Classifications

• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • 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
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/10—Laxatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2121/00—Preparations for use in therapy

Definitions

• Pain is the most common reason people seek medical care. Mild to moderate pain is usually treated with acetaminophen and non-steroidal anti-inflammatory drugs.
• Opioid analgesics agonists at endogenous ⁇ -( ⁇ ), ⁇ - (delta) and/or ⁇ - (kappa) opioid receptors primarily in the central nervous system (“CNS”), are prescribed for moderate to severe acute and chronic pain. Prolonged use of opioid analgesics can result in physical dependence and has side effects such as sedation, mental clouding, nausea, vomiting, constipation and itching.
• OIC Opioid-induced constipation
• OBD opioid induced bowel dysfunction
• OIC or OBD can be treated with laxative co-medication, but this approach often has limited efficacy and requires frequent dose adjustment and laxative switching.
• Other treatments include co-administration of selective opioid receptor antagonists such as naloxone, naltrexone, and N-methylnaltrexone.
• selective opioid receptor antagonists such as naloxone, naltrexone, and N-methylnaltrexone.
• Sub-pharmacological threshold concentrations of opioid antagonists in the CNS have thus far been achieved either by carefully titrating low doses of centrally active antagonists (e.g., naloxone), formulating an antagonist with low systemic bioavailability (e.g., controlled-release naloxone), or by using opioid antagonists that are restricted to the periphery, i.e., that have restricted access to the CNS (e.g., N-methylnaltrexone).
• centrally active antagonists e.g., naloxone
• formulating an antagonist with low systemic bioavailability e.g., controlled-release naloxone
• opioid antagonists that are restricted to the periphery, i.e., that have restricted access to the CNS (e.g., N-methylnaltrexone).
• a fixed-ratio combined formulation of controlled-release naloxone and controlled- release oxycodone has been approved in Europe as a way of reducing the severity of OIC.
• ENTEREG® (alvimopari) has been approved for sale in the United States, and is indicated to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis. This usage is restricted to the short-term treatment of postoperative ileus following bowel resection in hospitalized patients aged 18 years or older. Postoperative ileus is believed to be at least partially caused or exacerbated by exogenous opioid analgesics.
• RELISTOR® n-methylnaltrexone
• the present disclosure provides a method of treating or preventing OIC or OBD in a subject, which may be an animal or a human, by administering to the subject an amount of 5- (2-methoxy-4- ⁇ [2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl ⁇ -phenoxy)-pyrazine-2- carboxamide (Compound I) and/or a pharmaceutically acceptable salt thereof effective to alleviate the symptoms of OIC or OBD without reducing opioid analgesia or precipitating central opioid withdrawal.
• a subject may be an animal or a human
• the present disclosure further provides the use of 5-(2-methoxy- 4- ⁇ [2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl ⁇ -phenoxy)-pyrazine-2-carboxamide (Compound I) and/or a pharmaceutically acceptable salt thereof for the preparation of a medicament to alleviate the symptoms of OIC or OBD without reducing opioid analgesia or precipitating central opioid withdrawal.
• the invention described herein is based, in part, on the inventors' surprising discovery that Compound I, an opioid receptor antagonist with comparable potency to known opioid receptor antagonists naltrexone and alvimopan, is sufficiently peripheralized in humans that it will be able to effectively treat OIC or OBD without compromising analgesia or precipitating central opioid withdrawal.
• the inventor has studied the results of experiments in known animal models designed to determine the potency and pharmacokinetic properties of opioid receptor antagonists and determined that the data for Compound I were consistent with a potent opioid receptor antagonist that was significantly peripheralized at low doses.
• the inventor discerned from the data that Compound I is at least 100 times less potent as an antagonist of opioid receptors in the central nervous system than naltrexone (Example 1, Figure 1).
• the inventor also noted that Compound I was approximately 20 times more potent at reversing morphine-induced slowing of gut motility in mice when the morphine was administered systemically (i.e., was acting peripherally) than when the morphine was administered directly to the CNS. (Example 1, Figure 2)
• the inventor further examined data on the distribution of Compound I in the bodies of rats and mice and noted that there was a much higher concentration (17 times more) in the blood plasma than in the brain. Examination of the distribution in knock-out mice deficient in the P-glycoprotein ("P-gp") transporter revealed that blood-brain penetration increased about 7- to 19-fold. (Example 1) These data indicated to the inventors that Compound I was transported from the CNS by the P-gp transporter, and that the compound was significantly peripheralized in rodents.
