylnaltrexone
  • OIC Opioid Induced Constipation
  • Constipation was defined as ⁇ 3 Rescue-Free Bowel Movements (RFBMs) per week on average (no laxative use within 24 hours prior to bowel movement) that were associated with 1 or more of the following (based on subject's diary report):
  • Subjects who remained eligible at the baseline visit (day 1) were randomly assigned to either OM tablet formulation 150 mg, 300 mg, 450 mg, or placebo initially in a 1: 1: 1: 1 allocation ratio. Subjects were required to take three tablets per day, first thing in the morning on an empty stomach (prior to breakfast). Subjects were instructed to swallow the tablets whole and never to chew, divide, or crush them and wait at least one half hour before ingesting any food. Subjects participated in the study for up to 84 days. The first 28 days were once daily dosing; the remaining 56 days were dosing as needed (PRN). Dosing remained double -blind throughout the 12 week period (84 days). The 84 day treatment period were followed by a 14-day post-treatment follow-up period (+ 2 days). Enrollment continued until a total of approximately 802 subjects had been randomized and dosed.
  • the efficacy endpoint of this study was the average proportion of rescue-free laxation responses per subject within 4 hours of all doses during the first four weeks of dosing.
  • the other efficacy endpoints include: Change in weekly number of RFBM from baseline during Weeks 1 to 4; and
  • responder to study drug during Weeks 1 to 4, where responder was defined as having > 3 RFBM/week, with at least 1 RFBM/week increase over baseline, for at least 3 out of the first 4 weeks
  • AEs adverse events
  • SAEs serious adverse events
  • Vital signs physical examinations (including rectal examination), laboratory evaluations, serum/urine pregnancy tests, ECGs, the Objective Opioid Withdrawal Scale (OOWS), the Subjective Opioid Withdrawal Scale (SOWS) and the Pain Intensity scale were performed at scheduled intervals during the study.
  • Standard 12-lead ECGs were obtained after the subject had been resting for at least five minutes at the visits designated in the Schedule of Study Visits and Evaluations. The Investigator was responsible for reviewing, interpreting, and retaining hard copies of the reports. Clinically significant abnormalities at any time point after the normal or non- clinically significant screening ECG were recorded as adverse events, as defined below.
  • the Numerical Rating of Pain Intensity Scale The scale, an 11-point rating scale ranging from 0 (None) to 10 (Worst Pain Possible), is a subject assessment tool and subjects should complete the evaluation based on their pain experienced during the 24 hours prior to completing the scale.
  • the Bristol Stool Scale is a 7-point scale rating the characteristics of the stool sample. The range is from Type 1, Separate hard lumps, like nuts (hard to pass) to Type 7, Watery, no solid pieces, entirely liquid.
  • the Bristol Stool Scale is a recognized, general measure of stool consistency or form.
  • Measures of straining were recorded for each bowel movement using the Straining Scale.
  • the scale a five-point scale to rate the amount of straining (None to Very Severe), is a subject assessment tool and subjects were to complete the evaluations for each bowel movement.
  • Measures of the sense of complete evacuation were recorded for each bowel movement using the Sense of Complete Evacuation Scale.
  • the scale is a subject assessment tool and subjects were to complete the evaluations for each bowel movement.
  • the PROs are for the purpose of exploring the subject's experience of constipation symptoms and the impact of constipation on quality of life and work productivity. Every effort was to be made to maintain an unbiased assessment. The investigator was to not influence the subject's self-assessments.
  • the PAC consists of two complementary questionnaires: the PAC-Symptoms (SYM) and the PAC-Quality of Life (QoL).
  • SYM PAC-Symptoms
  • QoL PAC-Quality of Life
  • the PAC-SYM is a 12 item survey that measures the severity of constipation symptoms across three domains: stool symptoms, rectal symptoms and abdominal symptoms.
  • the PAC-SYM scale has been use primarily to evaluate chronic constipation.
  • the PAC-QoL is a 28-item survey that measures constipation- specific quality of life across four domains: worries and concerns, physical discomfort, psychosocial discomfort, and satisfaction.
  • EQ-5D European Quality of Life-5 Dimensions
  • the EQ-5D is a 5-item standardized instrument for use as a measure of PRO. Applicable to a wide range of health conditions and treatments, it provides a simple descriptive profile and a single index value for health status.
  • the WPALGH is a 6-item questionnaire to quantify lost time from work and loss in productivity for health problems.
  • the WPALGH yields 4 types of scores: absenteeism (work time missed), "presenteeism” (impairment at work/reduced on-the-job effectiveness), work productivity loss (overall work impairment/absenteeism plus presenteeism), and activity impairment.
  • the GCIC Global Clinical Impression of Change
  • the GCIC is a 7 point rating scale designed to assess subject's and clinician's impression of the subject's change in bowel status while on study drug. The scale ranges from 1 (Much Worse) to 7 (Much Better). This scale was completed by the subject and clinician at the end of daily dosing (Visit 4) and End of Treatment (Visit 7).
  • efficacy is evidenced by demonstration of an efficacy endpoint, e.g.., the average proportion of rescue free bowel movements per subject within 4 hours of all doses during the first 4 weeks of dosing. Additional details can be found in U.S. Patent Publication No. 2013- 0317050, which is incorporated herein by reference in its entirety.
  • Methylnaltrexone bromide can be prepared, for example, according to the methods described in detail in international PCT Patent Application publication number, WO 2006/127899.
  • Formulations containing methylnaltrexone were prepared using pharmaceutically acceptable excipients.
  • Spheroids containing methylnaltrexone were prepared.
  • Tablets were prepared from spheroids, using conventional techniques. The tablets dissolve in under 10 minutes.
  • the spheroids were prepared by a wet granulation process followed by extrusion and spheronization, as described in the following general method. Methylnaltrexone bromide and pharmaceutically acceptable excipients were combined in an aqueous solution. Water was added until wet mass suitable for extrusion was obtained. The wet mass was passed through an extruder, and the extrudate was spheronized in a spheronizer. The resulting spheroids were dried in a fluid bed drier and passed through a screen. The uncoated spheroids were stored in appropriate container.
  • Methylnaltrexone bromide can be prepared, for example, according to the methods described in detail in international PCT Patent Application publication numbers WO 2011/112816.
  • Formulations containing methylnaltrexone were prepared using pharmaceutically acceptable excipients.
  • Pharmaceutically acceptable excipients include, for example, colloidal silicon dioxide, crospovidone, edetate disodium calcium dihydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, siliconized microcrystalline cellulose, sodium bicarbonate, sodium lauryl sulfate, and talc.
  • Spheroids containing methylnaltrexone were prepared. Tablets were prepared from spheroids, using conventional techniques.
  • the spheroids were prepared by a wet granulation process followed by extrusion and spheronization, as described in the following general method. Methylnaltrexone bromide and pharmaceutically acceptable excipients were combined in an aqueous solution. Water was added until wet mass suitable for extrusion was obtained. The wet mass was passed through an extruder, and the extrudate was spheronized in a spheronizer. The resulting spheroids were dried in a fluid bed drier and passed through a screen. The uncoated spheroids were stored in appropriate container.
  • Formulations containing methylnaltrexone were prepared using pharmaceutically acceptable excipients using a direct compression technique. Methylnaltrexone and excipients are sieved, screened and dry blended. The blend is then weighed and compressed into tablets using standard procedures. A non-functional coating is then applied to the compressed tablets.
  • Pharmaceutically acceptable excipients include, for example, colloidal silicone dioxide, EDTA calcium disodium dehydrate, sodium lauryl sulfate, microcrystalline cellulose, crospovidone, croscaraiellose sodium, poloxamer 407, siliconized microcrystalline cellulose and stearic acid.
  • EXAMPLE 5 CLINICAL PHARMACOKINETICS OF ADMINISTERED METHYLNALTREXONE
  • Study C investigated the single and multiple dose pharmacokinetics of methylnaltrexone (MNTX) and its metabolites (M2: methylnaltrexone sulfate; M4: 6a- methylnaltrexol; and M5: 6P-methylnaltrexol) following the subcutaneous administration of 12 mg methylnaltrexone.
  • MNTX methylnaltrexone
  • M5 6P-methylnaltrexol
  • MNTX methylnaltrexone
  • M2, M4 and M5 3 metabolites
  • Pharmacokinetic parameters included C max , AUC t , AU nf , t max , tm, Re 24 , accumulation factor (R) as defined below and metabolite/parent drug ratio.
  • R Accumulation Factor (based on AUCo- 24 (ng.h/mL): Day 7 AUC AUCo- 24 / Day
  • T ma x Median (Min, Max) * Harmonic mean (harmonic SD)
  • Tables 1 and 2 indicate that following oral and subcutaneous administrations, MNTX was readily absorbed with maximum MNTX plasma concentrations observed at 2 h and 0.25 h following oral dose and subcutaneous administration, respectively. Less than 4% of the orally administered dose was recovered in urine as an unconverted MNTX, markedly lower than the 31.5% - 49.6% recovered in in urine following IV administration (Yuan et al. 2005 J Clin Pharm 45:538-546).
  • MNTX oral administration resulted in extensive metabolism, resulting in the formation methylnaltrexone sulfate (M2) and stereo specific hydroxylation to form 6a- (M4) and 6P-methylnaltrexol (M5) of which M4 was found to be the favored route of metabolite formation.
  • M2 methylnaltrexone sulfate
  • M4 stereo specific hydroxylation to form 6a-
  • M5 6P-methylnaltrexol
  • Metabolic enzymes AKRC1C, SULT2A1 and SULT1E1 enzymes were reported be responsible for the MNTX metabolism into M2, M4 and M5.
