WO2008072061A1 - Méthode de traitement de l'obésité à l'aide d'un inhibiteur de la mtp conjointement à une diète riche en graisse - Google Patents
Méthode de traitement de l'obésité à l'aide d'un inhibiteur de la mtp conjointement à une diète riche en graisse Download PDFInfo
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- WO2008072061A1 WO2008072061A1 PCT/IB2007/003855 IB2007003855W WO2008072061A1 WO 2008072061 A1 WO2008072061 A1 WO 2008072061A1 IB 2007003855 W IB2007003855 W IB 2007003855W WO 2008072061 A1 WO2008072061 A1 WO 2008072061A1
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- fat
- mtp inhibitor
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Classifications
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Definitions
- the present invention generally relates to therapy for obesity or related eating disorders and/or reducing food consumption using MTP inhibitors in conjunction with an 5 increased-fat diet.
- Obesity is a major public health concern because of its increasing prevalence and associated health risks. Moreover, obesity may affect a person's or animal's quality 10 of life through limited mobility and decreased physical endurance as well as through social, academic and job discrimination.
- Inhibitors of microsomal triglyceride transfer protein (MTP) and/or Apo B secretion are useful in reducing food intake in mammals (European patent application publication No. 1 099 438 A2), reducing intestinal fat absorption (European patent 15 application publication No. 1 099 439 A2) and for treating obesity and associated diseases. See, for example, PCT patent application publication Nos. WO 03/002533, WO 2005/046644 and WO 2005/080373, and US 6,066, 653.
- WO 03/002533 may cause emesis when admininstered according to conventional treatment regimens.
- the invention provides a method of treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, the method comprising 30 administering to the subject a therapeutically effective amount of an MTP inhibitor in conjunction with an increased-fat diet.
- the invention also provides the use of an MTP inhibitor in the manufacture of a medicament for treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, wherein a therapeutically effective amount of an MTP inhibitor is administered in conjunction with an increased-fat diet.
- the invention also provides a method of treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, the method comprising administering to the subject a therapeutically effective amount of an MTP inhibitor in conjunction with an increased-fat diet optionally followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.
- the invention also provides the use of an MTP inhibitor in the manufacture of a medicament for treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, wherein a therapeutically effective amount of an MTP inhibitor is administered in conjunction with an increased-fat diet optionally followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.
- the invention also provides a method of treating 1 a subject suffering from obesity or related eating disorders and/or reducing food consumption, the method comprising administering to the subject an MTP inhibitor in conjunction with an increased-fat diet such that the amount of said MTP inhibitor required to be therapeutically effective is reduced compared with conventional treatment regimens.
- the invention also provides a method of increasing the rate of weight loss in a subject suffering from obesity or related eating disorders, the method comprising administering to the subject a therapeutically effective amount of an MTP inhibitor in conjunction with an increased-fat diet.
- the invention also provides a method of treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, the method comprising administering to the subject an initial amount of an MTP inhibitor effective to ameliorate the obesity or disorder yet low enough to reduce the side effects associated with administration of the MTP inhibitor in conjunction with an increased-fat diet, optionally followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.
- the invention also provides a method of treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, the method comprising administering to the subject an initial amount of an MTP inhibitor in the range of 0.025 to 0.30 mg/kg/day in conjunction with an increased-fat diet, optionally followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.
- the invention further provides a method for inhibiting MTP in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an MTP inhibitor in conjunction with an increased-fat diet.
- the invention further provides a method of treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, or a method for inhibiting MTP in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an MTP inhibitor in conjunction with an increased-fat diet, and wherein said administration is in combination with at least one additional pharmaceutical agent, such as another anti-obesity agent.
- a method of weight control in a subject the method comprising administering to the subject an effective weight-controlling amount of an MTP inhibitor in conjunction with an increased-fat diet.
- the MTP inhibitor may be used alone or in combination with at least one additional pharmaceutical agent, preferably an anti-obesity agent.
- the MTP inhibitor is dirlotapide ((S)-N- ⁇ 2-
- BMI body mass index
- Overweight is typically defined as a BMI of 25-29.9 kg/m 2
- obesity is typically defined as a BMI of 30 kg/m 2 or higher.
- BCS Body Condition Score
- phrases "pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologicallyi with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
- therapeutically effective amount means an amount of a compound that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein (e.g., reduces food intake or the desire to consume food).