• P-gp P-glycoprotein
• the inventor further determined an efficacious dose of Compound I for treating OIC or OBD in humans using multiple rationales, described below, based on pharmacokinetic and pharmacological data for Compound I and for the highly peripheralized opioid receptor antagonist alvimopan. In all cases, the calculated effective dose of
• Compound I for treating OIC or OBD was surprisingly much lower than the dose that affects the CNS, as determined by measured effects on human pharmacodynamic markers for antagonism of opioid receptors in the CNS.
• Compound I was a potent opioid antagonist that, at very low doses, is sufficiently peripheralized in humans to be useful for treating OIC or OBD and other conditions described herein where selective inhibition of opioid receptors in the periphery is highly desirable, as opposed to inhibition of both peripheral and CNS opioid receptors.
• Figure 1 Results of rat formalin test.
• the centrally-acting opioid receptor antagonist naltrexone (given subcutaneously) was found to be more than 100 times more potent than Compound I (2136231, given orally) in reversing opioid analgesia in rats.
• Figure 2 Results of oral administration of Compound I on the reversal of the inhibition of gastrointestinal (GI) transit in mice produced by intracerebroventricular (direct CNS) administration of morphine.
• the minimum effective dose of Compound I required to begin to reverse the inhibitory effect of centrally-administered morphine on GI transit was about 3.0 mg/kg.
• Figure 3 Modeled free plasma versus time profile of Compound I given as a 0.15 mg oral dose in humans. "MOR (solid horizontal line) is the measured K; of Compound I for the human ⁇ -opioid receptor.
• Figure 4 Measured (3 mg and 10 mg) and modeled (0.15 mg and 0.05 mg) free plasma versus time profiles of Compound I given to humans at indicated doses.
• MOR 3 ⁇ 4" solid horizontal line
• Figure 5 (expanding Y-axis of Figure 4): Measured (3 mg and 10 mg) and modeled (0.15 mg and 0.05 mg) free plasma versus time profile of Compound I given to humans at indicated doses.
• MOR solid horizontal line
• Figure 6 Alvimopan free plasma versus time profile (data-based modeling) in human OIC patients for a 0.5 mg oral dose, i.e., a dose associated with efficacy in clinical studies.
• Figures 7A-7C Profiles of plasma concentration of Compound I versus time measured in a Phase I clinical study of subjects with OIC over the dosing interval of 12 hours. Levels of Compound I in plasma were measured at 15 min, 30 min, 60 min, 90 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h and 12 h after the first dose. The measured MOR 3 ⁇ 4 of Compound I is indicated by a dashed line.
• Figure 7A shows levels of Compound I in the plasma of subjects for each of the five doses tested.
• Figure 7B shows levels of Compound I in the plasma of subjects dosed with 0.1 mg, 0.25 mg, 0.35 mg and 0.50 mg of Compound I.
• Figure 7C shows levels of Compound I in the plasma of subjects dosed with 0.1 mg and 0.25 mg of Compound I.
• the present disclosure relates to methods of selectively modulating the activity of a ⁇ - , ⁇ - and/or ⁇ -opioid receptor in the periphery, as compared to the CNS, comprising contacting the ⁇ -, ⁇ - and/or ⁇ -opioid receptor with an effective amount of 5-(2-methoxy-4- ⁇ [2-(tetrahydro-pyran-4-yl)-ethylamino]-methyl ⁇ -phenoxy)-pyrazine-2-carboxamide (Compound I).
• Compound I has previously been described as a potent centrally active opioid antagonist. See U.S. Patent No. 7,381,719, which is hereby incorporated by reference in its entirety.
• the present disclosure relates to methods of treating or preventing a condition associated with the activation of a ⁇ -, ⁇ - and/or ⁇ -opioid receptor in the periphery.
• the disclosure relates to methods of treating or preventing a condition associated with the activation of a ⁇ -opioid receptor in the periphery.
• the present disclosure relates to methods of treating or preventing a gastrointestinal disorder by administering to a subject a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof. More specifically, the present disclosure relates to methods of treating or preventing a gastrointestinal disorder in a subject resulting from the use of opioid analgesics without reducing analgesia or producing central opioid withdrawal, which comprises administering to the subject a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof.