  • EXAMPLE 6 CLINICAL PHARMACOKINETICS OF ORAL ADMINISTRATION OF METHYLNALTREXONE COMPARED TO SUBCUTANEOUS ADMINISTRATION OF THE SAME
  • the oral dosage levels and formulation of MNTX evaluated here were the same as those in a study of oral MNTX tablets, with the exception of a nonfunctional coating on the MNTX tablets.
  • This nonfunctional coating is comprised of inactive ingredients polyvinyl alcohol, polyethylene glycol, and titanium dioxide.
  • the pharmacokinetics of the uncoated tablet used in the study and the coated tablets used in the current study were compared in a separate study.
  • the current study was designed to evaluate the comparative bioavailability of orally administered, 150, 300, and 450 mg MNTX doses versus a 12 mg subcutaneous (SC) injection of MNTX.
  • SC subcutaneous
  • the objectives of this study were to evaluate the comparative bioavailability of 150, 300, and 450 mg single oral doses of MNTX tablets (Example 3) versus a 12 mg single SC dose of MNTX, and to characterize the pharmacokinetics of MNTX tablets after single oral dose administration in healthy subjects.
  • a randomized, open-label, crossover study consisting of 6 dosing sequences, each with 2 dosing periods; the dosing periods were separated by 7 days. All subjects were housed in the clinical research unit from Day -1 through Day 14 and were discharged on Day 15, which concluded their participation in the study. Prior to receiving study drug on Days 1 and 8, the subjects underwent an overnight fast of at least 10 hours, beginning on Days 0 and 7, respectively. In both dosing periods, the subjects received a single oral dose of MNTX tablets (150, 300, or 450 mg) or a single SC injection of MNTX (12 mg). The dosing was conducted in a crossover fashion (e.g., a tablet was administered at one visit and a SC injection was administered at the alternate visit).
  • Each oral dose was administered with 240 mL of room temperature drinking water. The subjects were instructed to drink all of the water and were told to swallow the tablets whole (e.g., not to chew, divide, or crush them). Blood samples were collected for pharmacokinetic analyses prior to dosing (approximately 1 hour prior) on Day 1, and at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing on Days 1 and 8.
  • Each tablet contained 150 mg of the active pharmaceutical ingredient, MNTX.
  • each tablet contained the following inactive ingredients: colloidal silicon dioxide, crospovidone, edetate disodium calcium dihydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, siliconized microcrystalline cellulose, sodium bicarbonate, sodium lauryl sulfate, and talc.
  • Each injection vial contained 12 mg of the active pharmaceutical ingredient, MNTX, per 0.6 mL of solution (i.e., 20 mg/mL solution).
  • the formulation also contained the following inactive ingredients: edetate calcium disodium, sodium chloride, glycine hydrochloride, and sodium hydroxide.
  • inactive ingredients edetate calcium disodium, sodium chloride, glycine hydrochloride, and sodium hydroxide.
  • C max and AUC Comparison of systemic exposure parameters demonstrates at least 4-fold higher mean C max following SC MNTX 12 mg versus each of the oral MNTX doses; however, mean AUCo- ⁇ following SC MNTX 12 mg was only 16% higher versus oral MNTX 300 mg and 28% lower versus oral MNTX 450 mg (Table 26).
  • Mean C max values were 174.0 ng/mL following SC MNTX 12 mg versus 26.2 and 39.9 ng/mL following oral MNTX 300 mg and 450 mg, respectively; and mean AUCo- ⁇ values following SC MNTX 12 mg were 269.1 versus 231.2 and 373.3 ng « h/mL following oral MNTX 300 mg and 450 mg, respectively.
  • Oral MNTX 450 mg resulted in a C max that was approximately 20% of the C max from SC MNTX 12 mg and an AUC 0 - ⁇ that was approximately 123% of the AUC 0 - ⁇ from SC MNTX 12 mg; the geometric mean ratios of the oral tablet (test) to the SC injection (reference) were 20.0% for C max and 123.2% for AUCo- ⁇ (Table 5).
  • the lower bound of the 90% confidence interval for C max (4.3%) was well below 80% and the upper bound of the 90% confidence interval for AUCo- ⁇ (150.7%) was greater than 125% indicating that both parameters were nonbioequivalent by the 80% to 125% rule.
  • the C max values were approximately 13% and 6% following oral MNTX 300 mg and 150 mg, respectively, of the C max following SC MNTX 12 mg, and the AUCo- ⁇ values following these oral doses were approximately 75% and 36%, respectively, of the AUCo- ⁇ following SC MNTX 12 mg (geometric mean ratios in Table 27).
  • the 90% confidence intervals of the C max and AUCo- ⁇ geometric mean ratios indicated nonbioequivalence of the 300 mg and 150 mg oral doses with SC MNTX 12 mg by the 80% to 125% rule (lower bounds of the 90% confidence intervals were ⁇ 80%).
  • the bioavailability of oral MNTX relative to SC MNTX was 3.7% (normalized to dose in mg/kg [assuming mean of 81 kg body weight, based on subject mean demographics] by the following calculation: 373.3 ng « h/mL/[450 mg/81 kg] ⁇ 269.1 ng « h/mL/[12 mg/81 kg] x 100).
  • Dose-normalized bioavailability of oral MNTX relative to SC MNTX for the 300 mg and 150 mg doses were 3.4% and 3.2%, respectively.
  • CI confidence interval
  • GMR geometric means ratio calculated as the tablet/injection x 100
  • LSM least squares mean
  • MNTX methylnaltrexone bromide
  • SC subcutaneous.
  • C max and AUC Comparison of systemic exposure parameters demonstrates 4- to 13- fold higher mean C max following SC MNTX 12 mg versus each of the oral MNTX doses; however, mean AUCo- ⁇ following SC MNTX 12 mg was only 16% higher versus oral MNTX 300 mg and 28% lower versus oral MNTX 450 mg.
  • Mean C max values were 174.0 ng/mL following SC MNTX 12 mg versus 26.2 and 39.9 ng/mL following oral MNTX 300 mg and 450 mg, respectively; and mean AUCo- ⁇ values were 269.1 following SC MNTX 12 mg versus 231.2 and 373.3 ng » h/mL following oral MNTX 300 mg and 450 mg, respectively.
  • the dose-normalized bioavailability of oral MNTX relative to SC MNTX injection comparing arithmetic mean AUCo- ⁇ values for an oral MNTX 450 mg, 300 mg, or 150 mg dose to the 12 mg SC MNTX injection, were 3.7%, 3.4%, and 3.2%, respectively.
  • the subjects received a single oral dose of MNTX tablets (150, 300, or 450 mg) or a single SC injection of MNTX (12 mg).
  • the dosing was conducted in a crossover fashion (i.e., a tablet was administered at one visit and a SC injection was administered at the alternate visit).
  • Forty-eight subjects were enrolled and 47 subjects (97.9%) completed the study; one subject discontinued due to personal reasons after receiving study drug in both study periods.
  • the subjects received study drug in accordance with the randomization schedule; specifically, 16 subjects each received a single oral dose of 150, 300, and 450 mg MNTX tablets and all 48 subjects received a single 12 mg SC injection of MNTX.
  • C max and AUC Comparison of systemic exposure parameters demonstrates at least 4-fold higher C max following SC MNTX 12 mg versus each of the oral MNTX doses; however, mean AUCo- ⁇ following SC MNTX 12 mg was only 16% higher versus oral MNTX 300 mg and 28% lower versus oral MNTX 450 mg.
  • the T max was shorter following SC MNTX 12 mg (15 minutes) than following oral MNTX 150 mg 300 mg, or 450 mg, (2, 1.5, and 2 hours, respectively).
  • the t 1 ⁇ 2 value was shorter, 9.2 versus 16.6 hours, for SC MNTX 12 mg compared with oral MNTX 450 mg (t 1/2 were 14.2 and 14. 0 hours following oral MNTX 300 mg and 150 mg, respectively).
  • the single-dose pharmacokinetics of oral MNTX 150 mg tablet (ion-pairing) formulation was also studied in a recent study of healthy adults and in prior studies of subjects with noncancer pain and OIC and subjects on stable methadone maintenance.
  • the single-dose pharmacokinetic parameters of oral MNTX were generally similar in the current study and in these other studies, although there were some quantitative differences in C max and AUC in the current study and recent study of healthy adults when compared with prior studies of subjects with noncancer pain and OIC and of subjects on stable methadone maintenance.
  • Methylnaltrexone by SC injection was compared to MNTX administered orally in a pharmacokinetic study in subjects on stable methadone maintenance.
  • the oral MNTX formulation was different in the current study than in the previous study, in which the oral formulations were enteric-coated granules in capsules and enteric-coated tablets. Although it is difficult to compare the current study and the previous study due to different oral MNTX formulations, the comparative pharmacokinetic profiles between SC dosing and oral dosing were similar between studies.
  • T max was shorter, C max was higher, and t was shorter following SC dosing compared with oral dosing; whereas differences in AUC values between SC and oral administrations were less pronounced than the differences in C max , T max , and t 1/2 .
  • Dose-normalized oral bioavailability relative to SC injection was 2.43% for enteric-coated capsules and 2.27% for enteric-coated tablets in the previous study, compared with 3.7% for the oral tablet (ion-pairing) formulation in the current study.
  • EXAMPLE 7 STRAINING AND STOOL CONSISTENCY SCORES IMPROVE AFTER SUBCUTANEOUS ADMINISTRATION OF METHYLNALTREXONE
  • a 48-week open-label safety study was conducted to evaluate the safety of subcutaneous administration of methylnaltrexone to subjects having chronic non-cancer pain and opioid- induced constipation.
