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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4196—1,2,4-Triazoles
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• HSDs Ib-hydroxy steroid dehydrogenases
• the HSD enzymes consist of two isoforms: the nicotinamide-adenine dinucleotide phosphate reduced-dependent type 1 (HSD1) in vivo generally converts inactive cortisone to active cortisol, and the nicotinamide-adenine dinucleotide dependent oxidative type 2 (HSD2) converts cortisol to cortisone.
• HSD1 nicotinamide-adenine dinucleotide phosphate reduced-dependent type 1
• HSD2 nicotinamide-adenine dinucleotide dependent oxidative type 2
• HSD1 selective inhibitor could potentially ameliorate side effects associated with corticosteroid administration, such as hyperglycemia, insulin resistance, obesity, hyperlipidemia, hypertension, and the like.
• PMR Polymyalgia rheumatica
• GCA giant cell arteritis
• PMR typically presents acutely with bilateral upper extremity pain.
• GCA typically presents with unilateral or bilateral headache, myalgias, fatigue, fever, weight loss, and sometimes acute vision loss.
• PMR and GCA represent either different manifestations of the same disease or overlapping conditions.
• GCA may present as classic cranial (temporal) arteritis, large-vessel vasculitis, or single-organ arteritis. From 40% to 60% of patients diagnosed with GCA also have PMR, and 16% to 21% of PMR patients have GCA.
• PMR occurs 3 to 10 times more frequently than GCA.
• GCA is the most frequent primary vasculitis with an incidence of 18 per 100 000.
• Oral corticosteroids (CS) have been the mainstay of PMR therapy for decades, and are the only medications indicated by FDA for PMR therapy. Clinical trials evidence for therapeutic efficacy in PMR (including for oral CS) is quite limited.
• FIG. 1 shows the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone for clinical trial subjects after a single dose of placebo or Compound A.
• placebo placebo
• Compound A 1 mg
• Compound A 3 mg
• Compound A 6 mg
• Compound A (e) 10 mg Compound A; (f) 30 mg Compound A; (g) 60 mg Compound A. (i) 0-24 hr; (ii); 24-48 hr; (iii) 0-last. A lower value indicates inhibition of liver HSD1.
• FIG. 2 shows the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone for clinical trial subjects prior to, and after single (on Day 1) and multiple (daily on Days 5 through 18) doses of Compound A.
• a lower value indicates inhibition of liver HSD1.
• the abscissa is labeled as Day, where -1 is prior to the first dose of study drug.
• FIG. 3 shows the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone for clinical trial subjects prior to, and after single (on Day 1) and multiple (daily on Days 2 through 14) doses of Compound A. (a) 0.4 mg and (b) 0.2 mg of Compound A. A lower value indicates inhibition of liver HSD1. The abscissa is labeled as Day, where -1 is prior to the first dose of study drug.
• FIG. 4 provides a schematic of the population pharmacokinetics model for Compound A, with 4-compartment transient absorption, saturable binding from the central compartment, and first-order elimination.
• FIG. 5 shows the relationship between plasma concentration and brain HSD1 enzyme occupancy for Compound A. Abscissa: logio(Compound A plasma concentration in ng / mL), ordinate: brain HSD1 enzyme occupancy (%). Intra-graph lines indicate plasma concentration ranges associated with daily doses of (a) 0.2 mg, (b) 0.4 mg, (c) 0.7 mg, and (d) 2.0 mg Compound A at steady state.
• FIG. 6 shows simulations of HSD1 inhibition for patients by Compound A. 3 mg first dose, then daily doses of (a) 1 mg QD; (b) 0.1 mg QD. The abscissa is labeled as days of dose administration.
• FIG. 7 shows simulations of HSD1 inhibition for patients by Compound A. 4 mg first dose, then daily doses of (a) 1 mg QD; (b) 0.1 mg QD. The abscissa is labeled as days of dose administration.
• FIG. 8 shows simulations of HSD1 inhibition for patients by Compound A. Three 1 mg daily doses, then daily doses of 0.1 mg QD. The abscissa is labeled as days of dose administration.
• FIG. 9 shows reversal of CS-induced tail biting behavior by Compound A.
• FIG. 10 shows restoration of CS-induced deficit of maze exploration behavior by Compound A.
• Vertical axis alternation rate (%). * P ⁇ 0.05; ** P ⁇ O.Olvs 0 dose (a) no CS; (b) - (1) CS; dosage of Compound A (mg / kg): (b) 0; (c) 0.01; (d) 0.03; (e) 1; (f) 3.