• the present disclosure relates to methods of treating or preventing OIC in a subject without reducing analgesia provided by the opioid agonist or producing central opioid withdrawal, comprising administering to the subject a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof.
• the present disclosure relates to methods of treating or preventing OBD in a subject without reducing analgesia provided by the opioid agonist or producing central opioid withdrawal, comprising administering to the subject a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof.
• the present disclosure relates to the use of Compound I for the preparation of a medicament to selectively modulate the activity of a ⁇ -, ⁇ - and/or ⁇ - opioid receptor in the periphery, as compared to the CNS.
• the present disclosure relates to the use of Compound I for the preparation of a medicament for treating or preventing a condition associated with the activation of a ⁇ -, ⁇ - and/or ⁇ -opioid receptor in the periphery.
• the disclosure relates to the use of Compound I for the preparation of a medicament for treating or preventing a condition associated with the activation of a ⁇ -opioid receptor in the periphery.
• the present disclosure relates to the use of an effective amount of Compound I, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of a gastrointestinal disorder in a subject. More specifically, the present disclosure relates to the use of Compound I, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing a gastrointestinal disorder in a subject resulting from the use of opioid analgesics without reducing analgesia or producing central opioid withdrawal. In some specific embodiments, the present disclosure relates to the use of Compound I for the preparation of a medicament for treating or preventing OIC in a subject without reducing analgesia provided by the opioid agonist or producing central opioid withdrawal. In some specific embodiments, the present disclosure relates to the use of Compound I for the preparation of a medicament for treating or preventing OBD in a subject without reducing analgesia provided by the opioid agonist or producing central opioid withdrawal.
• treating includes the amelioration or cessation of a condition or a symptom thereof, as well as acceleration of recovery from a condition.
• treating includes inhibiting, for example, decreasing the overall frequency of episodes of a condition or a symptom thereof.
• prevention of include the avoidance of the onset of a condition or a symptom thereof.
• subject includes, but is not limited to, a human or a non-human animal, such as, e.g., a cow, monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig.
• a human or a non-human animal such as, e.g., a cow, monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig.
• opioid refers to a class of pain management substances that includes natural or synthetic compounds that bind to and agonize one or more of the ⁇ -, ⁇ - and K-opioid receptors.
• the present disclosure relates to a method of treating or preventing a condition in a subject associated with activation of peripheral opioid receptors, comprising administering to the subject an effective amount of 5-(2-methoxy-4- ⁇ [2- (tetrahydro-pyran-4-yl)-ethylamino]-methyl ⁇ -phenoxy)-pyrazine-2-carboxamide having the structure shown in formula (I):
• salts are any salt that can be prepared from Compound I including a salt formed from a basic functional group, such as a nitrogen group, of Compound I.
• Illustrative salts include, but are not limited, to sulfate, citrate, acetate, trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, malate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, /?-toluenes
• the disclosure relates to other forms of Compound I, such as prodrugs, radiolabeled forms, solvates (e. g., hydrates, or addition compounds that contain acid in excess of the number of their basic nitrogen atoms due to hydrogen bonding), amorphous solid forms and crystalline solid forms.
• Compound I can be obtained by any method known in the art. In certain aspects,
• Compound I can be synthesized using the starting materials 5-(4-formyl-2- methoxyphenoxy)pyrazine-2-carboxamide and 2-(tetrahydropyran-4-yl)ethylamine and the protocol and reagents set forth in Example 720 of U.S. Patent No. 7,381,719, which is hereby incorporated by reference in its entirety. 5.2. Therapeutic Uses
• Compound I Due to its activity as a peripherally-selective opioid receptor antagonist, Compound I is advantageously useful in human and veterinary medicine to treat or prevent a condition that can be alleviated by selective antagonism of an opioid receptor in the periphery.
• Compound I can be administered to any subject requiring inhibition of a peripheral opioid receptor.
• Compound I is advantageously useful to treat or prevent a condition that can be alleviated by selective antagonism of a peripheral ⁇ -opioid receptor.