  • the study involved 1034 patients who were administered 12 mg of methylnaltrexone bromide once per day (QD), as needed. The patients were required to take at least one dose per week.
  • a method of decreasing the risk of a cardiovascular event a subject suffering from opioid-induced constipation comprising administering a composition comprising methylnaltrexone to the subject.
  • the methylnaltrexone is administered subcutaneously.
  • the methylnaltrexone is administered orally.
  • the subject is receiving opioids chronically.
  • administration of the composition results in a decrease of about one point in a bowel movement straining scale.
  • administration of the composition results in an improvement of at least one point in a stool consistency scale (e.g. Bristol Stool Scale).
  • the improvement in strain or stool scale is observed for at least two weeks, at least four weeks, at least eight weeks, at least 12 weeks, at least 24 weeks or at least 48 weeks.
  • the cardiovascular event can be at least one selected from the group of: myocardial infarction, acute myocardial infarction, cardiac arrest, cardiorespiratory arrest, congestive cardiac failure, cardiovascular disorder, coronary artery disease, cyanosis, ischemic coronary artery disorders, rate and rhythm disorders, and supraventricular arrhythmias.
  • methylnaltrexone bromide also provided sustainable rapidity and durable efficacy of response during 48 weeks of treatment (Figure 6).
  • patients undergoing treatment with methylnaltrexone demonstrated significant improvements from baseline over the course of the study in terms of rapid response (e.g. rescue-free bowel movement within four hours of dosing) and weekly rescue-free bowel movements (e.g. ⁇ 3 rescue-free bowel movements per week).
  • embodiments are also directed to a method of treating constipation in a subject, comprising administering a composition comprising methylnaltrexone to the subject, wherein administration of the composition results in a rapid response. In some embodiments, administration of the composition results in a bowel movement within four hours of dosing. Embodiments are also directed to a method of treating constipation in a subject, comprising administering a composition comprising methylnaltrexone to the subject, wherein administration of the composition results in an improvement in the number of weekly rescue- free bowel movements. In some embodiments, administration of the composition results in at least three or more bowel movements per week. In the foregoing embodiments, the methylnaltrexone can be administered subcutaneously.
  • the methylnaltrexone can be administered orally.
  • the subject can be receiving opioids chronically.
  • the rapid response or improvement that results from administration of the composition can be observed for at least two weeks, at least four weeks, at least eight weeks, at least 12 weeks, at least 24 weeks or at least 48 weeks.
  • EXAMPLE 8 CLINICAL DATA RELATED TO ADMINISTRATION OF METHYLNALTREXONE
  • methylnaltrexone bromide was administered intravenously at amounts up to 24 mg every 6 hours (Q6H). Blood pressure and pulse were evaluated among 1421 patients using measures for acute and long-term change from baseline, potentially clinically significant outliers, and repeated measures analyses incorporating changes relative to acute and chronic dosing.
  • Figure 7 provides a summary of mean pulse (beats per minute [bpm] and supine blood pressure (mm Hg) changes from baseline on Day 1 and Day 3 in the post-operative ileus studies.
  • mean pulse beats per minute [bpm]
  • supine blood pressure mm Hg
  • Figure 8 provides a summary of outliers for pulse and blood pressure parameters over 10 days of observation in the post-operative ileus studies. At the individual patient level, there were no apparent differences from placebo in the incidence of potentially-clinically significant decreases or increases in pulse of blood pressure at the high doses evaluated in these studies.
  • Figure 20 illustrates a comparison of the time to event for MI in patients administered with alvimopan compared with that in patients administered with methylnaltrexone, which supports the safety of methylnaltrexone administration.
  • the treatment groups include: (1) the population who were randomized to receive methylnaltrexone during double-blinded studies for post-operative ileus or for opioid-induced constipation (advanced illness or chronic non-cancer pain) and (2) the population involved in an open-label study of methylnaltrexone for opioid-induced constipation.
  • Figures 13 through 18 illustrate data from studies involving administration of methylnaltrexone in clinical studies that indicate that there are no apparent dose-dependent effects of methylnaltrexone on pulse or blood pressure. This was observed for subcutaneous doses up to 12 mg QOD and 12 mg QD as well as for intravenous doses up to 24 mg administered every 6 hours.
  • embodiments are directed to a method of administering methylnaltrexone to a subject in need thereof, wherein administration of methylnaltrexone does not elevate the risk of an adverse cardiovascular event.
  • the methylnaltrexone is administered subcutaneously.
  • the methylnaltrexone is administered orally.
  • the subject is receiving opioids chronically.
  • administration of the composition results a bowel movement within about 4 hours after dosing.
  • administration of the composition results in the subject having > 3 rescue-free bowel movements per week.
  • the improvement in weekly bowel movement rate is observed for at least two weeks, at least four weeks, at least eight weeks, at least 12 weeks, at least 24 weeks or at least 48 weeks.
  • the cardiovascular event can be at least one selected from the group of: myocardial infarction, acute myocardial infarction, cardiac arrest, cardiorespiratory arrest, congestive cardiac failure, cardiovascular disorder, coronary artery disease, cyanosis, ischemic coronary artery disorders, rate and rhythm disorders, and supraventricular arrhythmias.
  • Eligible subjects were receiving oral or transdermal opioids daily for at least 30 days prior to Day -4.
  • a RFBM was defined as a bowel movement with no laxative use within 24 hours prior to the bowel movement.
  • eligible subjects entered an open-label phase (Day -4) to determine if they responded to a 12 mg subcutaneous (SC) dose of methylnaltrexone.
  • SC subcutaneous
  • Each eligible subject received a 12 mg SC MNTX injection about 1 hour after taking his/her opioid dose. If the subject had a RFBM within 4 hours of the SC methylnaltrexone dose, they returned in 2 days and entered a 4-day in-patient double-blind treatment phase, followed by a 1-week follow-up phase.
  • Responders entered the in-patient treatment phase and were randomized in a 1: 1: 1 ratio (minimum of 25 subjects per arm) to: (i) a single dose of Formulation A MNTX oral tablets (450 mg dose, 3 tablets), (ii) a single dose of Formulation B MNTX oral tablets (450 mg dose, 3 tablets), or (iii) placebo direct compression formulation oral tablets (3 tablets) as a single dose.
  • Subjects were administered the study drug about 1 hour after taking the opioid dose and had fasted for at least 8 hours prior to study drug administration.
  • each tablet contained 150 mg of the active pharmaceutical ingredient, MNTX.
  • each tablet contained the following inactive ingredients: colloidal silicon dioxide, crospovidone, edetate disodium calcium dihydrate, microcrystalline cellulose, siliconized microcrystalline cellulose, sodium lauryl sulfate, stearic acid, poloxamer 407, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and croscarmellose sodium.
  • the tablets were made by a direct compression process. (Example 4)
  • each tablet contained 150 mg of the active pharmaceutical ingredient, MNTX.
  • each tablet contained the following inactive ingredients: colloidal silicon dioxide, crospovidone, edetate disodium calcium dihydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, siliconized microcrystalline cellulose, sodium bicarbonate, sodium lauryl sulfate, and talc.
  • the tablets were made by a wet granulation process.
  • Formulation B tablets had previously demonstrated safety and efficacy in clinical studies (Examples 1, 5 and 6).
  • One efficacy endpoint was clinical response, defined as the proportion of subjects who had a RFBM within 4 hours after a single oral dose of study drug (double-blind treatment phase).
  • a RFBM was defined as a bowel movement with no laxative use within 24 hours prior to the bowel movement.
  • PK parameters were estimated for methylnaltrexone if adequate data were available: (i) AUCo- ⁇ (area under the plasma concentration versus time curve from time 0 (pre-dose) extrapolated to time infinity, (ii) ⁇ (terminal phase rate constant), (iii) t1 ⁇ 2 (half-life), and (iv) apparent oral clearance (CL/F).
  • the metabolite to parent ratio for C max and AUCo-4 was calculated for each MNTX metabolite after SC and oral administration of MNTX.
  • exploratory analyses was carried out to evaluate pharmacokinetic/pharmacodynamics relationships between methylnaltrexone systemic exposure and efficacy.
  • the 90% confidence interval (CI) for the difference in clinical response rate between the Formulation A group and the Formulation B group was -17%, 20%; this 90% CI was within the protocol-defined interval of -20%, 20% (-0.20; +0.20) , which demonstrated the clinical equivalence of the two oral MNTX formulations.
  • MNTX methylnaltrexone
  • RFBM rescue-free bowel movement. Notes: Rescue-free bowel movement was defined as a bowel movement with no laxative use within 24 hours prior to the bowel movement.
  • DB Double-Blind
  • MNTX methylnaltrexone
  • RFBM Rescue Free Bowel Movement.
  • RFBM was a bowel movement without laxative use within 24 hours prior to the bowel movement.
  • Stool consistency score is considered zero for subjects with no RFBM during the DB phase.
  • Straining score is considered 5 (very severe) for subjects with no RFBMs during the DB phase.
  • Percentage was calculated as the number of RFBMs with straining score of 0 (none) or 1 (mild)/total
  • LS Least Square
  • LS mean difference LS mean difference
  • p-value p-value
  • Mean C max was approximately 4-fold greater following SC MNTX (132.82 ng/mL) than following oral MNTX from each tablet formulation (Formulation A: 34.58 ng/mL; Formulation B: 35.35 ng/mL). Also, median T max was 4- to 6-fold shorter following SC MNTX (0.35 hour) as compared with each oral tablet formulation (Formulation A: 1.53 hours; Formulation B: 2.00 hours) (Table 8). Statistical analyses comparisons (analysis of variance) of PK following oral dosing indicate that mean C max and mean AUCo- ⁇ were not different between the two oral MNTX formulations (Formulation A versus Formulation B; p > 0.05).