- the term "subject” or "animal” means humans as well as all other warm-blooded members of the animal kingdom possessed of a homeostatic mechanism, including mammals (e.g., companion animals, zoo animals and food-source animals) and birds.
- mammals e.g., companion animals, zoo animals and food-source animals
- companion animals are canines (e.g., dogs), felines (e.g., cats) and horses; some examples of food-source animals are pigs, cows, sheep, poultry and the like.
- the animal is a mammal.
- the mammal is a human, a companion animal or a food-source animal.
- the animal is a human or is a canine (e.g., a cat or a dog).
- the animal is a canine (e.g. a cat or, preferably, a dog).
- the terms “treating”, “treat”, or “treatment” embrace both preventative, i.e. prophylactic, and palliative treatment.
- the MTP inhibitors are preferably intestinal-acting MTP inhibitors and these are preferably intestinal selective.
- the term “selectivity” refers to a greater effect of a compound in a first assay, compared to the effect of the same compound in a second assay.
- the first assay is for the ability of the compound to inhibit intestinal fat absorption and the second assay is for the ability of the compound to lower serum triglycerides.
- the ability of the compound to inhibit intestinal fat absorption is measured by the dose that produces 25% fat absorption inhibition (ED 25 ) of the compound in an intestinal fat absorption assay, such that a greater effect of the compound results in the observation of a lower absolute (numerical) value for the ED 25 .
- the ability of the compound to lower serum triglycerides is measured by the ED 2 s of the compound in a serum triglyceride assay. Again, a greater effect of a compound in the serum triglyceride lowering assay results in the observation of a lower absolute (numerical) value for the ED 25 .
- any assay capable of measuring the effectiveness of a compound in inhibiting intestinal fat absorption, or capable of measuring the effectiveness of a compound in lowering serum triglycerides is encompassed by the present invention.
- suitable assays are given in PCT Publication No. WO 03/002533.
- Intestinal selectivity may be achieved by controlling the solubility of the inhibitor in the. intestinal tract and/or release of the inhibitor from the dosage form or by increasing lipid (fat) in the gut, i.e. administer with food and increase the dietary fat in the food.
- Figure 1 and Figure 2 relate to a study to show efficacy and safety of dirlotapide at a starting dose of 0.1 mg/kg in the treatment of excessive body weight in overweight
- Figure 1 provides a summary of the dose volumes administered throughout the study period
- Figure 2 provides a summary of the mean cumulative body weight change (%) during the weight loss phase
- Figure 3 provides a summary of the mean daily food intake in rats treated with (4'-trifluoromethyl-biphenyl-2-'carboxylic acid [2-(2H-[1 ,2,4]triazol-3-ylmethyl)-1 ,2,3,4- tetrahydro-isoquinolin-6-yl] amide) at 10, 30 or 100mg/kg or vehicle with diets of 45% (A) or 10% (B) of total calories from fat;
- Figure 4 provides a summary of the mean daily food intake in rats treated with dirlotapide at 10mg/kg or vehicle with "high” or “low” fat diets.
- MTP inhibitors are effective anti-obesity agents when used with any diet
- the efficacy of MTP inhibitors as anti- obesity agents is significantly enhanced when the MTP inhibitor is administered in conjunction with an increased-fat diet.
- weight loss can be achieved with lower doses of MTP inhibitor when the subject is fed with a higher-fat diet as opposed a lower-fat diet.
- Subjects also lost weight at a higher rate when the MTP inhibitor was administered in conjunction with an increased-fat diet.
- significant reductions in food intake can be achieved when the MTP inhibitor is administered in conjunction with an increased-fat diet.
- the term "increased-fat diet” or “high-fat diet” or similar when used in connection with the present invention means a diet having a fat content of approximately 10% or greater than 10%, i.e. at least approximately 10% (based on air dry matter as fed).
- "Air dry matter as fed” relates to the air dry form of the feed as fed which typically includes around 1.0% moisture in dry dog food. Therefore, for example, 10% fat based on air dry matter as fed would be equivalent to approximately 11% fat on a dry matter basis and 15% fat based on air dry matter as fed would be equivalent to approximately 16.7% fat on a dry matter basis.
- the term "increased-fat diet” includes those conventional pet (e.g. dog) foods marketed as typical fat or maintenance diets (having fat contents, for example, in the range of 10 to 17%) and those conventional pet (e.g. dog) foods marketed as high fat or active or performance diets (having fat contents, for example, greater than 18%) both based on air dry matter as fed.
