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
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • 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
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the invention relates to the use of an enantiomer of ketoconazole for treating diabetes and other conditions.
• Ketoconazole l-acetyl-4- [4-[[2-(2,4-dichlorophenyl)-2-[(lH-imidazol-l-yl)- methyl]-l ,3-dioxolan-4-yl] methoxy] phenyl] piperazine, is a racemic mixture of the cis enantiomers (-)-(2S, 4R) and (+)-(2R, 4S). Racemic ketoconazole is an approved drug (NIZORAL®) for the treatment of fungal infections.
• ketoconazole was found to decrease plasma Cortisol and to be useful, alone and in combination with other agents, in the treatment of a variety of diseases and conditions, including type 2 diabetes, Metabolic Syndrome (also known as the Insulin Resistance Syndrome, Dysmetabolic Syndrome or Syndrome X), and other medical conditions that are associated with elevated Cortisol levels. See U.S. Patent Nos. 5,584,790; 6,166,017; and 6,642,236, each of which is incorporated herein by reference.
• Cortisol is a stress-related hormone secreted from the cortex of the adrenal glands.
• ACTH adenocorticotropic hormone
• ACTH cortisol secretion.
• ACTH corticotropin releasing hormone
• Ketoconazole has also been reported to lower cholesterol levels in humans (Sonino et al. (1991). "Ketoconazole treatment in Cushing's syndrome: experience in 34 patients.” Clin Endocrinol (Oxj). 35(4): 347-52; Gylling et al (1993) "Effects of ketoconazole on cholesterol precursors and low density lipoprotein kinetics in hypercholesterolemia.” J Lipid Res. 34(1): 59-67) each of which is incorporated herein by reference).
• the 2S, 4R enantiomer is more active against the cholesterol synthetic enzyme 14a-lanosterol demethylase than is the other (2R,4S) enantiomer (Rotstein et al.
• ketoconazole as a therapeutic is complicated by the effect of ketoconazole on the P450 enzymes responsible for drug metabolism. Several of these P450 enzymes are inhibited by ketoconazole (Rotstein et al., supra).
• ketoconazole itself (Brass et al., "Disposition of ketoconazole, an oral antifungal, in humans.” Antimicrob Agents Chemother 1982; 21(1): 151-8, incorporated herein by reference) and several other important drugs such as Glivec (Dutreix et al., "Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects.” Cancer Chemother Pharmacol 2004; 54(4): 290-4) and methylprednisolone (Glynn et al., "Effects of ketoconazole on methylprednisolone pharmacokinetics and Cortisol secretion.” Clin Pharmacol Ther 1986; 39(6): 654-9).
• the exposure of a patient to ketoconazole increases with repeated dosing, despite no increase in the amount of drug administered to the patient.
• This exposure and increase in exposure can be measured and demonstrated using the "Area under the Curve” (AUC) based on the concentration of the drug found in the plasma and the time period over which the measurements are made.
• AUC Absolute under the Curve
• the AUC for ketoconazole following the first exposure is significantly less than the AUC for ketoconazole after repeated exposures.
• This increase in drug exposure means that it is difficult to provide an accurate and consistent dose of the drug to a patient. Further, the increase in drug exposure increases the likelihood of adverse side effects associated with ketoconazole use.
• ketoconazole inhibits several P450 enzymes responsible for drug metabolism and this inhibition can lead to increased plasma levels of drugs that are co-administered with ketoconazole. This increase in the plasma levels of co-administered drugs can prevent the optimal use of either of ketoconazole or the coadministered drug.
• liver reactions One of the adverse side effects of ketoconazole administration exacerbated by this AUC problem is liver reactions.
• Asymptomatic liver reactions can be measured by an increase in the level of liver specific enzymes found in the serum and an increase in these enzymes has been noted in ketoconazole treated patients (Sohn, "Evaluation of ketoconazole.” Clin Pharm 1982; 1(3): 217-24, and Janssen and Symoens, "Hepatic reactions during ketoconazole treatment.” Am J Med 1983; 74(1B): 80-5, each of which is incorporated herein by reference).
• 1 12,000 patients will have more severe liver failure (Smith and Henry, "Ketoconazole: an orally effective antifungal agent.
• the present invention relates to administration of a 3-hydroxy 3- methylglutaryl coenzyme A (HMG CoA) reductase inhibitor (statin) to a patient in need of such treatment, in combination with a therapeutically effective amount of 2S,4R ketoconazole enantiomer substantially or entirely free of the 2R,4S ketoconazole enantiomer (sometimes simply "2S,4R ketoconazole enantiomer").