  • AUCo-t area under the plasma concentration versus time curve from time 0 (predose) to the last quantifiable plasma concentration-time point
  • AUCo-4 AUC from time 0 (predose) to 4 hours post-dose
  • AUCo-oo AUC from time 0 (predose) to time infinity
  • CL/F apparent oral clearance
  • C max maximum observed plasma concentration
  • MNTX methylnaltrexone
  • NC not calculated
  • SD standard deviation
  • max time to C max .
  • C max and AUCo-4 Systemic exposure parameters, C max and AUCo-4, for the MNTX metabolites methylnaltrexone sulfate (M2), methyl-6a-naltrexol (M4), and methyl-6P-naltrexol (M5), were greater following oral administration compared with SC administration, as were the metabolite to parent ratios for C max and AUCo-4 for each of the three MNTX metabolites (Table 9).
  • AUCo-4 mean metabolite to parent ratios following oral administration were approximately 3- to 4-fold greater compared with SC administration for each of the 3 metabolites.
  • the mean metabolite to parent ratios were approximately 8- to 9-fold greater for methylnaltrexone sulfate following oral administration compared with SC administration, and approximately 6- to 8-fold greater for methyl-6a-naltrexol and methyl- ⁇ -naltrexol following oral administration compared with SC administration.
  • AUCo-t area under the plasma concentration versus time curve from time 0 (predose) to the last quantifiable plasma concentration-time point
  • AUCo-4 AUC from time 0 (predose) to 4 hours post-dose
  • AUCo- ⁇ AUC from time 0 (predose) to time infinity
  • CL/F apparent oral clearance
  • C ma x maximum observed plasma concentration
  • MNTX methylnaltrexone
  • NC not calculated
  • SD standard deviation
  • T ma x time to maxj
  • Ratios of AUCo-4 and C ma x represent the metabolite to parent ratios
  • a phase 1, two-arm, randomized, open-label, crossover study was carried out to evaluate the pharmacokinetics of a single oral dose of methylnaltrexone tablets (Formulation B, Example 3) after a high-fat meal or after fasting in healthy subjects.
  • Subjects were randomized at a 1: 1 ratio to Arm 1 (fasted then fed) or Arm 2 (fed then fasted). Each subject received a single oral dose of 450 mg (3 x 150 mg tablets) MNTX (Formulation A) with a high fat meal (MNTX fed) and after fasting (MNTX fasted). The fasted/fed study periods were separated by 6 days. The sequence of fasted/fed or fed/fasted dosing on Days 1 and 8 were determined by randomization on Day 1. Blood samples for PK analyses of MNTX were collected predose and up to 96 hours postdose following both fasted and fed single-dose treatment administrations. Plasma concentrations of MNTX were determined by a validated LC/MS/MS assay with a LLOQ of 0.05 ng/mL.
  • embodiments are directed to the methods of administering methylnaltrexone to a subject, wherein the methylnaltrexone is provided in an oral pharmaceutical composition, and wherein the composition is administered to a subject without food (or on an empty stomach).
  • administration without food (or on an empty stomach) includes administration preceded by a fasting period of at least about 10 hours.
  • administration without food (or on an empty stomach) includes administration preceded by a fasting period of at least about 9 hours.
  • administration without food (or on an empty stomach) includes administration preceded by a fasting period of at least about 8 hours.
  • administration without food (or on an empty stomach) includes administration preceded by a fasting period of at least about 6 hours.
  • administration without food includes administration preceded by a fasting period of at least about 6, 7, 8, 9 or 10 hours and followed by a fasting period of at least about 1 hour. In some embodiments, administration without food (or on an empty stomach) includes administration preceded by a fasting period of at least about 6, 7, 8, 9 or 10 hours and followed by a fasting period of at least about 2 hours. In some embodiments, administration without food (or on an empty stomach) includes administration preceded by a fasting period of at least about 6, 7, 8, 9 or 10 hours and followed by a fasting period of at least about 3 hours.
  • Hepatic impairment can result in increased intestinal permeability as well as reduced first-pass metabolic clearance for orally- administered drugs.
  • a phase 1, open-label study was conducted to evaluate the single-dose pharmacokinetics (PK) of oral methylnaltrexone (MNTX) tablets (Example 4) in subjects with hepatic impairment and in healthy subjects.
  • PK pharmacokinetics
  • MNTX oral methylnaltrexone
  • the Child-Pugh classification system for the severity of liver disease is listed below (Table 11). The classification system determines severity of liver disease according to the degree of ascites (via clinical assessment), the plasma concentrations of bilirubin and albumin, the International Normalized Ratio, and the degree of encephalopathy.
  • Encephalopathy is classified as Grade 0-4 using the Conn scoring system provided as follows:
  • Grade 0 No personality or behavioral abnormality detected.
  • Grade 1 Trivial lack of awareness, euphoria or anxiety; shortened attention span; impairment of addition or subtraction.
  • Grade 2 Lethargy; disorientation for time; obvious personality change; inappropriate behavior.
  • Grade 3 Somnolence to semi-stupor, responsive to stimuli; confused; gross disorientation; unusual behavior.
  • Grade 4 Coma; unable to test mental state.
  • a total score of 5-6 is considered Child- Pugh grade A (well-compensated disease); 7- 9 is Child Pugh grade B (significant functional compromise); and 10-15 is Child-Pugh grade C (decompensated disease).
  • Eligible subjects completed a screening period of up to 21 days, followed by a 5-day treatment period. Following the screening period, subjects checked in at the clinical research unit (CRU) on Day -1 and remained in the CRU through the 96-hour blood sample collection on Day 5. A follow-up phone call occurred 3 (+1) days after discharge from the CRU.
  • CRU clinical research unit
  • each tablet contained 150 mg of the active pharmaceutical ingredient, MNTX.
  • each tablet contained the following inactive ingredients: colloidal silicon dioxide, crospovidone, edetate disodium calcium dihydrate, microcrystalline cellulose, siliconized microcrystalline cellulose, sodium lauryl sulfate, stearic acid, poloxamer 407, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and croscarmellose sodium.
  • the tablets were made by a direct compression process.
  • a minimum number of patients having hepatic impairment were enrolled. This included at least 6 Child-Pugh A and 6 Child-Pugh B subjects as well as 6 healthy subjects. In addition to the minimum number of hepatic impairment subjects required by the protocol (6 Child-Pugh A and 6 Child-Pugh B), a cohort of subjects with severe hepatic impairment (Child-Pugh C) was evaluated, thereby placing total enrollment in the study at 24 subjects.
  • cytochrome P450 enzymes e.g., grapefruit juice, grapefruits, Seville [bitter] oranges, pomelos, pomelo juice, star fruit, broccoli, Brussels sprouts, or chargrilled meats
  • stable pharmacotherapy could be continued according to the normal schedule of administration, except for the following exclusions: (i) non-study MNTX within 14 days prior to Day 1, (ii) opioid agonists, partial opioid agonists (e.g., buprenorphine), non-study opioid antagonists, or combination agonists/antagonists within 14 days prior to Day 1 and throughout the study, and/or (iii) lactulose or over-the-counter laxatives for 24 hours prior to and 48 hours following the MNTX dose.
  • opioid agonists e.g., buprenorphine
  • non-study opioid antagonists e.g., lactulose or over-the-counter laxatives for 24 hours prior to and 48 hours following the MNTX dose.
  • Plasma PK parameters calculated for MNTX and metabolites (MNTX sulfate [M2], methyl-6a-naltrexol [M4], and methyl-6P-naltrexol [M5]), if measurable, included: (i) maximum observed plasma concentration (C max ), (ii) time of C max (T max ), (iii) lag time of appearance in plasma (Ti ag ), (iv) area under the plasma concentration-time curve (AUC) from time 0 (predose) to 24 hours (AUCo-24), and (v) AUC from time 0 (predose) to last measured time point (AUCi ast ).
  • PK parameters were calculated: (i) AUC to infinity (AUCI P), (ii) AUC extrapolated beyond last measured time point, (iii) Terminal phase rate constant ( ⁇ ), (iv) terminal half-life (ti/2), (v) apparent oral volume of distribution (V/F) of MNTX, and (vi) apparent oral clearance (CL/F) of MNTX.
  • the safety endpoints were as follows: (i) incidence of treatment-emergent adverse events (TEAEs), (ii) changes from baseline in clinical laboratory assessments, (iii) changes from baseline in vital signs.
  • Clinical laboratory parameters that were assessed included hematology, standard blood chemistry, serum cystatin C, coagulation and urinalysis.
  • Vital signs that were measured included seated blood pressure (mm Hg), pulse (beats per minute) and oral temperature (°C).
  • MNTX and metabolites were determined by standard model-independent methods. MNTX and metabolite concentrations were summarized for each collection time point or collection interval by the number of subjects evaluated (N), arithmetic mean, SD, coefficient of variation, median, minimum, and maximum.
  • PK parameters for MNTX, M2, M4, and M5 were summarized for each hepatic impairment group by the number of subjects evaluated (N), arithmetic mean, SD, geometric mean, 95% confidence interval (CI), coefficient of variation, median, minimum, and maximum.