- diets can be defined by the percentage of metabolizable energy (Kcal) they provide from fat (Kcal).
- the term "increased-fat diet” or similar when used in connection with the present invention means a diet providing approximately 24% or greater than 24% of total calories from fat, such as approximately 34% or greater than 34% of total calories from fat, such as approximately 45% or greater than 45% of total calories from fat.
- the term "increased-fat diet” includes those conventional pet (e.g. dog) foods marketed as typical fat or maintenance diets (providing approximately, for example, 24 to 33% total calories from fat) and those ⁇ conventional pet (e.g. dog) foods marketed as high fat or active or performance diets (providing approximately, for example, 34 to 50% total calories from fat).
- the term "increased-fat diet” or similar when used in connection with the present invention means a diet having a fat content of approximately 15% or greater than 15%, i.e. at least approximately 15% (based on air dry matter as fed).
- the term “increased-fat diet” or similar when used in connection with the present invention means a diet providing approximately 45% or greater than 45%, i.e. at least approximately 45% of total calories from fat.
- MTP inhibitors for use in the present invention are known in the art.
- Suitable MTP inhibitors include compounds disclosed in U.S. Patent Nos. 4,453,913; 4,473,425; , 4,491,589; 4,540,458; 4,962,115; 5,057,525; 5,137,896; 5,286,647; 5,521 ,186; 5,595,872; 5,646,162; 5,684,014; 5,693,650; 5,712,279; 5,714,494; 5,721 ,279; 5,739,135; 5,747,505; 5,750,783; 5,760,246; 5,789,197; 5,811 ,429; 5,827,875; 5,837,733; 5,849,751 ; 5,883,099; 5,883,109; 5,885,983; 5,892,114; 5,919,795;
- MTP inhibitors Discovery of clinically active inhibitors using high-throughput screening and parallel synthesis paradigms," Current Opinion in Drug Discovery & Development,
- Preferred intestinal-acting MTP inhibitors for use in the instant invention include dirlotapide ((S)-N- ⁇ 2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl ⁇ -1-methyl-5-[4'- trifluoromethyl)[1 ,1'-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide) and 1 ⁇ nethyl-5-[(4Mrifluoromethyl-biphenyl-2-carbonyl)-arnino]-1 H-indole-2-carboxylic acid (carbamoyl-phenyl-methyl)-amide which can both be prepared using methods described in U.S. Patent No.
- the MTP inhibitor for use in the methods of the present invention is (4'-trifluorornethyl-biphenyl-2-carboxylicacid [2-(2H-[1 ,2,4]triazol-3- ylmethyl)-1 ,2,3,4-tetrahydro-isoquinolin-6-yl] amide, or more preferably, the compound dirlotapide.
- the conventional daily dose of the intestinal-acting MTPi is generally between about 0.05 mg to about 50 mg, preferably between about 0.5 mg to about 30 mg, more preferably between about 0.5 mg to about 20 mg, most preferably between about 1.0 mg to about 15 mg.
- the MTPi may be administered in combination with an agent to reduce fatty liver (e.g., fibrate or PPAR-alpha agonist). See, e.g., JP Publication No. 2002- 220345 (Application No. 2001-015602) entitled “Remedial Agent for Fatty Liver”; and Kersten, S., "Peroxisome Proliferator Activated Receptors and Obesity,” Eur J Pharm, 440, 223-234 (2002).
- the MTP inhibitor is administered at escalating dosages.
- the escalating dosages comprise at least an initial first dose level and a second dose level. In some embodiments, the escalating dosages comprise at least a first dose level, a second dose level and a third dose level. In some embodiments, the escalating dosages further comprise a fourth dose level. In some embodiments, the escalating dosages comprise at least a first dose level, a second dose level, a third dose level, a fourth dose level and a fifth dose level. In some embodiments, six and further dose levels are contemplated.
- the original dose level may be increased by 10 %, 20%, 25%, 50%, 100% or 300% to produce the next dose level.
- the next dose level is double the original dose level.
- the next dose level is four times the original dose level.
- the original dose level is increased by 25%, 50% or 100%.
- the original dose level is increased by 50% or 100%, for example 100%.
- the first dose level is in the range of 0.025 to 0.30 mg/kg/day, for example in the range of 0.025 to 0.10 mg/kg/day, such as about 0.05 or 0.10 mg/kg/day, preferably about 0.05 mg/kg/day.