• coadministration of the 2S,4R ketoconazole enantiomer changes the pharmocokinetic profile of the HMG CoA reductase inhibitor, reducing the Cmax for the HMG CoA reductase activity. This allows higher doses of the HMG CoA reductase inhibitor to be administered to a patient whilst avoiding side-effects that would be expected if the HMG CoA reductase inhibitor was administered as a monotherapy.
• the HMG CoA reductase inhibitor coadministered with the 2S,4R ketoconazole enantiomer may be, for example and not limitation, atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, rivastatin, itavastatin, or rosuvastatin.
• the HMG CoA reductase inhibitor is atorvastatin.
• the 2S,4R ketoconazole enantiomer is administered at a daily dose of from 100 mg - 600 mg.
• the patient treated using the 2S,4R ketoconazole enantiomer/HMG CoA reductase inhibitor cotherapy may be, for example, a patient with diabetes, a patient with metabolic syndrome, or a patient not diagnosed as diabetic.
• the invention relates to administration of a therapeutically effective amount of 2S,4R ketoconazole enantiomer to a patient who will benefit from reduced levels of C-reactive protein (CRP).
• CRP C-reactive protein
• elevated CRP is an indicator of systemic inflammation.
• agents that reduce CRP levels are considered to reduce systemic inflammation.
• the invention provides methods for reduction of systemic inflammation in a patient in need of such reduction, by administration of the 2S,4R ketoconazole enantiomer to the patient.
• Patients with either of type 2 diabetes or metabolic syndrome generally also have elevated systemic inflammation that increases the risk in these patients of cardiovascular disease. Current therapies inadequately treat the systemic inflammation in these patients.
• CRP levels can be measured in a variety of assays.
• the high- sensitivity C-reactive protein assay is used.
• a patient with plasma CRP levels greater than 2.0 mg/L is considered to have elevated CRP indicative of systemic inflammation.
• the patient is treated using the 2S,4R ketoconazole enantiomer to reduce CRP level (or maintain the patient's CRP level at a reduced level).
• a patient with plasma CRP levels greater than 3.0 mg/L is considered to have elevated CRP indicative of systemic inflammation.
• a patient with plasma CRP levels greater than 4.0 mg/L is considered to have elevated CRP indicative of systemic inflammation.
• a patient with plasma CRP levels greater than 5.0 mg/L is considered to have elevated CRP indicative of systemic inflammation.
• a patient with plasma CRP levels greater than 10.0 mg/L is considered to have elevated CRP indicative of systemic inflammation.
• the method involves (i) identifying or diagnosing a patient as diabetic, (ii) identifying or diagnosing the patient as in need of reduction of his/her CRP level, and (iii) administering a therapeutically effective dose of the 2S,4R ketoconazole enantiomer (e.g., from 100 - 600 mg/day for at least 14 days).
• the method involves (i) identifying or diagnosing a patient has having metabolic disease, (ii) identifying or diagnosing the patient as in need of reduction of CRP level, and (iii) administering a therapeutically effective dose of the 2S,4R ketoconazole enantiomer (e.g., from 100 - 600 mg/day for at least 14 days).
• a therapeutically effective dose of the 2S,4R ketoconazole enantiomer e.g., from 100 - 600 mg/day for at least 14 days.
• the method involves (i) identifying or diagnosing the patient as in need of reduction of CRP level, and (ii) administering a therapeutically effective dose of the 2S,4R ketoconazole enantiomer (e.g., from 100 - 600 mg/day for at least 14 days).
• a therapeutically effective dose of the 2S,4R ketoconazole enantiomer e.g., from 100 - 600 mg/day for at least 14 days.
• the patient treated using the 2S,4R ketoconazole enantiomer therapy may be, for example, a patient with diabetes, a patient with metabolic syndrome, or a patient not diagnosed as diabetic.
• Patients with either of type 2 diabetes or metabolic syndrome also have elevated total and LDL cholesterol and these elevated lipids increase the risk in these patients of cardiovascular disease.
• Patients with type 2 diabetes are characterized by hyperglycemia and insulin resistance and patients with metabolic syndrome are characterized by several of the following: insulin resistance, elevated fasting glucose, dyslipidemia, hypertension, and central obesity. In many patients with either of type 2 diabetes or metabolic syndrome the elevated total and LDL cholesterol are inadequately treated.