  • N the number of subjects evaluated
  • SD the number of subjects evaluated
  • CI 95% confidence interval
  • the geometric mean ratio (hepatic impairment/healthy) and associated 90% CI for C max , AUCiast, AUCo-24, and AUCo- ⁇ for each hepatic impairment group was calculated. Additionally, the effect of hepatic impairment on the PK of MNTX was assessed based on the clinical relevance of PK changes and the relationships between PK and safety.
  • Safety analyses were descriptive and evaluations were based on the incidence, intensity and types of treatment-emergent AEs, and changes in clinical laboratory results and vital signs.
  • AUCi ast area under the plasma concentration versus time curve from time 0 (predose) to the last quantifiable plasma
  • AUCo-24 AUC from time 0 (predose) to 24 hours post-dose
  • AUCo_ ⁇ AUC from time 0 (predose) to time infinity
  • %AUC Extrapolation percentage of AUC extrapolated beyond last measured time point to determine AUCo_ ⁇
  • CL/F apparent oral clearance
  • C max maximum observed plasma concentration
  • ti/2 half-life
  • MNTX methylnaltrexone
  • SD standard deviation
  • Ti ag lag time preceding absorption
  • T max time to C max
  • ⁇ ⁇ termination elimination constant
  • V/F apparent oral volume of distribution a Reported as median (range).
  • Median T max was shorter in liver impairment subjects (median T max ranging from 1 to 1.25 hours) when compared to healthy subjects (2.5 hours).
  • Oral clearance (CL/F) values were lower in Child-Pugh B (700 L/h) and Child-Pugh C (661 L/h) subjects as compared with healthy subjects (1228 L/h) and Child-Pugh A subjects (1564 L/h).
  • Mean t 1 ⁇ 2 of MNTX was 16 hours for healthy subjects, and was largely similar for subjects with hepatic impairment (Child-Pugh A: 19 hours, Child-Pugh B: 15 hours, Child-Pugh C: 17 hours).
  • Table 15 presents results of statistical evaluations of systemic exposure after single 450-mg oral doses of MNTX in healthy subjects (reference) and those with Child-Pugh A, B, or C hepatic impairment (test) conditions.
  • C max AUCo-24, AUCi ast , and AUCo- ⁇
  • the 90% CIs the geometric mean ratios of these parameters for healthy subjects versus those with hepatic impairment were outside of the range of 80% to 125%, indicating non-equivalent exposure in subjects with liver dysfunction.
  • AUCi ast area under the plasma concentration versus time curve from
  • AUCo-24 AUC from time 0 (predose) to 24 hours post-dose
  • AUCo_ ⁇ AUC from time 0
  • Table 16 illustrates methylnaltrexone urine concentrations.
  • the mean amount of MNTX excreted was slightly lower in Child-Pugh A subjects (6606 ⁇ g) than healthy subjects (8066 ⁇ g), but was markedly higher in Child-Pugh B (12648 ⁇ g) and Child-Pugh C subjects (16879 ⁇ g). Renal clearance rates were comparable for healthy subjects (306 mL/min), Child-Pugh A subjects (289 mL/min), and Child-Pugh C subjects (315 mL/min) and was slightly lower for Child-Pugh B subjects (244 mL/min). Renal clearance rates did not directly correlate to the MNTX concentration in urine. Table 16. Summary of Urine Concentrations of MNTX
  • TEAEs treatment-emergent adverse events
  • MNTX MNTX
  • MNTX was well tolerated in both healthy subjects and hepatic impairment subjects with a low incidence of TEAEs, none of which were considered related to study drug.
  • the right panel in each plot displays the predicted values in subjects with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment after a single dose of 150 mg MNTX.
  • a MNTX dose of 150 mg is anticipated to result in systemic exposures in Child- Pugh B and C subjects similar to those observed in healthy subjects that are administered a MNTX dose of 450 mg.
  • a dose of 150 mg QD is recommended for subjects suffering from moderate to severe hepatic impairment (Child-Pugh B or Child-Pugh C).
  • Embodiments are directed to methods of treating a subject with oral formulations of methylnaltrexone, wherein the subject suffers from hepatic impairment.
  • the subject suffers from moderate to severe hepatic impairment (Child-Pugh B or Child-Pugh C).
  • the subject is administered a dose of methylnaltrexone that is less than the amount that is delivered to a subject who does not suffer from hepatic impairment.
  • the subject can be administered a dose of methylnaltrexone, or salt thereof, that is less than about 450 mg per day.
  • the subject is administered a dose of methylnaltrexone, or salt thereof, of about 300 mg per day.
  • the subject is administered a dose of methylnaltrexone, or salt thereof, of about 150 mg per day.
  • EXAMPLE 12 EFFECT OF RENAL IMPAIRMENT UPON DOSING
  • MNTX is excreted unchanged in the urine.
  • SC subcutaneous
  • Example 9 Data from a comparison study (Example 9) and a pharmacokinetic/pharmacodynamics model (Example 13) were used to predict the range of C max and AUCo- ⁇ values after administration of a 450 mg or 300 mg oral dose of MNTX in OIC patients with severe renal impairment given the assumptions discussed above.
  • the predicted C max values were compared to the observed values after administration of 450 mg in the comparison study (Example 9).
  • Plots of the observed and predicted PK parameters are displayed in Figure 37.
  • the left panel of Figure 37 illustrates observed MNTX C max values after administration of 450 mg in the comparison study (Example 9) and predicted C max values after administration of 450 mg or 300 mg in subjects with severe renal impairment.
  • the right panel of Figure 37 illustrates observed MNTX AUCo- ⁇ values after administration of 450 mg PO in the comparison study (Example 9) and predicted AUCo- ⁇ values after administration of 450 mg or 300 mg in subjects with severe renal impairment. Open circles in Figure 37 represent individual observed or predicted values, and lines represent median observed or predicted values.
  • Oral administration of 300 mg MNTX in subjects with severe renal impairment is predicted to result in an approximate decrease of 20% in median C max and an approximate 27% increase in median AUCo- ⁇ relative to the observed values after administration of 450 mg in OIC patients in the comparison study (Example 9). Based on C max comparisons, an oral dose of 300 mg MNTX in patients with OIC and severe renal impairment is expected to provide efficacy comparable to that observed after administration of 450 mg in subjects with normal renal function and have an acceptable safety profile. Therefore, a dosing regimen of 300 mg once daily is recommended in patients with severe renal impairment.
  • Embodiments are directed to methods of treating a subject with oral formulations of methylnaltrexone, wherein the subject suffers from renal impairment.
  • the subject is administered a dose of methylnaltrexone that is less than the amount that is delivered to a subject who does not suffer from renal impairment.
  • the subject can be administered a dose of methylnaltrexone, or salt thereof, that is less than about 450 mg per day.
  • the subject is administered a dose of methylnaltrexone, or salt thereof, of about 300 mg per day.
  • the subject is administered a dose of methylnaltrexone, or salt thereof, of about 150 mg per day.
  • Concentration-response relationships generally are continuous such that the relationships determined from one dosage form or route of administration can be applied to the relationships for another dosage form even when plasma concentrations are different after administration of those dosage forms. Accordingly, data across multiple studies demonstrating dose -response and systemic exposure-response (ie, pharmacokinetic/pharmacodynamics, or PK/PD) relationships for MNTX were analyzed to, extrapolate efficacy results from the studies for administration of a subcutaneous (SC) formulation of methylnaltrexone to administration of an oral formulation of methylnaltrexone.
  • SC subcutaneous
  • the objectives of these analyses were to develop a PK/PD model of the relationship between plasma concentrations of MNTX and clinical endpoints measured in subcutaneous administration clinical trials and to examine the effect of the covariates of C max and T max of MNTX, age, sex, weight, and route of administration on the clinical endpoints.
  • the efficacy endpoints included in this analysis were the occurrence of a bowel movement (laxation) within 4 hours after administration and the time to laxation after administration of the first dose of study drug.
  • Blood samples for analysis of plasma MNTX concentrations were collected over different intervals across studies. Therefore, MNTX maximum observed plasma concentration (C max ) was used to develop the PK/PD models.
  • model development data set Seventy percent of the original data set was randomly selected to create a model development data set.
  • the model development data set was used to develop PK/PD models for two clinical endpoints (laxation within 4 hours after administration and time to laxation) and to test the effects of significant covariates (age, weight, sex, C max , T max and route of administration) on the clinical endpoints.
  • the remaining 30% of the data were used as a model validation data set.
  • the predictive performance of the models was investigated by comparing the clinical endpoints predicted with the final model parameters and the covariates from the validation data set to the observed clinical endpoints in the validation data set.
  • a logistic regression model was used to describe the relationship between the probability of laxation within 4 hours after MNTX administration and the selected covariates, including C max .
  • the data for laxation response within 4 h after dose administration was characterized as a binomial response and modeled using the following equation (1):
  • a is an intercept parameter, ⁇ ; is the model coefficient for the i covariate, and Covi is the 1 th covariate value.
  • TTE time to event
  • HR pred is the predicted hazard rate
  • SR pred is the predicted survival rate
  • t is the time at which the fraction surviving is estimated
  • ⁇ ⁇ , Covi, and v are as defined previously.
  • the TTE model identified a concentration-dependent effect on the time to laxation with T max as an additional significant covariate.
  • the model generally described the observed fraction of subjects that had experienced laxation over the 24 hour period after administration in subjects in the validation data set.
  • the logistic regression model demonstrated that MNTX Cmax and T max were the significant predictors of the probability of laxation within 4 hours after administration.
  • the effects of MNTX C max and T max on the probability of laxation within 4 hours after administration were independent of the route of administration (oral versus SC or intravenous).
  • the final model parameters and covariates from the validation data set adequately predicted the observed proportion of subjects who achieved laxation within 4 hours after administration in the validation data set.