• Compound I is useful for treating or preventing a condition selected from, but not limited to, postoperative ileus, postoperative nausea and vomiting, opioid- induced nausea and vomiting, opioid-induced respiratory depression, opioid-induced constipation, opioid-induced bowel dysfunction, chronic idiopathic constipation, constipation-predominant irritable bowel syndrome, intestinal pseudoobstruction, delayed gastric emptying, enteral feeding intolerance, narcotic ileus, obstipation, acceleration of gastrointestinal recovery following surgery and opioid-induced bloating.
• Compound I is useful for treating or preventing a gastrointestinal motility disorder in a subject.
• the subject is a human.
• Compound I is useful for treating or preventing a condition in a subject resulting from the use of opioids without reducing their analgesic effect or producing central opioid withdrawal.
• Compound I is useful for treating or preventing OIC without reducing the analgesic effect of the opioid or producing central opioid withdrawal.
• Compound I is useful for treating or preventing OBD without reducing the analgesic effect of the opioid or producing central opioid withdrawal.
• Compound I can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or excipient.
• the compositions comprising Compound I can be administered orally.
• the compositions can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, and intestinal mucosa, etc.) and can be administered together with a second therapeutically active agent (e.g., a laxative, a stool softener or an opioid analgesic).
• Administration can be systemic or local.
• Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, multiparticulates, capsules, etc., and can be used to administer Compound I.
• Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous, intranasal, oral, sublingual, transdermal, rectal, by inhalation, or topical. In most instances, administration will result in the release of Compound I into the bloodstream. In preferred embodiments, administration will not result in release in the CNS at pharmacologically relevant concentrations.
• Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
• Compound I can be formulated as a suppository, with traditional binders and excipients such as triglycerides.
• the formulation for parenteral administration can be in the form of a suspension, solution, emulsion in an oily or aqueous vehicle, and such formulations can further comprise pharmaceutically necessary additives such as one or more stabilizing agents, suspending agents, dispersing agents, and the like.
• Compound I can also be in the form of a powder for reconstitution as an injectable formulation.
• Compound I can be delivered in a vesicle, in particular a liposome (see Langer, Science 249: 1527-1533 (1990); and Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer 317-327 and 353-365 (1989)).
• Compound I can be delivered in a controlled-release system or sustained-release system (see, e.g., Goodson, "Dental Applications” (pp. 115-138) in Medical Applications of Controlled Release, Vol. 2, Applications and Evaluation, R.S. Langer and D.L. Wise eds., CRC Press (1984)).
• Other controlled or sustained-release systems discussed in the review by Langer, Science 249: 1527-1533 (1990) can be used.
• a pump can be used (Langer, Science 249: 1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng.
• polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974);
• compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the subject.
• a pharmaceutical excipient can be a diluent, suspending agent, solubilizer, binder, disintegrant, preservative, coloring agent, lubricant, and the like.
• the pharmaceutical excipient can be a liquid, such as water or an oil, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
• the pharmaceutical excipient can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
• the pharmaceutically acceptable excipient is sterile when administered to a subject.
• Water is a particularly useful excipient when the compound of formula (I) is administered intravenously.
• Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions.
• Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.
• the compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Specific examples of
• compositions comprising Compound I can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions, sublingual disintegrating dosage forms, or any other form suitable for use.
• the composition is in the form of a capsule (see, e.g., U.S. Patent No.
• Compound I is formulated in accordance with routine procedures as a composition adapted for oral administration to humans.
• Compound I to be orally delivered can be in the form of tablets, capsules, gelcaps, caplets, lozenges, sublingual disintegrating solid dosage forms, aqueous or oily solutions, suspensions, granules, powders, emulsions, syrups, or elixirs, for example.
• Such tablets can be compressed tablets, tablet triturates (e.g., powdered or crushed tablets), enteric-coated tablets, sugar-coated tablets, film-coated tablets, multiply compressed tablets or multiply layered tablets.
• Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, suspensions, and solutions and/or suspensions reconstituted from non-effervescent granules, optionally containing one or more suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, coloring agents, flavoring agents, and the like. Techniques and compositions for making liquid oral dosage forms are described in
• An orally administered composition can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
• sweetening agents such as fructose, aspartame or saccharin
• flavoring agents such as peppermint, oil of wintergreen, or cherry
• coloring agents such as peppermint, oil of wintergreen, or cherry
• preserving agents to provide a pharmaceutically palatable preparation.