• the present invention provides methods for treatment of patients with either of type 2 diabetes or metabolic syndrome by administering 2S,4R ketoconazole enantiomer substantially or entirely free of the 2R,4S ketoconazole enantiomer at a daily dose of from 100 mg - 600 mg, where the course of treatment results in a reduction in cholesterol levels and a reduction in CRP level, as well as improved glycemic control.
• Figure 1 shows the effect of a two-week administration of a ketoconazole enantiomer (DIO-902) on fructosamine levels.
• Figure 2 shows the effect of a two-week administration of a ketoconazole enantiomer (DIO-902) on fructosamine levels based on drug exposure (AUC tercile).
• Figure 3 shows trends to improved glucose homeostasis in subjects receiving a two-week course of DIO-902.
• Figure 4 shows the effect of a two-week administration of a ketoconazole enantiomer (DIO-902) on total cholesterol and LDL-cholesterol levels, presented as % change compared to baseline.
• DIO-902 ketoconazole enantiomer
• Figure 5 shows the effect of a two-week administration of a ketoconazole enantiomer (DIO-902) on total cholesterol and LDL-cholesterol levels (presented as change in mg cholesterol per deciliter plasma).
• DIO-902 ketoconazole enantiomer
• Figure 6 shows the effect of a two-week administration of a ketoconazole enantiomer (DIO-902) on levels of CRP.
• Figure 7 shows the effect of DIO-902 on atorvastatin pharmacokinetics levels in subjects receiving both drugs.
• the present invention provides for the therapeutic use of pharmaceutical compositions comprising the 2S,4R ketoconazole enantiomer substantially or entirely free of the 2R,4S enantiomer.
• “Substantially free" of the 2R,4S enantiomer in one embodiment, means that the ketoconazole content of the pharmaceutical composition is less than 2% of the 2R,4S enantiomer and more than 98% of the 2S,4R enantiomer.
• substantially free of the 2R,4S enantiomer means the ketoconazole content of the pharmaceutical composition is less than 10% of the 2R,4S enantiomer and more than 90% of the 2S,4R enantiomer.
• substantially free of the 2R,4S enantiomer means that the ketoconazole content of the pharmaceutical composition is less than 20% of the 2R,4S enantiomer and more than 80% of the 2S,4R enantiomer.
• the 2S,4R ketoconazole enantiomer and pharmaceutical compositions containing the 2S,4R ketoconazole enantiomer substantially or entirely free of the 2R,4S ketoconazole enantiomer, and pharmaceutically acceptable salts of the 2S,4R enantiomer of ketoconazole may be prepared as described in PCT Publication WO06072881 entitled "Methods And Compositions For Treating Diabetes, Metabolic Syndrome And Other Conditions," the entire contents of which are incorporated by reference.
• the 2S,4R ketoconazole enantiomer may be administered in a variety of unit dosage forms, frequencies, and routes of administration, as described in PCT Publication WO06072881.
• DIO-902 refers to a pharmaceutical preparation of the 2S,4R ketoconazole enantiomer used in clinical trials.
• DIO-902 comprises 2S,4R ketoconazole purified from the racemic mixture and is largely (greater than 98%) free of the 2R,4S enantiomer.
• DIO-902 is an immediate release tablet to be taken orally and formulated as shown in Table 1 , below.
• CRP levels for improving glycemic control, and other uses as described herein is not limited to this particular formulation.
• Co-administration and “co-therapy” refer to the administration of two (or more) drugs in the same course of therapy in order to achieve a type or level of benefit not resulting from administration of either drug individually.
• administering means administering a drug or combination of drugs for at least one day, more often for at least seven days, even more often for at least fourteen days, even more often for at least one month, often for at least 4 months (120 days), and sometimes for several years.
• administering or "administration of a drug to a subject (and grammatical equivalents of this phrase) may refer to direct administration, including self-administration, and indirect administration, including the act of prescribing a drug.
• a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug may be administering the drug to the patient.
• Administration of a therapeutically effective amount of the 2S,4R ketoconazole enantiomer substantially free of the 2R,4S enantiomer is effective in treating, controlling, and ameliorating the symptoms of diabetes, particularly type 2 diabetes.
• Administration of a therapeutically effective amount of the 2S,4R ketoconazole enantiomer substantially free of the 2R,4S enantiomer is also effective for treating a lipid disorder selected from the group consisting of dyslipidemia (e.g., hypercholesterolemia) in a human patient in need of such treatment.