  • the model-predicted probabilities of laxation within 4 hours versus MNTX C max for four T max values are displayed in Figure 40.
  • the observed proportion of subjects who achieved laxation within 4 hours after administration versus the mean C max for each T max category from the validation data set are displayed on each graph.
  • the solid line in each plot ( Figure 40) represents the median predicted probability of laxation within 4 hours versus natural log of MNTX C max + 1.
  • the shaded area in each plot ( Figure 40) represents the 95% credible interval for predicted probability of laxation within 4 hours versus natural log of MNTX C max + 1.
  • the closed circles in each plot ( Figure40) represents the observed proportion of subjects that experienced laxation within 4 hours after administration versus mean ln(C max ) + 1 in each T max group in the validation data set.
  • the logistic regression model accurately predicted the proportion of subjects that achieved laxation within 4 hours after administration in the validation data set, demonstrating that the concentration-effect relationship was well-described. Although a concentration-dependent effect was detected during development of the TTE model, validation results indicate that C max , and T max alone cannot predict the time to laxation with accuracy. Both PK/PD models demonstrated that laxation is likely to occur more rapidly when C max is large and T max values are short (i.e. C max occurs rapidly).
  • Embodiments are directed to predicting a clinical response to administration of methylnaltrexone, wherein the methods include administering a composition comprising methylnaltrexone to a subject and analyzing the subject's plasma MNTX concentration, wherein a measurement of C max > 100 ng/mL indicates that the subject is a responder. In some embodiments, a measurement of C max > 125 ng/mL indicates that the subject is a responder. In some embodiments, a measurement of C max > 150 ng/mL indicates that the subject is a responder. In some embodiments, a measurement of C max > 175 ng/mL indicates that the subject is a responder.
  • a measurement of C max > 200 ng/mL indicates that the subject is a responder.
  • the clinical response is a laxation response within about four hours of administration of methylnaltrexone.
  • prediction of the clinical response indicates a response regardless of the route of administration of methylnaltrexone.
  • a clinical response based on measurement of C max after subcutaneous administration of methylnaltrexone is an indication that clinical response will occur in the subject after administration of methylnaltrexone by a non-subcutaneous route.
  • Embodiments are also directed to determining a suitable dosage amount for a given condition, wherein the methods include obtaining a group of subjects with the given condition, administering methylnaltrexone to the subjects, analyzing the group of subjects for plasma MNTX concentration, and comparing the median or mean plasma MNTX concentration for the group with the median or mean plasma MNTX concentration of a group of healthy subjects, wherein comparison of the Cmax values for each group is indicative of a suitable dosage amount for the group of subjects with the given condition.
  • determination of the suitable dosage amount is provided for oral administration of methylnaltrexone.
  • Methylnaltrexone does not have any known clinically significant drug interactions, therefore offering an important safety benefit, as illustrated by the studies described below.
  • the permeability of [15,16- H] MNTX across Caco-2 monolayers and status as a substrate for P-gp was evaluated in Study RPT-66293.
  • MNTX (1, 5, and 25 ⁇ ) had low permeability with transport rates of ⁇ 20 nm/sec.
  • the ratio of the transport rates (B ⁇ A:A ⁇ B) for MNTX were 0.922, 1.05 and 1.85 at 1, 5, and 25 ⁇ , respectively.
  • the ratios of B ⁇ A:A ⁇ B transport rates for MNTX were 1.04, 1.05, and 1.31 at 1, 5, and 25 ⁇ , respectively.
  • CYP isoform CYP2E1 was not part of the initial evaluation, a separate study was conducted to evaluate the potential of MNTX to induce the catalytic activity of CYP2E1 in freshly prepared human hepatocytes following in vitro exposure to 1, 5, or 25 ⁇ MNTX (RPT72520). None of the 5 human hepatocyte cultures exhibited induction of CYP2E1 activity at 1 ⁇ MNTX. Hepatocyte cultures from one donor showed limited CYP2E1 induction (119% of vehicle control) at 5 ⁇ MNTX and mild induction (133% of vehicle control) at 25 ⁇ MNTX. A second donor culture also exhibited CYP2E1 induction (139% of vehicle control) at the 25 ⁇ MNTX concentration.
  • CYP2E1 induction Variation in the occurrence of CYP2E1 induction was seen among hepatocyte cultures from different donors. CYP2E1 induction, when it did occur, was only observed with concentrations in excess of the anticipated clinical exposure levels. Therefore, clinically significant MNTX drug-drug interactions based on induction of CYP2E1 activity are unlikely.
  • the metabolites did not induce CYP1A2, CYP2B6, or CYP3A4 activity in vitro at concentrations up to 60 ⁇ (26.2 ⁇ g/mL, 21.5 ⁇ g/mL, and 21.5 ⁇ g/mL for MNTX sulfate, methyl-6a-naltrexol, and methyl-6P-naltrexol, respectively), with the exceptions of 4 points (XT23038). At none of the points was the induction greater than 2.8-fold the baseline activity and induction at all points was less than 12% the effect of the respective positive control inducer.
  • Methylnaltrexone and metabolites were investigated as substrates and inhibitors of the transporters P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, MATE1, and MATE2-K.
  • Methylnaltrexone was not a substrate for any of the transporters examined, with the exception of OCT2, MATE1, and MATE2-K.
  • Cimetidine is a known inhibitor of OCT1- and OCT2-mediated drug uptake. Concomitant administration of 400mg cimetidine daily and 24 mg MNTX SC resulted in a reduction in MNTX renal clearance but resulted in no clinical meaningful change in mean C max and AUCo- ⁇ relative to administration of MNTX alone. These results indicate that inhibition of OCTl and OCT2 had no clinically meaningful effects on systemic disposition of MNTX.
  • Methyl-6a-naltrexol and methyl-6P-naltrexol were not substrates for any of the transporters tested with the exception of OCTl, OCT2, MATE1, and MATE2-K.
  • Methylnaltrexone sulfate was a substrate for BCRP and MATE2-K only.
  • Methylnaltrexone did not inhibit any of the transporters at the concentrations tested (10 - 1800 ⁇ ). Inhibition of the transporters by the MNTX metabolites at concentrations of up to 10 ⁇ (3.59 ⁇ g/mL for methyl-6a-naltrexol and methyl-6P-naltrexol and 4.37 ⁇ g/mL for MNTX sulfate) also was investigated. No significant inhibition ( ⁇ 50%) was observed for any of the transporters by any of the metabolites. The MNTX C max :IC 5 o ratio was ⁇ 0.0114 for all transporters. The C max :IC 5 o ratios for the MNTX metabolites all were ⁇ 0.041. These results indicate that the risk of a clinically significant interaction due to induction or inhibition of drug metabolizing enzymes or drug transporters is minimal. Table 17 summarizes the results and interpretation of in vitro drug interaction studies for transporter- based interactions.
  • Methyl-6P-naltrexol P-gp >10 ⁇ 0.001 N
  • MNTX was a substrate of the human OCT1 transporter (RPT66294; RPT66295) and that MNTX urinary clearance exceeded the glomerular filtration rate by approximately 7-fold in a perfused rat kidney model (RPT 67270), consistent with pharmacokinetic findings in humans indicating that MNTX is actively secreted into urine following IV dosing (study MNTX 102 [RPT65255]).
  • Methylnaltrexone was found to be a substrate of the hOCTl transporter but not of the hOATl transporter in frog oocytes transfected with the corresponding human transporters (RPT66294; RPT66295). OCTl-mediated MNTX transport was only slightly inhibited by therapeutic concentrations of several common basic drugs.
  • MNTX1108 a subsequent clinical drug-drug interaction study (MNTX1108) with IV and SC MNTX was conducted to evaluate the potential for MNTX to inhibit CYP2D6 to a clinically significant extent; results showed no significant effect of MNTX on the metabolism of CYP2D6 substrate dextromethorphan. Because the expressions of CYP2D6 in the intestine and liver are minimal, 0.7% and 2% of all cytochromes P450, respectively (33), the potential for a drug-drug interaction effect following oral MNTX dosing is expected to be insignificant, consistent with what has been observed following parenteral MNTX administration. In addition, an MNTX-cimetidine drug-drug interaction study (described in the previous section) in human subjects indicated that there was no clinically relevant interaction.
  • RELISTOR® tablets and subcutaneous injection are indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.
  • RELISTOR® subcutaneous injection is indicated for the treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.
  • RELISTOR® has been shown to be efficacious in patients who have taken opioids for at least 4 weeks. Sustained exposure to opioids prior to starting RELISTOR® may increase the patient' s sensitivity to the effects of RELISTOR [see Clinical Studies (14.1)].
  • RELISTOR® Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR® after three days. Tablets
  • RELISTOR® is for subcutaneous use only.
  • RELISTOR® subcutaneously in the upper arm, abdomen or thigh. Do not inject at the same spot each time (rotate injection sites).
  • the recommended dosage of RELISTOR® tablets is 450 mg (three 150 mg tablets) taken orally once daily in the morning.
  • the recommended dosage of RELISTOR® subcutaneous injection is 12 mg once daily [see Clinical Studies (14.1 )].
  • the recommended dose of RELISTOR® administered subcutaneously is 8 mg for adult patients weighing 38 kg to less than 62 kg and 12 mg for patients weighing 62 kg to 114 kg.
  • Adult patients whose weight falls outside of these ranges should be dosed at 0.15 mg/kg.
  • the recommended dosage regimen is one dose every other day, as needed, but no more frequently than one dose in a 24-hour period, [see Clinical Studies (14.2)].