• the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
• Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions.
• compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.
• compositions can be formulated to release the active ingredient in the lower gastrointestinal tract, and particularly, in the colon.
• dosage forms for release of the active ingredient in the colon can include polymers having pH-dependent solubility that dissolve at the pH of the colon but not at the pH of the small intestine;
• compositions include hydroxypropylmethyl cellulose capsules coated with materials that provide for release in the colon, such as those disclosed in U.S. Patent No. 7,094,425. Still other compositions for release in the colon are disclosed in U.S. Patent No. 6,368,629 and include dosage forms that are coated with an acid-labile coating that is dissolved by enterobacteria.
• Compound I When Compound I is to be injected parenterally, it can be, e.g., in the form of an isotonic sterile solution. Alternatively, when Compound I is to be inhaled, it can be formulated into a dry aerosol or can be formulated into an aqueous or partially aqueous solution.
• Compound I can be formulated for intravenous
• compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent.
• a composition for intravenous administration can optionally include a local anesthetic such as benzocaine or prilocaine to lessen pain at the site of the injection.
• the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent.
• Compound I is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
• an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
• Compound I is in a dosage form together with an opioid analgesic.
• Opioid analgesics that can be formulated with Compound I include, but are not limited to, alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil and tramadol.
• Other opioid analgesics for inclusion in a dosage form comprising Compound I will be readily ascertained by the skilled artisan.
• the amount of Compound I that is effective for treating OIC or OBD in humans was extrapolated from pharmacokinetic and pharmacological data using calculations based on multiple rationales - for example, (i) comparison of pharmacokinetic and pharmacological data for Compound I with pharmacokinetic and pharmacological data with the peripheralized opioid receptor antagonist alvimopan from human efficacy studies in OIC, or (ii) calculations based on the dose of Compound I that would produce maximum free plasma concentrations (Cmax) equal to or greater than the K; of Compound I for the ⁇ -opioid receptor, as set forth below in Example 2.
• the whole body dose of Compound I that is effective in treating OIC or OBD without antagonizing ⁇ -opioid receptors in the CNS, and thus reducing opioid analgesia or producing central opioid withdrawal was calculated to be approximately 0.1 mg/day, to be administered either QD or BID.
• the amount of Compound I effective for treating OIC or OBD that was extrapolated from pharmacokinetic and pharmacological data as described above was confirmed in Phase I clinical studies of subjects with OIC to be approximately 0.1 mg/day.
• the dose margin i.e., the fold difference between the calculated effective dose of Compound I for treating OIC or OBD and the mean effective dose determined by experimentation to be required to reverse the effects of morphine in the CNS, is from about 25 to about 83. See Example 2. Accordingly, at low doses required for treating OIC or OBD, Compound I was found to be highly peripheralized, and thus unlikely to compromise opioid analgesia or to precipitate central opioid withdrawal.
• Suitable effective dosage amounts for treating OIC or OBD or other conditions described herein in an average-size human male ⁇ e.g., weighing about 70 kg range from about 0.01 mg to about 1.5 mg whole body dose per day. In certain embodiments, suitable effective dosage amounts range from about 0.02 mg to about 1.25 mg whole body dose per day, such as from about 0.03 mg to about 1.0 mg whole body dose per day, such as from about 0.04 mg to about 0.75 mg whole body dose per day, such as from about 0.05 to about 0.5 mg whole body dose per day.
• suitable effective dosage amounts range from about 0.1 to about 1 mg whole body dose per day. In various embodiments, suitable effective dosage amounts range from about 0.1 to about 0.75 mg whole body dose per day, such as from about 0.1 to about 0.5 mg whole body dose per day, such as from about 0.1 to about 0.35 mg whole body dose per day, such as from about 0.1 to about 0.25 mg whole body dose per day.
• suitable effective dosage amounts range from about 0.01 mg to about 1.0 mg whole body dose per day, such as from about 0.02 mg to about 0.9 mg whole body dose per day, such as from about 0.03 mg to about 0.8 mg whole body dose per day, such as from about 0.04 mg to about 0.7 mg whole body dose per day, such as from about 0.05 mg to about 0.6 mg whole body dose per day, such as from about 0.06 mg to about 0.5 mg whole body dose per day, such as from about 0.07 mg to about 0.4 mg whole body dose per day, such as from about 0.08 mg to about 0.3 mg whole body dose per day.