• a method for administering a corticosteroid to a patient in need thereof comprising:
• the corticosteroid is not prednisone
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s ratio of urinary
• the corticosteroid is not prednisone
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
• a method for administering a corticosteroid to a patient in need thereof comprising:
• the corticosteroid is not prednisone
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
• the corticosteroid is not prednisone
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
• Compound A refers to 4- ⁇ 5-[l-(4-chloro-2,6-difluorophenoxy)- l-methylethyl]-4-methyl-4H-l,2,4-triazol-3-yl-3-fluorobenzamide, which has the structure:
• co-administer and “co-administration” and variants thereof mean the administration of at least two drugs to a patient either subsequently, simultaneously, or consequently proximate in time to one another (e.g., within the same day, or week or period of 30 days).
• two or more active agents can be co-formulated as part of the same composition or administered as separate formulations. This also may be referred to herein as“concomitant” administration or variants thereof.
• administering to a patient refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.
• disorder is intended to be generally synonymous, and is used interchangeably with, the terms “disease,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms.
• a "dose” means the measured quantity of an active agent to be taken at one time by a patient.
• “dosing regimen” means the dose of an active agent taken at a first time by a patient and the interval (time or symptomatic) at which any subsequent doses of the active agent are taken by the patient. The additional doses of the active agent can be different from the dose taken at the first time.
• an agent, compound, drug, composition or combination is an amount which is nontoxic and effective for producing some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient).
• the precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.
• patient or “individual” or “ subject” means a human, for whom or which therapy is desired, and generally refers to the recipient of the therapy.
• pharmaceutically acceptable refers to a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
• pharmaceutically acceptable refers to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug
• “Pharmacologically active” as in a “pharmacologically active” (or “active”) derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
• pharmaceutically acceptable salts include acid addition salts which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as
• risk means the probability or chance of adverse reaction, injury, or other undesirable outcome arising from a medical treatment.
• An "acceptable risk” means a measure of the risk of harm, injury, or disease arising from a medical treatment that will be tolerated by an individual or group. Whether a risk is “acceptable” will depend upon the advantages that the individual or group perceives to be obtainable in return for taking the risk, whether they accept whatever scientific and other advice is offered about the magnitude of the risk, and numerous other factors, both political and social.
• An "acceptable risk” of an adverse reaction means that an individual or a group in society is willing to take or be subjected to the risk that the adverse reaction might occur since the adverse reaction is one whose probability of occurrence is small, or whose consequences are so slight, or the benefits (perceived or real) of the active agent are so great.
• An "unacceptable risk” of an adverse reaction means that an individual or a group in society is unwilling to take or be subjected to the risk that the adverse reaction might occur upon weighing the probability of occurrence of the adverse reaction, the consequences of the adverse reaction, and the benefits (perceived or real) of the active agent.
• “At risk” means in a state or condition marked by a high level of risk or susceptibility. Risk assessment consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product.
• safety means the incidence or severity of adverse events associated with administration of an active agent, including adverse effects associated with patient-related factors (e.g., age, gender, ethnicity, race, target illness, abnormalities of renal or hepatic function, co-morbid illnesses, genetic characteristics such as metabolic status, or environment) and active agent-related factors (e.g., dose, plasma level, duration of exposure, or concomitant medication).
• patient-related factors e.g., age, gender, ethnicity, race, target illness, abnormalities of renal or hepatic function, co-morbid illnesses, genetic characteristics such as metabolic status, or environment
• active agent-related factors e.g., dose, plasma level, duration of exposure, or concomitant medication
• treating refers to therapeutic applications to slow or stop progression of a disorder, prophylactic application to prevent development of a disorder, or reversal of a disorder.
• Reversal of a disorder differs from a therapeutic application which slows or stops a disorder in that with a method of reversing, not only is progression of a disorder completely stopped, cellular behavior is moved to some degree, toward a normal state that would be observed in the absence of the disorder.
• a method for administering a corticosteroid to a patient in need thereof comprising:
• the corticosteroid is not prednisone
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
• the corticosteroid is not prednisone
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
• a method for administering a corticosteroid to a patient in need thereof comprising:
• the corticosteroid is not prednisone
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
• the corticosteroid is not prednisone
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
• a method for administering a corticosteroid to a patient in need thereof comprising:
• the corticosteroid is not prednisone
• the HSD1 inhibitor is 4- ⁇ 5-[l-(4-chloro-2,6-difluorophenoxy)-l-methylethyl]- 4-methyl-4H-l,2,4-triazol-3-yl-3-fluorobenzamide or a pharmaceutically acceptable salt thereof (Compound A) or N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]- a,a-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l-piperazineacetamide (Compound B); and
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
• the corticosteroid is not prednisone
• the HSD1 inhibitor is 4- ⁇ 5-[l-(4-chloro-2,6-difluorophenoxy)-l-methylethyl]- 4-methyl-4H-l,2,4-triazol-3-yl-3-fluorobenzamide or a pharmaceutically acceptable salt thereof (Compound A) or N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]- a,a-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l-piperazineacetamide (Compound B); and
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
• a method for administering a corticosteroid to a patient in need thereof comprising:
• the corticosteroid is not prednisone
• the HSD1 inhibitor is 4- ⁇ 5-[l-(4-chloro-2,6-difluorophenoxy)-l-methylethyl]- 4-methyl-4H-l,2,4-triazol-3-yl-3-fluorobenzamide or a pharmaceutically acceptable salt thereof (Compound A) or N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]- a,a-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l-piperazineacetamide (Compound B); and
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
• the corticosteroid is not prednisone
• the HSD1 inhibitor is 4- ⁇ 5-[l-(4-chloro-2,6-difluorophenoxy)-l-methylethyl]- 4-methyl-4H-l,2,4-triazol-3-yl-3-fluorobenzamide or a pharmaceutically acceptable salt thereof (Compound A) or N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]- a,a-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l-piperazineacetamide (Compound B); and
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
• the HSD1 inhibitor is chosen from 4- ⁇ 5-[l-(4-chloro-2,6- difluorophenoxy)-l-methylethyl]-4-methyl-4H-l,2,4-triazol-3-yl-3-fluorobenzamide or a pharmaceutically acceptable salt thereof (Compound A) and N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]-a,a-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazineacetamide (Compound B), or a pharmaceutically acceptable salt thereof.