- the second dose level is 100% greater than the first, for example is in the range of 0.05 to 0.6 mg/kg/day, or for example is in the range of 0.05 to 0.2 mg/kg/day, such as about 0.10 or 0.2 mg/kg/day, preferably about 0.10 mg/kg/day.
- the third dose level is 100% greater than the second dose level, for example is in the range of 0.10 to 1.2 mg/kg/day, or for example is in the range of 0.10 to 0.4 mg/kg/day, for example about 0.2 or 0.4 mg/kg/day, preferably about 0.2 mg/kg/day.
- the fourth dose level is 50% greater than the third dose level, for example is in the range of 0.15 to 0.9 mg/kg/day, or for example is in the range of 0.15 to 0.6 mg/kg/day, for example about 0.3 or 0.6 mg/kg/day, preferably about 0.3 mg/kg/day.
- the fourth dose level is increased by 50% thereafter to produce fifth, six and subsequent dose levels.
- the first dose level is in the range of 0.025 to 0.10 mg/kg/day, for example about 0.05 or 0.10 mg/kg/day, preferably about 0.05 mg/kg/day.
- the second dose level is 100% greater than the first, for example is in the range of 0.05 to 0.2 mg/kg/day, for example about 0.10 or 0.2 mg/kg/day, preferably about 0.10 mg/kg/day.
- the third dose level is 100% greater than the second dose level, for example is in the range of 0.10 to 0.4 mg/kg/day, for example about 0.2 or 0.4 mg/kg/day, preferably about 0.2 mg/kg/day.
- the fourth dose level is 50% greater than the third dose level, for example is in the range of 0.15 to 0.6 mg/kg/day, for example about 0.3 or 0.6 mg/kg/day, preferably about 0.3 mg/kg/day.
- the fourth dose level is increased by 50% thereafter to produce fifth, six and subsequent dose levels.
- each dose level is administered to the subject for from about 1 to 4 weeks, for example, the dose levels may be increased after 1 week, 2 weeks, or monthly.
- the first dose level e.g. 0.05 mg/kg/day
- the second dose level e.g. 0.01 mg/kg/day
- the third dose level e.g.
- 0.2 mg/kg/day may be administered for about a month, with subsequent dose increases being made at, for example, monthly intervals.
- the initial dose may be 0.05 mg/kg/day.
- the initial dose may be doubled to 0.10 mg/kg/day for two weeks.
- dogs may be weighed monthly and dose adjustments may be made monthly according to the following guidelines.
- the percentage of body weight loss is determined. If the body weight loss since previous monthly weighing has been greater than or equal to 3% body weight per month (equivalent to 0.1% body weight per day); the dose may be kept the same.
- the dose may be increased without adjusting for the dog's current body weight.
- the first time a conditional increase is required the dose may be increased by 100% (doubled).
- the dose may be increased by 50% up to a maximum dose of the product of 1 mg/kg current body weight. These adjustments may be continued until the weight targeted at the start of therapy is achieved.
- the dose may be reduced by 25%.
- a mean weight loss of about 18 to 20% after six months of weight loss therapy can be anticipated.
- the initial "weight loss" phase may last a number of months, for example about 4 months (i.e. about 16 weeks) to 6 months, or for example, about 112 to 196 days, or may last until the target weight loss is achieved, or may last until a particular Body Condition Score (BCS) is reached, for example a BCS of five.
- BCS Body Condition Score
- the weight maintenance/management or retraining phase may last for a period of months, for example about 3 months (i.e. about 12 weeks) or, for example, 84 days.
- the dose may be decreased, for example by 50%, or increased, for example by 100%, if the patient was losing or gaining too much weight (for example, more than 5%) from the start of the weight maintenance/management retraining phase, respectively.
- the weight maintenance/management or retraining phase can be commenced.
- the optimal level of food intake and physical activity needed should be established.
- Administration of the MTP inhibitor should be continued during the weight maintenance/management or retraining phase until the food intake and physical activity needed to stabilize body weight at the desired weight is established.
- the dose adjustment during the weight maintenance/management or retraining phase may be as follows: First dose adjustment
- the dose should be decreased by 50%.
- the dose should be increased or decreased by 25% to maintain a constant weight.
- the dose should remain unchanged.
- the dose should be decreased by 25%. If the dog gained greater than 5% body weight, then the dose should be increased by 25%. Based on the dog's current body weight a daily dose of 1 mg/kg should not be exceeded.