• suitable effective dosage amounts for treating OIC or OBD or other conditions described herein in an average-size human male range from about 0.05 mg to about 0.5 mg whole body dose per day, such as from about 0.06 mg to about 0.25 mg whole body dose per day, such as from about 0.07 mg to about 0.2 mg whole body dose per day, such as from about 0.08 mg to about 0.15 mg whole body dose per day.
• suitable effective dosage amounts for treating OIC or OBD or other conditions described herein in an average-size human male range from about 0.01 mg to about 0.5 mg whole body dose BID, such as from about 0.02 mg to about 0.45 mg whole body dose BID, such as from about 0.03 mg to about 0.4 mg whole body dose BID, such as from about 0.04 mg to about 0.35 mg whole body dose BID, such as from about 0.05 mg to about 0.3 mg whole body dose BID, such as from about 0.06 mg to about 0.25 mg whole body dose BID, such as from about 0.07 mg to about 0.2 mg whole body dose BID, such as from about 0.08 mg to about 0.15 mg whole body dose BID.
• Suitable effective dosage amounts for treating OIC or OBD or other conditions described herein range from about 0.0001 mg/kg/day to about 0.02 mg/kg/day. In certain embodiments, suitable effective dosage amounts range from about 0.0003 mg/kg/day to about 0.017 mg/kg/day, such as from about 0.0004 mg/kg/day to about 0.014 mg/kg/day, such as from about 0.0005 mg/kg/day to about 0.01 mg/kg/day, such as from about 0.0007 mg/kg/day to about 0.007 mg/kg/day.
• suitable effective dosage amounts range from about 0.0001 mg/kg/day to about 0.014 mg/kg/day, such as from about 0.0003 mg/kg/day to about 0.013 mg/kg/day, such as from about 0.0004 mg/kg/day to about 0.01 1 mg/kg/day, such as from about 0.0006 mg/kg/day to about 0.01 mg/kg/day, such as from about 0.0007 mg/kg/day to about 0.009 mg/kg/day, such as from about 0.0009 mg/kg/day to about 0.007 mg/kg/day, such as from about 0.001 mg/kg/day to about 0.006 mg/kg/day, such as from about 0.001 mg/kg/day to about 0.004 mg/kg/day.
• suitable effective dosage amounts for treating OIC or OBD or other conditions described herein range from about 0.0007 mg/kg/day to about 0.007 mg/kg/day, such as from about 0.0009 mg/kg/day to about 0.004 mg/kg/day, such as from about 0.001 mg/kg/day to about 0.003 mg/kg/day, such as from about 0.001 mg/kg/day mg to about 0.002 mg/kg/day.
• suitable effective dosage amounts for treating OIC or OBD or other conditions described herein range from about 0.00015 mg/kg to about 0.007 mg/kg BID, such as from about 0.0003 mg/kg to about 0.006 mg/kg BID, such as from about 0.0004 mg/kg to about 0.004 mg/kg BID, such as from about 0.0006 mg/kg to about 0.005 mg/kg BID, such as from about 0.0007 mg/kg to about 0.004 mg/kg BID, such as from about 0.0009 mg/kg to about 0.004 mg/kg BID, such as from about 0.001 mg/kg to about 0.003 mg/kg BID, such as from about 0.001 mg/kg to about 0.002 mg/kg BID.
• Compound I is administered to a subject that is sensitized to its effects and that thereby requires a lower dose for efficacy in treating a condition as described herein.
• the lower effective dose produces a free plasma concentration of Compound I that is about 0.75IQ.
• the lower effective dose produces a free plasma concentration that is about 0.5K.
• the lower effective dose produces a free plasma concentration that is about 0.33K;.
• the lower effective dose produces a free plasma concentration of Compound I that is about 0.75K b .
• the lower effective dose produces a free plasma concentration that is about 0.5Kb.
• the lower effective dose produces a plasma concentration that is about 0.333 ⁇ 4.
• the amount of Compound I that is effective for the treatment or prevention of a condition described herein can be determined by standard clinical techniques.
• in vitro and/or in vivo assays can optionally be employed to help identify optimal dosage ranges.