• dyslipidemia e.g., hypercholesterolemia
• ketoconazole enantiomer is administered at a daily dose of from 100 to 600 mg, more usually at a dose of from 100 to 450 mg, and often at a dose of from 200 to 400 mg.
• Exemplary daily doses include 100, 125, 150, 200, 250, 300, 375, 400 or 450 mg.
• An example of the composition of a 150 mg strength, 300 mg weight tablet is described in Table 2. Table 2: Composition of 150 mg strength (300 mg) weight tablet
• Administration of the ketoconazole enantiomer at an aforementioned dose beneficially results in a reduction in cholesterol levels compared to baseline.
• Administration of the ketoconazole enantiomer at an aforementioned dose beneficially results in improved glycemic control compared to baseline.
• Administration of the ketoconazole enantiomer at an aforementioned dose beneficially results in a reduction in CRP levels compared to baseline.
• baseline means the level prior to commencement of therapy. In some embodiments, "baseline” is determined in a subject not receiving another therapy intended to reduce cholesterol and/or improve glycemic control (excluding therapy using insulin, glucagon or analogs of either) and/or reduce inflammation.
• Assessment of changes in markers at baseline and after the commencement of therapy can be based on measurements in a single patient or, more often, based on a statistically significant average or mean of several individuals or a large group of individuals.
• a clinical endpoint e.g., reduced cholesterol
• the invention provides a method for reducing cholesterol levels in a diabetic patient by administering a 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to said patient at a daily dose of from 100-600 mg, preferably 200-450 mg, where 14 days of treatment results in a reduction, compared to baseline, of LDL cholesterol by at least 15% and/or total cholesterol by at least 25%.
• the invention provides a method for reducing cholesterol levels in a diabetic patient by administering a 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to said patient at a daily dose of from 100-600 mg, preferably 150 mg-500 mg, such as 150 mg- 450 mg, or 200-450 mg, where 90 days of treatment results in a reduction, compared to baseline, of LDL cholesterol by at least 15%, at least 20% or at least 30% and/or reduction of total cholesterol by at least 15%, at least 20%, at least 30%, or at least 40%.
• the invention provides a method for improving glycemic control in diabetic patient by administering a 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to said patient at a daily dose of from 100-600 mg, preferably 150 mg-500 mg, such as 150 mg- 450 mg, or 200-450 mg, where 14 days of treatment results in a reduction, compared to baseline, of (a) HbAIc levels by at least 0.3% and/or (b) fructosamine levels by at least 10 umol/L and/or (c) fasting blood glucose levels by at least 15 mg/dL.
• the invention provides a method for improving glycemic control in a diabetic patient by administering a 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to said patient at a daily dose of from 100-600 mg, such as 150 mg-500 mg, 150 mg- 450 mg, or preferably 200-450 mg, where 90 days of treatment results in a reduction, compared to baseline, of (a) HbAIc levels by at least 0.4%, preferably at least 0.6%, and sometimes at least 0.8% and/or (b) fructosamine levels by at least 20 umol/L, preferably at least 30 umol/L, and sometimes at least 40 umol/L, and/or (c) fasting blood glucose levels by at least 20 mg/dL, preferably at least 25 mg/dL and sometimes at least 30 mg/dL.
• the patient to whom ketoconazole enantiomer is administered is also treated with an antihyperglycemic agent, such as metformin.
• the invention provides a method for reducing risk of developing vascular disease by administering the 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to said patient at a daily dose of from 100-600 mg, preferably 150 mg-500 mg, such as 150 mg- 450 mg, 200 mg -450 mg, or 300 mg - 450 mg, where 14 days of treatment results in a reduction CRP level of at least 15%, at least 25%, preferably at least 40%, and more preferably at least 45%.
• Administration of the 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer, alone or in combination with other agents, is also indicated for, without limitation, prevention of cardiovascular disease, reducing risk of myocardial infarction, reducing the risk of stroke, and reducing the risk for revascularization procedures and angina.
• the invention provides a method for reducing risk of developing vascular disease by administering a 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to said patient at a daily dose of from 100-600 mg, preferably 200-450 mg, where 90 days of treatment results in a reduction CRP level of at least 40%, and preferably at least 45%.
• exemplary daily doses include 150 mg, 300 mg and 450 mg.
• administering a 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to said patient at a daily dose of from 100-600 mg, preferably 200-450 mg results in improved glycemic control, and reduced cholesterol and reduced CRP.