• the HSD1 inhibitor is Compound A, or a pharmaceutically acceptable salt thereof.
• the HSD1 inhibitor is Compound B, or a pharmaceutically acceptable salt thereof.
• the HSD1 inhibitor is AMG 221 ((5S)-2-[[(lR,3S,4S)-3- bicyclo[2.2.1]heptanyl]amino]-5-methyl-5-propan-2-yl-l,3-thiazol-4-one).
• the HSD1 inhibitor is Xanamem ((5-(lH-pyrazol-4- yl)thiophen-3-yl)((lR,3r,5S)-3-hydroxy-3-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-8- yl)methanone): [0050] In some embodiments, the HSD1 inhibitor is a compound as disclosed in
• the target threshold for the ratio of urinary is the target threshold for the ratio of urinary
• the target threshold is about 0.2 and the patient has an additional risk factor.
• the additional risk factor is chosen from diabetes, hypertension, elevated cholesterol, elevated triglycerides, nonalcoholic steatohepatitis, obesity, history of major adverse cardiovascular event, osteoporosis, osteonecrosis, ocular hypertension, or history of glaucoma.
• the additional risk factor is age.
• the additional risk factor is gender and the patient is female.
• the additional risk factor is prior cumulative corticosteroid exposure.
• the additional risk factor is a history of adverse events associated with corticosteroid administration.
• the target threshold for the ratio of urinary is the target threshold for the ratio of urinary
• the patient has been administered a corticosteroid for a period of time prior to being administered the HSD1 inhibitor.
• the patient is being administered the corticosteroid at a first dose for a first time period.
• the method further comprises administering a second dose of the corticosteroid to the patient.
• the second dose of the corticosteroid is a different amount than the first dose.
• the second dose of the corticosteroid is the same amount as the first dose.
• the corticosteroid is administered orally.
• the corticosteroid is administered intravenously or intramuscularly.
• the corticosteroid is administered intravenously. In some embodiments, the corticosteroid is administered intravenously and the HSD1 inhibitor is administered orally. In some embodiments, the corticosteroid is administered intravenously and the HSD1 inhibitor is administered orally at the same time as the intravenous
• the corticosteroid is administered intravenously and the HSD1 inhibitor is administered orally prior to the intravenous administration of the corticosteroid. In some embodiments, the corticosteroid is administered intravenously and the HSD1 inhibitor is administered orally in a manner sufficient to provide protection across multiple administrations of the corticosteroid, which may occur during a single day or more than one day. In some embodiments, the corticosteroid is administered intravenously and the HSD1 inhibitor is administered intravenously. In some embodiments, the corticosteroid and HSD1 inhibitor are co-formulated for intravenous administration. In some embodiments, the corticosteroid and HSD1 inhibitor are administered separately.
• the corticosteroid is administered intramuscularly. In some embodiments, the corticosteroid is administered intramuscularly at a frequency less than daily. In some embodiments, the corticosteroid is administered intramuscularly every other day. In some embodiments, the corticosteroid is administered intramuscularly twice a week. In some embodiments, the corticosteroid is administered intramuscularly once a week. In some embodiments, the corticosteroid is administered intramuscularly every other week. In some embodiments, the corticosteroid is administered intramuscularly and the HSD1 inhibitor is administered intramuscularly. In some embodiments, the corticosteroid and HSD1 inhibitor are co-formulated for intramuscular administration.