• the precise dose to be employed will also depend on, e.g., the route of administration, formulation, the seriousness of the condition, and level of narcotic analgesia, and can be decided according to the judgment of a practitioner and/or each subject's circumstances.
• the dose per day can be any dose per day.
• the dose per day can be administered as a divided dose.
• the dose of Compound I can be administered as needed (PRN).
• Compound I is administered prior to or subsequent to administration of an opioid analgesic. In other embodiments, Compound I is administered at the same time as administration of an opioid analgesic. In some embodiments, Compound I and the opioid analgesic can be administered by the same route of administration (e.g., orally). In other embodiments, Compound I and the opioid analgesic are administered by different routes of administration. In certain embodiments where Compound I and the opioid analgesic are administered together, the opioid analgesic and Compound I are administered in a single dosage form (e.g., in a capsule, co-formulated tablet or disintegrating sublingual solid dosage form).
• Rats were injected with the irritant formalin and with 10 mg/kg of morphine subcutaneously.
• the amount of analgesia was determined by the reduction in the number of times the rat licked or paid attention to the site of formalin injection (events).
• Rats were dosed either with 0.02 mg/kg naltrexone (subcutaneous dose) or 1, 3 or 10 mg/kg Compound I (oral dose) to determine the ability of the compounds to reverse the analgesic effect of morphine. Naltrexone was found to be approximately 100 times more potent than
• mice were either dosed with 10 ⁇ g/kg morphine intracerebroventricularly or with 1 mg/kg morphine subcutaneously.
• the degree of gastrointestinal transit of charcoal meal in the mice was measured in the absence of Compound I and in the presence of varying oral doses of Compound I in order to determine the ability of the compound to reverse the inhibition of gastrointestinal (GI) transit induced by morphine.
• the minimum effective dose of Compound I required to reverse GI transit inhibition in mice dosed with morphine directly into the CNS was determined to be about 3.0 mg/kg oral dose.
• Figure 2 In contrast, the effective dose of Compound I required to reverse GI transit inhibition in mice dosed with morphine systemically was determined to be about 0.16 mg/kg oral dose.
• Compound I was about 20 times more potent in reversing the peripheral effects of morphine in slowing GI transit as compared to the central effects of morphine in slowing GI transit. This suggests that Compound I was about 20 times more effective in antagonizing opioid receptors in the periphery than in the CNS.
• Wild-type or P-glycoprotein (P-gp) knockout mice were dosed with 2.5 mg/kg of Compound I intravenously. The mice were sacrificed and the amounts of Compound I in the blood and in the brain were assayed using standard techniques. The results of these experiments showed that 17 times more Compound I was found in the blood plasma than in the brain of wild type mice. Moreover, blood-brain barrier penetration of Compound I increased 7- to 19-fold in knockout mice that were deficient in the P-gp transporter. The results of these experiments indicated that Compound I was actively transported out of the CNS by P-gp, resulting in a steady-state exclusion of Compound I from the CNS, and that Compound I was therefore signifcantly peripheralized in mice.
• Compound I that produces antagonism of opioid receptors in the CNS; and (ii) the doses of Compound I that would be expected to produce sufficient levels of antagonism of opioid receptors in peripheral tissues to be efficacious for treating OIC or OBD.
• pharmacologically relevant antagonism of opioid receptors in the CNS were conservatively estimated to be in the range of from about 3 mg to about 10 mg.
• the first approach was a calculation based on comparison of pharmacokinetic and pharmacological data for the highly peripheralized opioid receptor antagonist alvimopan. Specifically, pharmacokinetic and pharmacological data determined for Compound I were compared with the pharmacokinetic and pharmacological data for alvimopan measured in Phase 2 efficacy studies for treating patients with OIC or OBD. Webster et al. (2008) Pain 137:428-440. The question to be answered was what dose of Compound I would produce comparable systemic levels of ⁇ -opioid receptor antagonism in the periphery to alvimopan, which is a function of the two drugs' affinity (3 ⁇ 4) for the ⁇ -opioid receptor, drug
• the KiS of alvimopan and Compound I were determined by in vitro receptor binding in CHO cell membranes expressing cloned human ⁇ -opioid receptors. As shown in Table 1, the ⁇ - opioid receptor K; of alvimopan was 0.27 nM and the ⁇ -opioid receptor K; of Compound I was 0.36 nM.