- the daily amount of food offered and physical activity should be continued as established during the weight maintenance/management or retraining phase.
- reduce the side effects associated with administration of the MTP inhibitor refers to an amelioration or elimination of one or more undesired side effects occurring as a result of administering MTP inhibitors according to traditional treatment regimens, for example at higher initial doses without dose escalation and without being administered in conjunction with an increased-fat diet.
- Such side effects include emesis (vomiting), diarrhoea, lethargy, inappetence and anorexia, for example emesis (vomiting), diarrhea and lethargy and particularly include emesis.
- the methods further comprise the administration of at least one additional pharmaceutical agent.
- additional pharmaceutical agents include other anti-obesity agents such as cannabinoid-1 (CB-1) antagonists (such as rimonabant), 11 ⁇ -hydroxy steroid dehydrogenase-1 (11 ⁇ -HSD type 1) inhibitors, peptide YY (PYY) and PYY agonists (such as PYY 3 .
- MCR-4 agonists such as cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c receptor agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e.
- anorectic agents such as a bombesin agonist
- neuropeptide-Y receptor antagonists e.g., NPY Y5 receptor antagonists
- thyromimetic agents dehydroepiandrosterone or an analog thereof
- glucocorticoid receptor agonists or antagonists orexin receptor antagonists
- glucagon-like peptide-1 receptor agonists ciliary neurotrophic factors (such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH)
- human agouti-related protein (AGRP) inhibitors such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH
- human agouti-related protein (AGRP) inhibitors ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists and the like.
- lipid modifying compounds which include HMG CoA reductase inhibitors, cholesterol absorption inhibitors, ezetimide, squalene synthetase inhibitors, fibrates, bile acid sequestrants, statins, probucol and derivatives, niacin, niacin derivatives, PPAR alpha agonists, PPAR gamma agonists, thiazolidinediones, and cholesterol ester transfer protein (CETP) inhibitors.
- HMG CoA reductase inhibitors HMG CoA reductase inhibitors
- cholesterol absorption inhibitors ezetimide
- squalene synthetase inhibitors fibrates
- bile acid sequestrants statins
- statins probucol and derivatives
- niacin niacin derivatives
- PPAR alpha agonists PPAR alpha agonists
- PPAR gamma agonists thiazolidinediones
- LDL-cholesterol lowering agents include LDL-cholesterol lowering agents, triglyceride lowering agents, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an inhibitor of HMG-CoA reductase gene expression, a squalene synthetase inhibitor, a squaline epoxidase inhibitor, a squaline cyclase inhibitor, a combined squaline epoxidase/cyclase inhibitor, a cholesterol synthesis inhibitor, a cholesterol absorption inhibitor such as ZetiaTM (ezetimibe), a CETP inhibitor, a PPAR modulator or other cholesterol lowering agent such as a fibrate, an ion- exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant.
- LDL-cholesterol lowering agents include LDL-cholesterol lowering agents, triglyceride lowering agents, an HMG-CoA reducta
- bile acid reuptake inhibitors include bile acid reuptake inhibitors, ileal bile acid transporter inhibitors, ACC inhibitors, antihypertensive agents (such as Norvasc®), diuretics, garlic extract preparations, bile acid sequestrants, antibiotics, antidiabetics, and anti-inflammatory agents such as aspirin or, preferably, an anti-inflammatory agent that inhibits cyclooxygenase-2 (Cox-2) to a greater extent than it inhibits cyclooxygenase-1 (Cox-1) such as celecoxib (U.S. patent No. 5,466,823), valdecoxib (U.S. patent No.
- additional pharmaceutical agents include naturally occurring substances that act to lower plasma cholesterol levels. These naturally occurring materials are commonly called nutraceuticals and include, for example, garlic extract, Hoodia plant extracts and niacin.
- the dosage of the additional pharmaceutical agent is generally dependent upon a number of factors including the health of the subject being treated, the extent of treatment desired, the nature and kind of concurrent therapy, if any, and the frequency of treatment and the nature of the effect desired. In general, the dosage range of the additional pharmaceutical agent is in the range of from about 0.001 mg to about 100 mg per kilogram body weight of the individual per day, preferably from about 0.1 mg to about 10 mg per kilogram body weight of the individual per day.
- the additional pharmaceutically active agents are administered according to traditional treatment regimens. In some embodiments, the additional pharmaceutically active agents are administered at escalating dosages.