  • the pre-filled syringe is designed to deliver a fixed dose; therefore, adult patients requiring dosing calculated on a mg/kg basis should not be prescribed pre-filled syringes.
  • the injection volume for these patients should be calculated using the following method: Multiply the patient weight in kilograms by 0.0075 and round up the volume to the nearest
  • the pre-filled syringe is designed to deliver a fixed dose; therefore, adult patients with severe renal impairment should be prescribed single-use vials to ensure correct dosing.
  • RELISTOR® tablets should be taken orally with water on an empty stomach at least 30 minutes before the first meal of the day [see Clinical Pharmacology (12.3)].
  • RELISTOR® is a sterile, clear, and colorless to pale yellow aqueous solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the vial if any of these are present.
  • RELISTOR® is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation [see Warnings and Precautions (5.1)].
  • Symptoms consistent with opioid withdrawal including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR® [see Adverse Reactions (6.1)].
  • Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia. Take into account the overall risk-benefit profile when using RELISTOR® in such patients. Monitor for adequacy of analgesia and symptoms of opioid withdrawal in such patients.
  • RELISTOR® tablets The safety of RELISTOR® tablets was evaluated in a double-blind, placebo- controlled trial in adult patients with opioid-induced constipation and chronic non-cancer pain receiving opioid analgesia.
  • This study (Study 1) included a 12- week, double-blind, placebo-controlled period in which adult patients were randomized to receive RELISTOR® tablets 450 mg (200 patients) orally or placebo (201 patients) [see Clinical Studies (14.1)]. After 4 weeks of double-blind once daily treatment, patients continued double-blind treatment on an as needed basis (but no more than one dose per day) for an additional 8 weeks.
  • RELISTOR® subcutaneous injection was evaluated in a double-blind, placebo-controlled trial in adult patients with opioid-induced constipation and chronic non- cancer pain receiving opioid analgesia.
  • This study included a 4-week, double-blind, placebo-controlled period in which adult patients were randomized to receive RELISTOR® 12 mg once daily (150 patients) or placebo (162 patients) [see Clinical Studies (14.1)].
  • patients began an 8-week open-label treatment period during which RELISTOR® 12 mg was administered less frequently than the recommended dosage regimen of 12 mg once daily.
  • RELISTOR® subcutaneous injection was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with opioid-induced constipation and chronic non-cancer pain (Study 3). Patients were allowed to administer RELISTOR® 12 mg less frequently than the recommended dosage regimen of 12 mg once daily, and took a median of 6 doses per week. A total of 624 patients (60%) completed at least 24 weeks of treatment and 477 (46%) completed the 48-week study. The adverse reactions seen in this study were similar to those observed during the 4- week double-blind period of Study 2. Additionally, in Study 3, investigators reported 4 myocardial infarctions (1 fatal), 1 stroke (fatal), 1 fatal cardiac arrest and 1 sudden death. It is not possible to establish a relationship between these events and RELISTOR®. Opioid- Induced Constipation in Adult Patients with Advanced Illness
  • Study 4 included a single-dose, double-blind, placebo-controlled period
  • Study 5 included a 14-day multiple dose, double-blind, placebo-controlled period [see Clinical Studies (14.2)].
  • a subcutaneous dose of 0.30 mg/kg of methylnaltrexone did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate.
  • RELISTOR® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • methylnaltrexone administered during the period of organogenesis to rats at intravenous doses up to 25 mg/kg/day (about 20 times the MRHD of 0.2 mg/kg/day based on body surface area) and did not cause any adverse effects on embryofetal development.
  • intravenous doses of methylnaltrexone up to 16 mg/kg/day (about 26 times the MRHD of 0.2 mg/kg/day based on body surface area) did not show any embryofetal toxicity.
  • a pre- and postnatal development study in rats showed no evidence of any adverse effect on pre- and postnatal development at subcutaneous doses of methylnaltrexone up to 100 mg/kg/day (about 81 times the MRHD of 0.2 mg/kg/day based on body surface area).
  • Dose-reduction by one half is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault) [see Dosage and Administration (2.4)].
  • a dose of 1 tablet once daily (150 mg per day) is recommended in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Dosage and Administration (2.5)].
  • a patient on opioid therapy receives an overdose of RELISTOR®, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect.
  • opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect.
  • RELISTOR® methylnaltrexone bromide is a mu-opioid receptor antagonist.
  • the chemical name for methylnaltrexone bromide is (R)-N-(cyclopropylmethyl) noroxymorphone methobromide.
  • the molecular formula is C 2 iH 26 N0 4 Br, and the molecular weight is 436.36.
  • RELISTOR® tablets for oral administration are film-coated and contain 150 mg of methylnaltrexone bromide.
  • Inactive ingredients are silicified microcrystalline cellulose, microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, crospovidone, poloxamer 407, stearic acid (vegetable source), colloidal silicon dioxide, edetate calcium disodium, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.
  • RELISTOR® subcutaneous injection is a sterile, clear and colorless to pale yellow aqueous solution.
  • Each 3 mL vial contains 12 mg of methylnaltrexone bromide in 0.6 mL of water.
  • the excipients are 3.9 mg sodium chloride USP, 0.24 mg edetate calcium disodium USP, and 0.18 mg glycine hydrochloride.
  • the pH may have been adjusted with hydrochloric acid and/or sodium hydroxide.
  • Each 8 mg/0.4 mL pre-filled syringe (1 mL syringe) contains 8 mg of methylnaltrexone bromide in 0.4 mL of water.
  • the excipients are 2.6 mg sodium chloride USP, 0.16 mg edetate calcium disodium USP, and 0.12 mg glycine hydrochloride.
  • Each 12 mg/0.6 mL pre-filled syringe (1 mL syringe) contains 12 mg of methylnaltrexone bromide in 0.6 mL of water.
  • the excipients are 3.9 mg sodium chloride USP, 0.24 mg edetate calcium disodium USP, and 0.18 mg glycine hydrochloride.
  • Methylnaltrexone is a selective antagonist of opioid binding at the mu-opioid receptor. As a quaternary amine, the ability of methylnaltrexone to cross the blood-brain barrier is restricted. This allows methylnaltrexone to function as a peripherally- acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids without impacting opioid-mediated analgesic effects on the central nervous system.
  • methylnaltrexone achieved peak concentrations (C max ) at approximately 1.5 hours. Based on the half-life of methylnaltrexone in OIC patients (6.6 h), no accumulation is expected after once-daily administration. Table 22. Pharmacokinetic Parameters of Methylnaltrexone Following Oral Doses
  • methylnaltrexone achieved peak concentrations (C max ) at approximately 0.5 hours. Across the range of doses from 0.15 mg/kg to 0.50 mg/kg, mean C max and area under the plasma concentration-time curve (AUC) increased in a dose-proportional manner. There was no accumulation of methylnaltrexone following once-daily subcutaneous dosing of methylnaltrexone bromide 12 mg for seven consecutive days in healthy subjects.
  • Vss The steady-state volume of distribution (Vss) of methylnaltrexone is approximately 1.1 L/kg.
  • the fraction of methylnaltrexone bound to human plasma proteins is 11.0% to 15.3%, as determined by equilibrium dialysis.
  • the mean t 1/2 was approximately 6.6 hours.
  • the total clearance of methylnaltrexone is approximately 10.5 + 1.5 mL/min/kg, with renal clearance of 6.37 + 3.0 mL/min/kg.
  • the terminal half-life (t ⁇ ) is approximately 8 hours.
  • the mean AUCo-24 ratio of metabolites to methylnaltrexone at steady-state was 30%, 19%, and 9% for methylnaltrexone sulfate, methyl-6cc-naltrexol, and methyl-6 -naltrexol, respectively.
  • the mean AUCo-24 ratio of metabolites to methylnaltrexone at steady-state was 79%, 38%, and 21% for methylnaltrexone sulfate, methyl-6cc-naltrexol, and methyl-6 -naltrexol, respectively.
  • Methyl-6cc-naltrexol, and methyl-6 -naltrexol are active mu-opioid receptor antagonists and methylnaltrexone sulfate is a weak mu-opioid receptor antagonist; however, metabolites do not appear to contribute to clinical activity.
  • Methylnaltrexone is conjugated by sulfotransf erase SULT1E1 and SULT2A1 isoforms to methylnaltrexone sulfate. Conversion to methyl-6-naltrexol isomers is mediated by aldo-keto reductase 1C enzymes.
  • Methylnaltrexone is excreted primarily as the unchanged drug in the urine and feces. Active renal secretion of methylnaltrexone is suggested by renal clearance of methylnaltrexone that is approximately 4-5 fold higher than creatinine clearance.
  • mean clearance was about 20% lower (56 L/h versus 70 L/h) and AUC ⁇ was 26% higher than in subjects between 18 and 45 years of age (mean age 30 years old).
  • renal impairment had a marked effect on the renal excretion of methylnaltrexone. Severe renal impairment decreased the renal clearance of methylnaltrexone by 8- to 9-fold and resulted in a 2-fold increase in total methylnaltrexone exposure (AUC). Mean C max was not significantly changed. No studies were performed in patients with end- stage renal impairment requiring dialysis.
  • methylnaltrexone in subjects with hepatic impairment resultsed in higher systemic exposure when compared to healthy subjects.
  • the mean C max in subjects with Child-Pugh A hepatic impairment was approximately 1.8- fold higher than that of healthy subjects; in Child-Pugh B and C subjects, C max was approximately 4.8- and 3.7-fold higher, respectively.
  • Systemic exposure, as measured by AUCo-oo was comparable between healthy subjects and Child-Pugh A subjects (437 ng.h/mL versus 393 ng.h/mL, respectively), and was 2.5- and 2-fold higher, respectively, in Child- Pugh B and C subjects as compared to healthy subjects.