• the mean free alvimopan C max plasma level following the efficacious dose of 0.5 mg BID alvimopan to patients suffering from OIC or OBD in Phase 2 clinical studies was measured as approximately 0.1 ng/ml.
• Compound I has an approximately linear relationship between dose and plasma C max and area under the curve (AUC) over the dose range from 1 to 100 mg.
• the dose of Compound I needed to achieve C max equal to 0.1 ng/ml i.e., the free plasma concentration of alvimopan effective for treating OIC or OBD
• the dose of Compound I needed to produce a free drug plasma C max of 0.1 ng/ml is 0.087 mg.
• a second approach was a calculation based on the potency ( ⁇ ;) of Compound I as an antagonist for the ⁇ -opioid receptor.
• pharmacokinetic and pharmacological data for Compound I were used to determine the dose of the compound that would produce a systemic plasma free drug concentration (C max ) in the periphery equal to the K; for the ⁇ - opioid receptor (i.e., 0.36 nM as determined by in vitro human ⁇ -opioid receptor binding in CHO cells - Table 1).
• the mean free C max plasma level following a 1 mg single oral dose of Compound I to healthy subjects was measured as 1.15 ng/ml, or 2.98 nM (molecular weight of Compound I: 386.4 g/mol).
• the dose of Compound I needed to achieve 0.36 nM of free drug was calculated to be the surprisingly low 0.12 mg whole body dose. Again, this dose is 25- to 83-fold lower than doses associated with antagonism of central opioid receptors, likewise indicating that, though centrally active at higher doses, Compound I is still sufficiently peripheralized to treat OIC or OBD at very low doses without compromising central opioid analgesia or precipitating central opioid withdrawal.
• a third approach was to generate a pharmacokinetic model for Compound I at low doses. This was accomplished by assuming a linear relationship between dose and all parameters of the plasma time course for the 1 mg dose of Compound I, and extrapolating these to lower doses. This model shows that, following a dose of 0.15 mg of Compound I to humans, free plasma concentrations of the compound were at or above the ⁇ -opioid receptor K; (0.36 nM) for about 6 hours ( Figure 3), i.e., sufficient time to produce an efficacy signal.
• a fourth approach was to evaluate a clinical pharmacokinetic model for alvimopan that suggests a period of exposure to free drug concentrations that are only approximately 0.33 of the 3 ⁇ 4 for the ⁇ -opioid receptor may be sufficient to produce efficacy in OIC patients.
• Figure 6 Using the pharmacokinetic model and assumptions described above, a dose of 0.5 mg Compound I would result in free plasma concentrations at or above 0.33 of the ⁇ -opioid receptor K; (0.36 nM) for greater than 4 hours, i.e., sufficient time to produce an efficacy signal.
• This dose is 60- to 200-fold lower than doses associated with antagonism of central opioid receptors, again indicating that, though centrally active at higher doses, Compound I is still sufficiently peripheralized to treat OIC or OBD without compromising central opioid analgesia or precipitating central opioid withdrawal.
• Compound I has a measured plasma half-life in humans of approximately 12 hours. If there is a potential for a degree of drug accumulation upon repeated dosing regimens, the doses associated with efficacy for treating OIC or OBD may be appreciably lower than the doses calculated above, i.e., as low as 0.01 to 0.02 mg whole body dose QD or BID (for a human male weighing approximately 70 kg).
• OIC constipation
• the first part of the study was a randomized, double blind, placebo controlled, multiple ascending dose study during which subjects took 4 oral doses of study medication over 2 days while confined to the study unit.
• the 0.75 mg BID cohort included only 2 subjects.
• Assessments of clinical effect included the following measures, which were assessed starting immediately after the first dose of study medication through discharge on day 3: (i) time to first bowel movement after the first dose of study medication; (ii) number of bowel movements; and (iii) bowel movement Comfort Scores, stool weight, and stool consistency as measured by the Bristol Stool Scale for each bowel movement that occurs while the subject was confined to the study unit.
• FIG. 7 A, 7B and 7C indicate the plasma levels of Compound I obtained after the first dose over the dosing interval of 12 h and for each of the 5 doses tested (0.10 mg, 0.25 mg, 0.35 mg, 0.50 mg and 0.75 mg BID).

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