- the MTP inhibitor and any additional pharmaceutical agent (referred to herein as a "combination") is administered to a subject in need of such treatment, preferably in the form of a pharmaceutical composition.
- the MTP inhibitor and the other pharmaceutical agent e.g., another anti-obesity agent, may be administered either separately or in a pharmaceutical composition comprising both. It is generally preferred that such administration be oral. When a combination of MTP inhibitor and any other pharmaceutical agent are administered together, such administration may be sequential in time or simultaneous.
- the agents may be administered in any order. It is generally preferred that such administration be oral. It is especially preferred that such administration be oral and simultaneous.
- the administration of each may be by the same or by different methods.
- the MTP inhibitor or a combination is preferably administered in the form of a pharmaceutical composition.
- Administration of the agents can be separately or together in any conventional oral, rectal, transdermal, parenteral (e.g., intravenous, intramuscular or subcutaneous), intracisternal, intravaginal, intraperitoneal, topical (e.g., powder, ointment, cream, spray or lotion), buccal or nasal dosage form (e.g., spray, drops or inhalant).
- the MTP inhibitors or combinations can be administered alone but will generally be administered in an admixture with one or more suitable pharmaceutical excipients, adjuvants, diluents or carriers known in the art and selected with regard to the intended route of administration and standard pharmaceutical practice.
- the MTP inhibitors or combination may be formulated to provide immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release dosage forms depending on the desired route of administration and the specificity of release profile, commensurate with therapeutic needs.
- the pharmaceutical composition comprises an MTP inhibitor or a combination in an amount generally in the range of from about 1% to about 75%, 80%, 85%, 90% or even 95% (by weight) of the composition, usually in the range of about 1 %, 2% or 3% to about 50%, 60% or 70%, more frequently in the range of about 1 %, 2% or 3% to less than 50% such as about 25%, 30% or 35%.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
- the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame seed oil and the like), Miglyol ® (available from CONDEA Vista Co., Cranford, NJ.) , glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixture
- composition may also include excipients, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- excipients such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- Oral liquid forms of the MTP inhibitors or combinations include solutions, wherein the active compound is fully dissolved.
- solvents include all pharmaceutically precedented solvents suitable for oral administration, particularly those in which the compounds of the invention show good solubility, e.g., polyethylene glycol, polypropylene glycol, edible oils and glyceryl and glyceride- based systems.
- Glyceryl- and glyceride- based systems may include, for example, the following branded products (and corresponding generic products): CaptexTM 355 EP (glyceryl tricaprylate/caprate, from Abitec, Columbus OH), CrodamolTM GTC/C (medium chain triglyceride, from Croda, Cowick Hall, UK) or LabrafacTM CC (medium chain triglyides, from Gattefosse), CaptexTM 500P (glyceryl triacetate i.e.
- Suspensions in addition to the MTP inhibitor or the combination, may further comprise carriers such as suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
- suspending agents e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
- the MTP inhibitor (or combination) can be carried in the drinking water so that a therapeutic dosage of the compound is ingested with the daily water supply.
- the compound can be directly metered into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water-soluble salt).
- the MTP inhibitor (or combination) can also be added directly to the feed, as such, or in the form of an animal feed supplement.
- the present invention has several advantageous veterinary features.
- the instant invention provides the means by which this may be accomplished.
- utilization of the method of the present invention yields leaner animals that command higher sale prices from the meat industry.
- composition per mL - Dirlotapide 5mg
- the study consisted of three consecutive phases: the weight loss phase was up to 168 days and the dose adjusted to achieve a body weight loss of approximately 1-3% per week; the retraining phase was up to 196 days and the dose adjusted to maintain body weight ⁇ 5% body weight at the end of the weight loss phase and finally, the post treatment phase where no test article was administered and was up to 31 days.
- the dogs were fed diets with varying fat contents based on air dry matter as fed: 5% fat diet (T1 , T4 and 17), 10% fat diet (T2, T5 and T8), or 15% fat diet (T3, T6 and T9).
- the dogs were weighed, assessed for body condition, blood sampled, assessed for faecal consistency and clinically examined every 28 days throughout the weight loss, retraining and post-treatment phases.
- the dogs were sampled for serum on day 24 or 25 of the weight loss phase, clinical observations performed on days 0 to 14, inclusive, and faecal consistency assessed on days 0 to 7 and days 13 and 14, of the weight loss phase.