• the aforementioned benefits result from a daily dose of from 100 to 450 mg of the 2S,4R ketoconazole enantiomer, such as from 200 to 400 mg (e.g., 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 420 or 450 mg).
• the patient to whom drug is administered has alanine aminotransferase (ALT) aspartate aminotransferase (AST) and alkaline phosphatase (AP) levels in the normal range normal.
• ALT alanine aminotransferase
• AST aspartate aminotransferase
• AP alkaline phosphatase
• at least one liver function test level (AST/ALT/AP) of the patient was not in the normal range at baseline (prior to initiation of the therapy).
• the invention provides a method for treatment of a diabetic patient by (a) administering a therapeutically effective amount of 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to the patient and (b) administering a therapeutically effective amount of a cholesterol-lowering HMG-CoA reductase inhibitor.
• the amount of HMG-CoA reductase inhibitor administered is greater than the amount indicated for the patient in the absence of administration of ketoconazole enantiomer (e.g., 20% greater, 50% greater, 100% greater (i.e., 2-fold greater) or more).
• the HMG-CoA reductase inhibitor is administered to a patient receiving ketoconazole enantiomer where administration of the HMG-CoA reductase inhibitor would be contraindicated in the patient in the absence of ketoconazole enantiomer.
• the HMG-CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, itavastatin, ZD- 4522, or rivastatin.
• HMG-CoA reductase inhibitors are the primary treatment in the management of atherosclerotic vascular disease.
• the benefits of statin treatment are believed to result from their capacity to lower LDL-cholesterol (LDL-C).
• LDL-C LDL-cholesterol
• statins invoke a generalized anti-inflammatory action (reviewed in Lutgens and Daemen, 2004, "HMG-coA reductase inhibitors: lipid-lowering and beyond" Drug Discovery Today: Therapeutic Strategies 1 :189-194).
• the effects of 2S,4R ketoconazole enantiomer on cholesterol levels and systemic inflammation suggests an additive or synergistic effect when used in combination with a statin.
• the dose of HMG-CoA reductase inhibitor administered to a patient may be reduced when a therapeutically effective amount of 2S,4R ketoconazole enantiomer is coadministered.
• the invention provides a method for reducing the amount of a HMG-CoA reductase inhibitor required to be administered to a patient for therapeutic efficacy, said method comprising administering a therapeutically effective amount of 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to the patient.
• the HMG-CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, itavastatin, ZD- 4522, or rivastatin.
• the invention provides a method for treatment of a diabetic patient by (a) administering a therapeutically effective amount of 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to the patient and (b) administering a therapeutically effective amount of a cholesterol-absorption inhibitor (e.g., ezitemibe).
• a cholesterol-absorption inhibitor e.g., ezitemibe
• the invention provides a method for the treatment of a non- diabetic patient with elevated cholesterol by administering a therapeutically effective amount of 2S,4R ketoconazole enantiomer substantially free of the 2R,4S enantiomer to the patient and (b) administering a therapeutically effective amount of a HMG-CoA reductase inhibitor.
• the amount of HMG-CoA reductase inhibitor administered is greater than the amount indicated for the patient in the absence of the administration of ketoconazole enantiomer (e.g., 20% greater, 50% greater, 100% greater (i.e., 2-fold greater) or more.
• the HMG-CoA reductase inhibitor is administered to a patient receiving ketoconazole enantiomer where administration of the HMG-CoA reductase inhibitor would be contraindicated in the patient in the absence of ketoconazole enantiomer.
• HMG-CoA reductase inhibitors are lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, itavastatin, ZD-4522 and rivastatin.
• the invention provides a method for treatment of a diabetic patient presenting with abnormal level of at least one marker of liver function (e.g., ALT, AST or AP), where the patient is in need of treatment to reduce cholesterol and/or improve glycemic control, comprising administering a therapeutically effective amount of 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to the patient.
• ALT ALT
• AST AST
• AP e.g., ALT, AST or AP
• ketoconazole when ketoconazole is administered as the racemate the Cmax of the drug (sum of both enantiomers) in hepatocytes will be greater than the Cmax of the drug (single enantiomer) when administered as the 2S,4R enantiomer.
• administration of the 2S,4R enantiomer will produce a lower Cmax in hepatocytes and reduced likelihood of any liver toxicity (at any dose).
• the primary objective was to evaluate the safety and tolerability of 14 daily doses of the 2S,4R enantiomer in subjects with type 2 diabetes.