  • methylnaltrexone did not significantly inhibit or induce the activity of cytochrome P450 (CYP) isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A4.
  • CYP cytochrome P450
  • methylnaltrexone did not induce the enzymatic activity of CYP2E1.
  • methylnaltrexone was a substrate of Organic Cation Transporter 1 but not a substrate of Organic Anion Transporter 1 or P-glycoprotein, Breast Cancer Resistance Protein, Multidrug Resistance Protein 2, or Organic Anion-Transporting Polypeptide 1B1 or 1B3. Methylnaltrexone did not inhibit uptake of substrates by P- glycoprotein, BCRP, or Organic Cation Transporter 2 to an extent anticipated to be clinically relevant.
  • methylnaltrexone metabolites did not inhibit CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A4.
  • the metabolites of methylnaltrexone did not induce activity of CYP1A2, CYP2B6, or CYP3A4.
  • a clinical drug interaction study in healthy adult subjects evaluated the effects of cimetidine, a drug that inhibits the active renal secretion of organic cations, on the pharmacokinetics of methylnaltrexone (24 mg administered as an ⁇ infusion over 20 minutes).
  • a single dose of methylnaltrexone was administered before cimetidine dosing and with the last dose of cimetidine (400 mg every 8 hours for 6 days).
  • Mean C max and AUC of methylnaltrexone increased by 10% with concomitant cimetidine administration.
  • the renal clearance of methylnaltrexone decreased about 40%.
  • methylnaltrexone in CD-I mice at doses up to 200 mg/kg/day (about 81 times the maximum recommended human (MRHD) dose of 0.2 mg/kg/day based on body surface area) in males and 400 mg/kg/day (about 162 times the MRHD of 0.2 mg/kg/day based on body surface area) in females and in Sprague Dawley rats at oral doses up to 300 mg/kg/day (about 243 times the MRHD of 0.2 mg/kg/day based on body surface area).
  • Oral administration of methylnaltrexone for 104 weeks did not produce tumors in mice and rats.
  • Methylnaltrexone bromide was negative in the Ames test, chromosome aberration tests in Chinese hamster ovary cells and human lymphocytes, in the mouse lymphoma cell forward mutation tests and in the in vivo mouse micronucleus test.
  • methylnaltrexone bromide caused concentration-dependent inhibition of hERG current (1%, 12%, 13% and 40% inhibition at 30, 100, 300 and 1000 ⁇ concentrations, respectively). Methylnaltrexone bromide had a hERG IC 50 of > 1000 ⁇ .
  • methylnaltrexone bromide caused prolongations in action potential duration (APD). The highest tested concentration (10 ⁇ ) in the dog Purkinje fiber study was about 18 and 37 times the C max at human subcutaneous (SC) doses of 0.3 and 0.15 mg/kg, respectively.
  • methylnaltrexone bromide did not have an effect on APD, compared to vehicle control.
  • the highest methylnaltrexone bromide concentration (100 ⁇ ) tested was about 186 and 373 times the human C max at SC doses of 0.3 and 0.15 mg/kg, respectively.
  • methylnaltrexone bromide caused decreases in blood pressure, heart rate, cardiac output, left ventricular pressure, left ventricular end diastolic pressure, and +dP/dt at > 1 mg/kg.
  • methylnaltrexone bromide caused a dose-related increase in QTc interval.
  • Constipation due to opioid use had to be associated with 1 or more of the following: A Bristol Stool Form Scale score of 1 or 2 for at least 25% of the bowel movements (BM), straining during at least 25% of the BMs or a sensation of incomplete evacuation after at least 25% of the BMs.
  • Patients were required to be on a stable opioid regimen (daily dose > 50 mg of oral morphine equivalents per day) for at least 2 weeks before the screening visit and received their opioid medication during the study as clinically needed.
  • the mean patient age was 51 years, 62% were female, and 82% of patients were Caucasian.
  • the primary endpoint was the average percentage of dosing days that resulted in spontaneous bowel movements (SBMs) within 4 hours of dosing during Weeks 1 to 4.
  • SBM spontaneous bowel movements
  • a SBM was defined as a bowel movement that occurred without laxative use during the previous 24 hours.
  • Table 7 presents the average percentage of patients who responded during the double-blind once daily treatment period in the intent-to-treat (ITT) population, which included all randomized patients who received at least one dose of double-blind study medication.
  • CI confidence interval
  • ITT intent-to-treat
  • the responder endpoint was the proportion of patients who responded during Weeks 1 to 4, where a responder is defined as > 3 SBMs/week, with an increase of > 1 SBM/week over baseline, for > 3 out of the first 4 weeks of the treatment period.
  • Table 8 presents the proportion of patients who responded during the double-blind treatment period in the intent- to-treat (ITT) population, which included all randomized patients who received at least one dose of double-blind study medication.
  • Table 25 Responder Endpoint by Oral Treatment Group in the ITT Population
  • CI confidence interval
  • ITT intent-to-treat
  • Constipation due to opioid use had to be associated with 1 or more of the following: A Bristol Stool Form Scale score of 1 or 2 for at least 25% of the bowel movements (BM), straining during at least 25% of the BMs or a sensation of incomplete evacuation after at least 25% of the BMs.
  • the primary endpoint was the proportion of patients with > 3 spontaneous bowel movements (SBMs) per week during the 4-week double-blind period.
  • SBM spontaneous bowel movements
  • a SBM was defined as a bowel movement that occurred without laxative use during the previous 24 hours.
  • Table 26 presents the proportion of subjects with weekly SBM rate > 3 during the double-blind treatment period in the modified intent-to-treat (mITT) population, which included all randomized subjects who received at least one dose of double-blind study medication. As shown in Table 26, 59% of subjects in the RELISTOR® 12 mg once daily treatment group had > 3 SBMs/week compared to 38% in the placebo treatment group during the 4- week double-blind period.
  • Table 26 Primary Endpoint by Subcutaneous Injection Treatment Group in the mITT Population
  • CI confidence interval
  • mITT modified intent-to-treat
  • RELISTOR® in the treatment of opioid-induced constipation in advanced illness patients receiving palliative care was demonstrated in two randomized, double-blind, placebo-controlled studies. In these studies, the median age was 68 years (range 21-100); 51% were females. In both studies, patients had advanced illness and received care to control their symptoms. The majority of patients had a primary diagnosis of incurable cancer; other primary diagnoses included end-stage COPD/emphysema, cardiovascular disease/heart failure, Alzheimer's disease/dementia, HIV/AIDS, or other advanced illnesses.
  • Study 4 compared a single, double-blind, subcutaneous dose of RELISTOR® 0.15 mg/kg, or RELISTOR® 0.3 mg/kg versus placebo.
  • the double -blind dose was followed by an open-label 4-week dosing period, where RELISTOR® could be used as needed, no more frequently than 1 dose in a 24 hour period.
  • patients maintained their regular laxative regimen.
  • a total of 154 patients (47 RELISTOR® 0.15 mg/kg, 55 RELISTOR® 0.3 mg/kg, 52 placebo) were enrolled and treated in the double- blind period.
  • the primary endpoint was the proportion of patients with a rescue-free laxation within 4 hours of the double-blind dose of study medication.
  • RELISTOR®-treated patients had a significantly higher rate of laxation within 4 hours of the double-blind dose (62% for 0.15 mg/kg and 58% for 0.3 mg/kg) than did placebo-treated patients (14%); p ⁇ 0.0001 for each dose versus placebo.
  • Study 5 compared double-blind, subcutaneous doses of RELISTOR given every other day for 2 weeks versus placebo.
  • the patient's assigned dose could be increased to 0.30 mg/kg if the patient had 2 or fewer rescue-free laxations up to day 8.
  • the patient's assigned dose could be reduced based on tolerability.
  • RELISTOR® Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR® after three days.
  • Advise females of reproductive potential who become pregnant or are planning to become pregnant that the use of RELISTOR® during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood brain barrier.

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Abstract

L'invention concerne des procédés pour réduire le risque d'un événement cardiovasculaire chez un sujet souffrant de constipation induite par un opioïde, comprenant l'administration au sujet d'une composition pharmaceutique comprenant de la méthylnaltrexone. L'invention concerne également des procédés pour augmenter la compliance à un traitement par un opioïde chez un sujet soufrant d'une constipation induite par un opioïde, lesquels procédés comprennent l'administration d'une composition pharmaceutique comprenant de la méthylnaltrexone. Des modes de réalisation concernent également des procédés de traitement de la constipation induite par un opioïde chez des sujets présentant une insuffisance hépatique ou rénale, lesquels procédés comprennent l'administration d'une composition pharmaceutique comprenant de la méthylnaltrexone.
PCT/US2015/035063 2014-06-10 2015-06-10 Procédés d'administration de méthylnaltrexone WO2015191686A1 (fr)

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WO2021142288A1 (fr) * 2020-01-10 2021-07-15 Trevi Therapeutics, Inc. Méthodes d'administration de nalbuphine

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US20120070495A1 (en) * 2010-03-11 2012-03-22 Wyeth Llc Oral formulations and lipophilic salts of methylnaltrexone
US20130317050A1 (en) * 2011-12-19 2013-11-28 Enoch Bortey Methods for treatment and prevention of opioid induced constipation using oral compositions of methylnaltrexone

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Publication number Priority date Publication date Assignee Title
WO2021142288A1 (fr) * 2020-01-10 2021-07-15 Trevi Therapeutics, Inc. Méthodes d'administration de nalbuphine

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