• the corticosteroid and HSD1 inhibitor are administered separately. In some embodiments, the corticosteroid is administered intramuscularly and the HSD1 inhibitor is administered orally. In some embodiments, the corticosteroid is administered intramuscularly and the HSD1 inhibitor is administered orally as a single loading dose. In some embodiments, the corticosteroid is administered intramuscularly and the HSD1 inhibitor is administered orally as a single loading dose followed by one or more maintenance doses. In some embodiments, the corticosteroid is administered intramuscularly and the HSD1 inhibitor is administered orally as a plurality of doses, each of which may be the same amount or differing amounts.
• the corticosteroid is chosen from alclometasone, amcinonide, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clocortolone, cloprednol, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinolone, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluticasone, fluprednidene, formocortal, halcinonide, halometasone,
• the corticosteroid is betamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.25 to about 20 mg. In some embodiments, the corticosteroid is betamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.6 to about 9 mg.
• the corticosteroid is prednisolone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.5 to about 200 mg. In some embodiments, the corticosteroid is prednisolone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.5 to 80 mg. In some embodiments, the corticosteroid is prednisolone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.5 to 60 mg. In some embodiments, the corticosteroid is prednisolone or a pharmaceutically acceptable salt or ester thereof, and the equivalent dosage of prednisolone is chosen from 1, 2.5, 5, 10, 20, and 30 mg.
• the corticosteroid is dexamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.1 to about 40 mg. In some embodiments, the corticosteroid is dexamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.1 to about 30 mg. In some embodiments, the corticosteroid is dexamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.1 to about 20 mg. In some embodiments, the corticosteroid is dexamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.1 to about 10 mg. In some embodiments, the corticosteroid is dexamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.1 to about 9 mg.
• the corticosteroid is budesonide or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.25 mg to 9 mg. In some embodiments, the corticosteroid is budesonide or a pharmaceutically acceptable salt or ester thereof, and is administered at a dosage chosen from the following:
• the corticosteroid is hydrocortisone or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the corticosteroid is hydrocortisone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 20 to about 800 mg. In some embodiments, the corticosteroid is hydrocortisone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 20 to about 240 mg orally. In some embodiments, the corticosteroid is hydrocortisone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 20 to about 500 mg every two hours (e.g., for anti-inflammatory). In some embodiments, the corticosteroid is hydrocortisone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 20 to about 800 mg daily for the treatment of multiple sclerosis.
• the corticosteroid is deflazacort or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.25 mg to about
• the corticosteroid is deflazacort or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of about 0.9 mg/kg/day.
• the corticosteroid is methylprednisolone or a
• the corticosteroid is methylprednisolone or a pharmaceutically acceptable salt or ester thereof, and is administered intravenously at a dose of from about 10 to about 40 mg.
• the corticosteroid is methylprednisolone or a
• the corticosteroid is administered at a dose equivalent to 1 mg prednisone. In some embodiments, the corticosteroid is administered at a dose equivalent to 2.5 mg prednisone. In some embodiments, the corticosteroid is administered at a dose equivalent to 5 mg prednisone. In some embodiments, the corticosteroid is administered at a dose equivalent to 10 mg prednisone. In some embodiments, the corticosteroid is
• the corticosteroid is administered at a dose equivalent to 30 mg prednisone.
• the side effects associated with corticosteroid are not limited to:
• administration are chosen from diabetes, fractures, obesity, Cushingoid appearance, hepatic steatosis, hypertension, hyperlipidemia, muscle weakness, dermal atrophy, impaired wound healing, osteoporosis/osteonecrosis, glaucoma, and mood/memory changes.
• the first dose of the HSD1 inhibitor is at least 0.7 mg. In some embodiments, the first dose of the HSD1 inhibitor is 0.7 mg. In some embodiments, the first dose of the HSD1 inhibitor is at least 1 mg. In some embodiments, the first dose of the HSD1 inhibitor is 1 mg. In some embodiments, the first dose of the HSD1 inhibitor is at least
• the first dose of the HSD1 inhibitor is 2 mg. In some embodiments, the first dose of the HSD1 inhibitor is at least 2.5 mg. In some embodiments, the first dose of the HSD1 inhibitor is 2.5 mg. In some embodiments, the first dose of the HSD1 inhibitor is at least 3 mg. In some embodiments, the first dose of the HSD1 inhibitor is 3 mg. In some embodiments, the first dose of the HSD1 inhibitor is at least 4 mg. In some embodiments, the first dose of the HSD1 inhibitor is 4 mg. In some embodiments, the first dose of the HSD1 inhibitor is at least 5 mg. In some embodiments, the first dose of the HSD1 inhibitor is 5 mg. In some embodiments, the first dose of the HSD1 inhibitor is 6 mg.
• the first dose of the HSD1 inhibitor is sufficient to achieve the target threshold for the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone.
• the HSD1 inhibitor is administered at a single dose of 5 mg to achieve the target threshold. In some embodiments, the HSD1 inhibitor is administered at a dose of 6 mg to achieve the target threshold.
• multiple administrations are required to achieve the target threshold for the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone.