- Dogs in T7, T8 and T9 were assessed for body composition on day -2, day 112 of the retraining phase and day 28 of the post treatment phase.
- day 194 of the retraining phase all remaining dogs (T4 to T9) were examined by an ophthalmologist for specific clinical signs of vitamin deficiencies.
- Subcutaneous adipose tissue samples were taken from all remaining dogs (T4 to T9) on ⁇ the final day of the retraining phase, and final day of study (T7 to T9). All remaining dogs (T4 to T9) were examined by a veterinarian for specific clinical signs of vitamin deficiencies on the final day of the retraining phase.
- the mean fat loss (based on body weight) in the dirlotapide -treated dogs was between 0.385 and 0.442% per week, whilst the mean lean mass change was between -0.0196 and +0.0021 % per week confirming that lean mass was spared.
- None of the dirlotapide -treated dogs gained a body condition score during the weight loss or retraining phase, whereas dogs treated with placebo either gained or had no change in body condition score. There were no serious suspected adverse drug experiences during the study period.
- the mean dose increased in all dirlotapide-treated groups (Figure 1) with the mean final dose ranging between 0.2 mg/kg and 0.6 mg/kg.
- the placebo-treated groups (T1 to T3) had a mean final dose volume ranging between 0.19 and 0.20 mL/kg, which was the maximum dose volume allowed.
- Final mean dosage at the end of the weight loss phase was 0.50, 0.40 and 0.22 mg/kg initial body weight for five, ten and 15% fat diets, respectively.
- Feed intake during the weight loss, retraining and post treatment phases were compared to feed intakes during the acclimatisation period.
- Table 1 provides a summary of the weekly body weight changes (%) during the weight loss phase;
- Table 2 provides a summary of daily feed intake changes (%) during the weight loss phase as a percent of intake during the acclimatisation phase;
- Figure 1 provides a summary of the dose volumes administered throughout the study period; and Figure 2 provides a summary of the mean cumulative body weight change
- Table 1 Summary of weekly body weight changes (%) during the weight loss phase
- Table 2 Summary of daily feed intake changes (%) during the weight loss phase as a percent of intake during the acclimatisation phase
- Rats Male Sprague Dawley rats (215-225 g) (Charles River Laboratories, Wilmington, MA) were individually housed in hanging wire mesh cages at 21 + 2 0 C with a 12:12 hour lightdark cycle. Rat were fed powdered purified diets providing either 10 or 45% of total calories as fat, with approximately equal caloric density (D01060501M, D01060502M Research Diets, New Brunswick, NJ) and had ad libitum access to water. A(I rats were acclimated to experimental diet and daily handling for 8 days prior to experimentation. All procedures were conducted in accordance with Institutional Animal Care and Use Committee guidelines and regulations. Study Design: A total of 56 rats were used in this study.
- Rats were randomly assigned to treatment groups according to a randomization plan generated by www.randomization.com with twenty-eight rats assigned to the low fat diet, and twenty- eight assigned to the high fat diet. Glass food cups were fitted with a metal lid and a feeding screen to minimize spillage. Twenty-four hour baseline food intake was measured for 4 days prior to compound administration to ensure that baseline food intake was not significantly different between treatment groups. Food intake measurements continued through the third day of compound administration. Body weights were obtained on day -1 , and daily from day 1 to 3 at approximately the same time each day.
- Rats Male Sprague Dawley rats (initial weight 125-135 grams) (Charles River Laboratories, Wilmington, MA) were individually housed in hanging wire mesh cages at 21 + ,, 2 0 C with a 12:12 hr lighfcdark cycle. Rats were fed powdered purified diets providing either 10 or 45% of total calories from fat (low and high fat diet, respectively), with approximately equal caloric density (D01060501M, D01060502M, Research Diets, New Brunswick, NJ) and had ad libitum access to water. Glass food jars fitted with a metal lid and a feeding screen were secured to the front of individual cages with a metal spring or ring to facilitate food intake measurement. All rats were acclimated to diet and handling for a minimum of 5 days prior to experimentation. All studies were approved and conducted in accordance with Institutional Animal Care and Use Committee guidelines and regulations. Design
- a total of 40 male rats were used in this experiment. Animals were randomly assigned to receive either the low or high fat diet, with 20 rats assigned to each group. Twenty-four hour food intake was measured for three consecutive days prior to compound administration (baseline) and during three consecutive days when rats received daily oral doses of compound or vehicle treatment. During the treatment period, 10 rats in each diet group were randomly assigned to receive either polyethylene glycol 400 (PEG 400): saline (80:20) vehicle or 10 mg/kg dirlotapide prepared in the same vehicle, both at dose volumes of 1 mL/kg body weight. Animals received treatments by standard oral gavage approximately 90 minutes prior to the onset of the dark cycle. Dirlotapide or vehicle was administered for 4 consecutive days with 24 hour food intake measured on the first three days and blood samples collected on the fourth day for analysis of compound exposure and potential plasma endocrine mediators of food intake.