• the secondary objective was to determine the pharmacokinetic (PK) profile in plasma of the 2S,4R enantiomer after a single dosing and after fourteen daily doses.
• PK pharmacokinetic
• the pharmacodynamic activity of fourteen daily doses of the 2S,4R enantiomer as reflected by changes in blood pressure, total and LDL cholesterol, CRP, plasma and salivary Cortisol, Cortisol binding globulin, measures of glycemic control (fructosamine, HbAIc and fasting blood glucose levels).
• the first dose of the study drug was given on Day 1 at 2200 h. Activity markers measured on Day 1 prior to administration of the drug ("Visit 1 "). The last dose of study drug was given on Day 14 at 2200 h and activity markers measured on Day 15 (“Visit 3"). Measurements of safety markers were taken on Visits 1 and 3, as well as Visit 2 (Day 8) and Visit 4 (Day 28).
• Measures of activity were: A) glycemic control; b) changes in lipid levels (total and LDL-cholesterol); 3) blood pressure and D) CRP as a marker of inflammation.
• HbAIc hemoglobin AIc test
• HbAlc in Subject 04-014 increased from 6.7 to 8.5; if this subject is omitted from the analysis, the mean change in HbAIc is -0.2.
• administration of DIO-902 for 14 days produces trends toward a reduction in HbAIc. It is anticipated that administration of drug for a longer period of time, such as twelve weeks or twenty-six weeks, will result in reductions of up to 0.8% or more relative to baseline (e.g., at least 0.4%, at least 0.6% or at least 0.8%).
• Fructosamine levels were measured at baseline and after two weeks of therapy (see Table 4 and Figures 1 and 2).
• Figure 1 shows changes in fructosamine levels for each study group on Day 15 compared to baseline.
• Figure 2 shows changes in fructosamine levels for each AUC tercile on Day 15 compared to baseline.
• Fructosamine levels reflect blood glucose levels over the preceding 2-3 weeks. Reductions in fructosamine were greatest in the DIO-902 treatment groups.
• Tables 5 and 6, below, and Figures 4 and 5 show changes in total- and LDL- cholesterol levels in the study groups. Statistically significant, dose dependent decreases in total and LDL-C were observed in subjects receiving DIO-902.
• CRP C-Reactive protein
• CRP C-Reactive Protein
• Levels of 1-3 mg/L are considered moderate risk; levels of > 3 mg/L are high risk.
• Reducing CRP levels in diabetic patients is correlated with improved prognosis, or lower risk of developing, microvascular and macrovascular disease. It is anticipated that administration of DIO-902 for a longer period of time, such as twelve weeks or twenty-six weeks will result in reductions of up to 20-50% more relative to baseline (e.g., reductions of at least 20%, at least 30%, at least 40% or at least 50% or more).
• Example 2 Absence of hepatotoxity and hepatoprotection with DIO-902 [0072] Liver toxicity has been observed in some patients receiving racemic ketoconazole. In contrast, evidence of hepatotoxicity was not observed in subjects receiving DIO-902. Moreover, evidence consistent with hepato-protection with DIO-902 was observed. Two (2) patients with liver function test values outside the normal range when measured at baseline normalized with DIO-902 treatment (see Table 8). Table 8 Hepatoprotection with DIO-902 (Sample of LFT results)
• a 3-way cross-over study (80 mg atorvastatin + 400 mg DIO-902, 400 mg racemic ketoconazole, or placebo) was carried out with a washout period of 14 days.
• atorvastatin + 400 mg DIO-902, 400 mg racemic ketoconazole, or placebo was carried out with a washout period of 14 days.
• Figure 7 when plasma levels of total active HMG CoA reductase inhibitor were measured, administration of DIO-902 reduced the Cmax of the total active inhibitor while increasing the AUC relative to the atorvastatin-only control. Racemic ketoconazole did not have as large an effect on the Cmax as did DIO-902.
• Total active inhibitor is the combined amount of atorvastin and the biologically active metabolites 2-hydroxy atorvastatin and 4- hydroxy atorvastatin.
• a cholesterol lowering HMGCoA reductase inhibitor e.g., a statin such as atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, rivastatin, itavastatin, rosuvastatin, and other statins
• a statin such as atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, rivastatin, itavastatin, rosuvastatin, and other statins
• the intraliver Cmax attained for the isolated 2S,4R enantiomer will be less than that for the racemate and as a consequence there is reduced risk of liver damage with the 2S,4R enantiomer as compared to racemic ketoconazole.

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