• the HSD1 inhibitor is administered at a dose of 2.5 mg for 2 days to achieve the target threshold. In some embodiments, the HSD1 inhibitor is administered at a dose of 2 mg for 3 days to achieve the target threshold. In some embodiments, the HSD1 inhibitor is administered at a dose of 1 mg for 5 days to achieve the target threshold. In some embodiments, the HSD1 inhibitor is administered at a dose of 0.7 mg for 7 days to achieve the target threshold.
• a second dose of the HSD1 inhibitor is not administered to the patient.
• the method further comprises administering a second dose of the HSD1 inhibitor. In some embodiments, prior to administering the second dose of the HSD1 inhibitor, the method further comprises measuring the ratio of urinary
• the method further comprising adjusting the dose of HSD1 inhibitor to maintain the patient’s ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
• the second dose of the HSD1 inhibitor is the same as the first dose of the HSD1 inhibitor.
• the second dose of the HSD1 inhibitor is more than the first dose of the HSD1 inhibitor.
• the second dose of the HSD1 inhibitor is less than the first dose of the HSD1 inhibitor.
• the target threshold for the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone is about 0.2
• the first dose of the HSD1 inhibitor is the same amount as the second dose, i.e.., the dosing amount is constant.
• the first and second dose are 2 mg. In some embodiments, the first and second dose are 2.5 mg.
• the target threshold for the ratio of urinary is the target threshold for the ratio of urinary
• tetrahydrocortisol + allotetrahydrocortisol to urinary tetrahydrocortisone is about 0.2
• the second dose of the HSD1 inhibitor is less than the first dose of the HSD1 inhibitor, e.g., the first dose is a loading dose and the second dose is a maintenance dose.
• the first or loading dose is at least 3 mg, such as 3 mg. In some embodiments, the first or loading dose is at least 4 mg, such as 4 mg. In some embodiments, the first or loading dose is at least 5 mg, such as 5 mg. In some embodiments, the first or loading dose is at least 6 mg, such as 6 mg. In some embodiments, the second dose is 0.2 mg. In some embodiments, the second dose is 0.1 mg.
• the first or loading dose is at least 0.7 mg, such as 0.7 mg. In some embodiments, e.g., when the target threshold is 0.66, the first or loading dose is at least 1 mg, such as 1 mg. In some embodiments, the first or loading dose is at least 2 mg, such as 2 mg. In some embodiments, the first or loading dose is at least 3 mg, such as 3 mg. In some embodiments, the first or loading dose is at least 4 mg, such as 4 mg. In some embodiments, the first or loading dose is at least 5 mg, such as 5 mg. In some embodiments, the first or loading dose is at least 6 mg. In some embodiments, the second dose is 0.2 mg. In some embodiments, the second dose is 0.1 mg.
• the corticosteroid is administered at decreasing levels over a period of time, e.g., a 6-day course of methylprednisolone in which patients take 6, 5, 4, 3, 2, and finally 1 dosage form on successive days, and the HSD1 inhibitor is administered at a dose of at least 0.833 mg with each corticosteroid dosage form.
• the corticosteroid is methylprednisolone
• the dosage form is a tablet
• each tablet is 4 mg.
• the corticosteroid is formulated as a capsule.
• the HSD1 inhibitor is administered orally.
• the HSD1 inhibitor is provided in fixed dose combination (“FDC”) tablets with the corticosteroid.
• the FDC tablets are supplied for once daily dosage.
• a course of once daily dosages is provided.
• the HSD1 inhibitor is provided for a dosing regimen consistent with sub-chronic treatment with a corticosteroid.
• the subject will be instructed to take a decreasing count of tablets for a course of treatment.
• the subject will be instructed to take a 6, 5, 4, 3, 2, and 1 tablets for the first, second, third, fourth, fifth, and sixth day of a six day once daily course of treatment.
• the HSD1 inhibitor is provided for a dosing regimen consistent with chronic treatment with a corticosteroid.
• the subject will be instructed to take a single tablet for each day of a course of treatment.
• the subject will be instructed to take two tablets for each day of a course of treatment.
• the course of treatment is chosen from 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 6 months, and 1 year.
• the HSD1 inhibitor is administered intravenously.
• the HSD1 inhibitor is administered daily, optionally with divided doses. In some embodiments, the HSD1 inhibitor is administered every other day.
• the corticosteroid is administered to treat a chronic disease or disorder. In some embodiments, the corticosteroid is administered to treat an acute disease or disorder.