- PEG 400 polyethylene glycol 400
- saline (80:20) vehicle 10 mg/kg dirlotapide prepared in the same vehicle, both at dose volumes of 1
- rats were sacrificed by carbon dioxide inhalation and blood samples were collected via cardiac puncture. Blood was placed in tubes containing EDTA and Aprotinin (0.6TIU/m!_, Phoenix Pharmaceuticals, Belmont, CA) to inhibit enzymatic protein degradation. Plasma samples were stored frozen at approximately - 2O 0 C.
- Total plasma peptide YY concentrations (PYY 1-36 and PYY 3-36) were determined by radioimmunoassay (RIA) using a commercially available kit according to manufacturers' instructions (Phoenix Pharmaceuticals, Inc. Belmont, CA, # RK-059-03).
- Plasma cholescystokinin (CCK), urocortin, and ghrelin concentrations were determined by enzyme-linked immunoassay (ELISA) using commercially available kits according to manufacturers' instructions (Phoenix Pharmaceuticals, Belmont, CA # EK-069-04, EK- 019-15, EK-069-04).
- Pancreatic polypeptide (PP) concentrations were determined by Linco Research Inc., St Charles MD by RIA methods.
- the weight loss efficacy and safety of dirlotapide administered once daily to obese dogs presented as veterinary patients was evaluated in a randomized study that was conducted in two phases: In the first phase the study was placebo-controlled and twenty-eight obese dogs (body condition score (BCS) > 7 on a 9-point scale) were enrolled.
- BCS body condition score
- MCT medium chain triglyceride
- the dose was adjusted by 10 or 20% at day 14 and 28 to produce between 1 % to 3% weight loss per week during 56 days of treatment.
- eight T2-treated dogs continued on treatment until day 84 (T2-extension) and eight placebo-treated dogs received dirlotapide at an initial dosage of 0.2 mg/kg
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Abstract
L'invention concerne une méthode destinée au traitement d'un sujet souffrant d'obésité ou d'autres troubles de l'alimentation et/ou à la réduction de la consommation d'aliments, la méthode consistant à administrer au sujet une dose thérapeutique d'un inhibiteur de la MTP et à soumettre le sujet à une diète riche en graisse.
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US7932268B2 (en) | 2004-03-05 | 2011-04-26 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects |
US8889674B2 (en) | 2009-03-05 | 2014-11-18 | Shionogi & Co., Ltd. | Piperidine and pyrrolidine derivatives having NPY Y5 receptor antagonism |
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US20060270655A1 (en) * | 2005-05-27 | 2006-11-30 | Swick Andrew G | Combination therapy for treating obesity or maintaining weight loss |
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---|---|---|---|---|
US7932268B2 (en) | 2004-03-05 | 2011-04-26 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects |
US8618135B2 (en) | 2004-03-05 | 2013-12-31 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects |
US9265758B2 (en) | 2004-03-05 | 2016-02-23 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects |
US9364470B2 (en) | 2004-03-05 | 2016-06-14 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects |
US9433617B1 (en) | 2004-03-05 | 2016-09-06 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects |
US9861622B2 (en) | 2004-03-05 | 2018-01-09 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects |
US10016404B2 (en) | 2004-03-05 | 2018-07-10 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects |
US10555938B2 (en) | 2004-03-05 | 2020-02-11 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects |
US11554113B2 (en) | 2004-03-05 | 2023-01-17 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects |
US8889674B2 (en) | 2009-03-05 | 2014-11-18 | Shionogi & Co., Ltd. | Piperidine and pyrrolidine derivatives having NPY Y5 receptor antagonism |
Also Published As
Publication number | Publication date |
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AR064343A1 (es) | 2009-04-01 |
TW200833336A (en) | 2008-08-16 |
JP2008179612A (ja) | 2008-08-07 |
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