• the corticosteroid is administered to treat a disease or disorder chosen from:
• endocrine disorders such as primary or secondary adrenocortical insufficiency, congenital adrenal hyperplasia, nonsuppurative thyroiditis, and hypercalcemia associated with cancer;
• rheumatic disorders such as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, acute and subacute bursitis, acute nonspecific tenosynovitis, acute gouty arthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis, acute rheumatic carditis, dermatomyositis, temporal arteritis, polymyositis, and systemic lupus erythematosus and epicondylitis;
• collagen diseases such as during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus, systemic dermatomyositis
• dermatologic diseases such as pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, exfoliative erythroderma, mycosis fungoides, severe psoriasis, and severe seborrheic dermatitis;
• allergic states such as control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment such as seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, serum sickness, transfusion reactions, and drug hypersensitivity reactions;
• ophthalmic diseases such as severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as allergic comeal marginal ulcers, herpes zoster ophthalmicus, anterior segment inflammation, diffuse posterior uveitis and choroiditis, sympathetic ophthalmia, allergic conjunctivitis, keratitis,
• chorioretinitis chorioretinitis, optic neuritis, ulcerative colitis, and ocular inflammatory conditions unresponsive to topical corticosteroids, and iridocyclitis;
• respiratory diseases such as symptomatic sarcoidosis, Loefflef s syndrome not manageable by other means, berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis, and aspiration pneumonitis;
• hematologic disorders such as idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, erythroblastopenia (RBC anemia), pure red cell aplasia, and congenital (erythroid) hypoplastic anemia;
• neoplastic diseases such as for palliative management of leukemias and lymphomas in adults and acute leukemia of childhood;
• edematous states such as to induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus;
• gastrointestinal diseases such as to tide the patient over a critical period of the disease in: ulcerative colitis or regional enteritis;
• nervous system such as acute exacerbations of multiple sclerosis, cerebral edema associated with primary or metastatic brain tumor, or craniotomy;
• renal diseases such as to induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus; and other diseases or disorders such as tuberculous meningitis with subarachnoid block or. impending block when used concurrently with appropriate antituberculous chemotherapy, and trichinosis with neurologic or myocardial involvement.
• the corticosteroid is administered to treat vasculitis, e.g., Behcet’s disease, central nervous system vasculitis, cryogioblinerma Churg-Strauss syndrome, giant cell arteritis (GCA), granulomatosis with polyangiitis, Henoeh-Schonlein purpura, hypersensitivity vasculitis, aortitis, microscopic polyangiitis, polyarteritis nodosa, polymyalgia rheumatica (PMR), rheumatoid vasculitis, Takayasu’s arteritis, and urticarial vasculitis.
• vasculitis e.g., Behcet’s disease, central nervous system vasculitis, cryogioblinerma Churg-Strauss syndrome, giant cell arteritis (GCA), granulomatosis with polyangiitis, Henoeh-Schonlein purpura, hyper
• the vasculitis is chosen from GCA and PMR.
• the GCA is new-onset GCA.
• the GCA is ongoing GCA.
• the PMR is new-onset PMR.
• the PRM is ongoing PMR.
• coadministration of the HSD1 inhibitor and the corticosteroid is effective at alleviating adverse effects that arise from administration of corticosteroid.
• the adverse effects are chosen from one or more of the following: diabetes, impaired glucose tolerance, insulin resistance, weight gain, lipodystrophy, hepatic steatosis, elevated blood pressure, increased blood lipids, muscle atrophy, skin atrophy, impaired wound healing, bone fracture, osteoporosis, glaucoma, elevated intraocular pressure, memory deficits, mood changes, and hypothalamic-pituitary- adrenal (HP A) axis suppression.
• the foregoing has focused on methods for measuring HSD1 activity using the urinary metabolite ratio, i.e., the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone for the patient.
• an alternative method is used to measure HSD1 activity.
• HSD1 activity is measured using a ratio of mass-labeled cortisol and cortisone in the blood, e.g., the plasma, or in the cerebrospinal fluid.
• the method as disclosed by Basu for measuring CS levels in the hepatic and portal veins is utilized. See Basu, et al. (2009) Diabetes 58: 39-45, which is incorporated herein by reference for all purposes.
• HSD1 activity is measured by a jugular mass-labeled cortisol: cortisone ratio.
• [9,11,12,12- 2 H4] cortisol (D4 cortisol) is used to characterize HSD1 inhibition as a precursor of the HSD1 substrate [9,12,12- 2 H3] cortisone (D3 cortisone) and the HSD1 product [9,12,12- 2 H3] cortisol (D3 cortisol).
• D4 cortisol is used to characterize HSD1 inhibition as a precursor of the HSD1 substrate [9,12,12- 2 H3] cortisone (D3 cortisone) and the HSD1 product [9,12,12- 2 H3] cortisol (D3 cortisol).
• HSD1 activity is measured using a ratio of active and inactive forms of a corticosteroid medication in the blood, e.g., the plasma, or in the cerebrospinal fluid.
• prednisone is used to characterize HSD1 inhibition as a precursor of the HSD1 product prednisolone.
• HSD1 activity is measured by conversion of a HSD1 substrate to a HSD1 product in a fat biopsy.
• the HSD1 substrate is mass labeled cortisone and the HSD1 product is mass labeled cortisol.
• the HSD1 substrate is [9,12,12- 2 H3] cortisone (D3 cortisone) and the HSD1 product is
• the HSD1 substrate is an 11-keto corticosteroid and that HSD1 product is an 11 -hydroxy corticosteroid.
• the HSD1 substrate is prednisone and the HSD1 product is prednisolone.
• HSD1 occupancy is measured rather than HSD1 activity or inhibition. Accordingly, also provided is a method for administering a corticosteroid to a patient in need thereof, comprising:
• the corticosteroid is not prednisone
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s target HSD1 occupancy by HSD1 inhibitor at a level below the target threshold.
• the corticosteroid is not prednisone; and the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s target HSD1 occupancy by HSD1 inhibitor at a level below the target threshold.
• a method for administering a corticosteroid to a patient in need thereof comprising:
• the corticosteroid is not prednisone
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s target HSD1 occupancy by HSD1 inhibitor at a level below the target threshold.
• the corticosteroid is not prednisone
• the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s target HSD1 occupancy by HSD1 inhibitor at a level below the target threshold.
• the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 21 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 14 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 2-11 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 5-7 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 7 days.
• the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 3-4 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 4 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 3 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 2 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within a single day.
• the target HSD1 occupancy is 80%. In some embodiments, the target HSD1 occupancy is 90%. In some embodiments, the HSD1 occupancy is determined for the brain. In some embodiments, the HSD1 occupancy is determined for adipose tissue. In some embodiments, the HSD1 occupancy is determined for liver. In some embodiments, the HSD1 occupancy is determined for more than one tissue. In some embodiments, the HSD1 occupancy is determined from using an imaging method. In some embodiments, the imaging method is positron emission tomography (“PET”) following administration of a radiolabeled HSD1 ligand as a tracer.
• PET positron emission tomography
• the HSD1 ligand is [ n C] AS2471907 (3-(2-chlorophenyl)-4-(methyl- n C)-5-[2-[2,4,6- trifluorophenoxy]propan-2-yl]-4H-l, 2, 4-triazole).
• the imaging method is similar to the method disclosed in Gallezot, J.-D. J Nucl. Med. 2019, jnumed-118.
• the HSD1 occupancy in adipose tissue is determined from a biopsy of adipose tissue.
• a pharmaceutical product comprising a HSD1 inhibitor and a corticosteroid, wherein the corticosteroid is not prednisone; and the HSD1 inhibitor is 4- ⁇ 5- [ 1 -(4-chloro-2,6-difluorophenoxy)- 1 -methy lethy 1] -4-methy 1-4H- 1 ,2,4-triazol-3 -y 1-3- fluorobenzamide or a pharmaceutically acceptable salt thereof (Compound A) or N-[5- (aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]-a,a-dimethyl-4-[5-(trifluoromethyl)-2- pyridinyl]-l-piperazineacetamide (Compound B).
• the pharmaceutical product is for intravenous or intramuscular administration.
• the pharmaceutical product is for oral administration.
• the pharmaceutical product comprises a combined preparation wherein the HSD1 inhibitor and the corticosteroid are co-formulated.
• the combined preparation is a tablet having two or more layers, wherein each of the HSD1 inhibitor and the corticosteroid are in different layers, optionally separated by a barrier layer.
• the combined preparation is a tablet having a core-shell configuration wherein the core comprises the HSD1 inhibitor and the shell comprises the corticosteroid, wherein the core and shell are optionally separated by a barrier layer.
• the combined preparation is a tablet having a core-shell configuration wherein the core comprises the corticosteroid and the shell comprises the HSD1 inhibitor, wherein the core and shell are optionally separated by a barrier layer.
• the combined preparation is a capsule containing the HSD1 inhibitor and the corticosteroid.
• the combined preparation is a combination of mini -tablets comprising the HSD1 inhibitor and mini -tablets comprising the corticosteroid.
• the pharmaceutical product comprises a combined preparation wherein the HSD1 inhibitor and the corticosteroid are co-packaged.
• the HSD1 inhibitor is formulated for oral administration and the corticosteroid is administered for intramuscular administration.
• the HSD1 inhibitor is Compound A, and is formulated for oral administration. In some embodiments, the HSD1 inhibitor is Compound B, and is formulated for oral administration.
• the HSD1 inhibitor is formulated as oral tablets. In some embodiments, the HSD1 inhibitor is formulated as oral tablets with a dosage of the HSD1 inhibitor chosen from 0.1, 0.2, 0.4, 0.7, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 and 6.0 mg. In some embodiments, the HSD1 inhibitor is formulated as oral tablets with Compound A. In some embodiments, the HSD1 inhibitor is formulated as oral tablets with Compound B.
• the pharmaceutical product comprises a twin pack.
• the pharmaceutical product comprises a kit comprising a first portion comprising the HSD1 inhibitor and a second portion comprising the
• the pharmaceutical product comprises a kit comprising a dosage form of HSD1 inhibitor at a loading dose and one or more dosage forms of the HSD1 inhibitor at a maintenance dose and one or more dosage forms of the corticosteroid.
• the pharmaceutical product comprises the following: (1) a loading dose of the HSD1 inhibitor together with six dosage forms comprising an amount of corticosteroid, which is to be administered on the first day; (2) a maintenance dose of the HSD1 inhibitor together with five dosage forms comprising the corticosteroid, which is to be administered on the second day; (3) a maintenance dose of the HSD1 inhibitor together with four dosage forms comprising the corticosteroid, which is to be administered on the third day; (4) a maintenance dose of the HSD1 inhibitor together with three dosage forms comprising the corticosteroid, which is to be administered on the fourth day; (5) a maintenance dose of the HSD1 inhibitor together with two dosage forms comprising the corticosteroid, which is to be administered on the fifth day; and (6) a maintenance dose of the HSD1 inhibitor together with one dosage form comprising the corticosteroid, which is to be administered on the sixth day.
• the loading dose of the HSD1 inhibitor is administered as six split doses wherein one of the split doses is administered with each of the dosage forms comprising the corticosteroid.
• the split dose is co-formulated with the dosage form comprising the corticosteroid.
• the maintenance dose of the HSD1 inhibitor is administered as split doses with each of the split doses co-formulated with the dosage forms comprising the corticosteroid. For example, on the third day, the maintenance dose of the HSD1 inhibitor is divided into four split doses, with each of the split doses being administered with a dosage form of the corticosteroid.
• the split maintenance dose of the HSD1 inhibitor is co-formulated with the corticosteroid.
• the pharmaceutical product further comprises one or more excipients.
• excipients such as binding agents, fillers, acceptable wetting agents, tabletting lubricants, and disintegrants can be used in tablets and capsules for oral administration.
• compositions for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
• compositions for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
• the compositions for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
• the compositions for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
• the compositions for oral can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
• administration can be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavorings and colorants can be added.
• compositions for intravenous or intramuscular administration can be prepared by dissolving the compounds in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampoule. These are just a few examples of the many appropriate methods well known in the art for preparing compositions for oral, intravenous or intramuscular administration.
• tetrahydrocortisone was used as an indicator of HSD-1 activity.
• Compound A decreased the 5a-tetrahydrocortisol + 5p-tetrahydrocortisol to urinary tetrahydrocortisone ratio with increasing dose compared to placebo, resulting in approximately 80% inhibition at 6 mg. Increasing the dose above 6 mg did not substantially increase the level of inhibition.
• Compound A after a standard breakfast was administered on Day 1, followed by daily doses on Days 7 through 20 (2 mg and 0.7 mg cohorts, FIG. 2) or on Days 2 through 14 (0.4 and 0.2 mg cohorts, FIG. 3). Urine samples were collected on multiple days.
• Compound A significantly decreased HSD-1 activity.
• a population pharmacokinetics model (FIG. 4) was developed using a maximal dose of 20 mg.
• the selected model to describe the pharmacokinetics of Compound A was a two-compartment disposition model, with a 4-compartment transit absorption, saturable binding from the central compartment, and first-order elimination. Inter-individual variability was implemented on clearance (CL), volume of distribution (V2), absorption rate constant (kA), second order association constant (Kon), first order dissociation constant (Kofi), and total number of saturable binding receptors (R). This model had satisfactory goodness-of-fit and acceptable relative standard errors.
• CL, kA, R, Kon, and Koff are defined above.
• BAV is relative bioavailabibty
• kTR is a transit rate constant (equal to kA)
• k23 and k32 are transfer rate constants between central and peripheral compartments.
• the estimated total number of saturable binding receptors corresponds to 1.347 mg of Compound A.
• Example 3 Brain occupancy by Compound A
• Example 1 The population pharmacokinetic model of Example 1 was used to simulate brain HSD-1 occupancy following single and multiple doses of SPI-62. Results are shown in FIG.
• FIG. 6 (3 mg initial dose, then (a) 1 mg QD; (b) 0.1 mg QD), FIG. 7 (4 mg initial dose, then (a) 1 mg QD; (b) 0.1 mg QD), and FIG. 8 (3 x 1 mg initial doses, then 0.1 mg QD).
• mice typically prefer to explore the novel arm of a Y-maze, a behavior considered indicative of short-term memory.
• Corticosterone (CS) decreases the percentage of times mice enter the novel arm of a Y maze, and so is considered to have a negative cognitive effect.
• Single doses of 0.3 to 3 mg/kg Compound A (FIG. 10(d) - (1)) restored a more normal behavior pattern.
• Example 7 Dose scenarios in clinical practice
• an initial dose of more than 4 mg of Compound A e.g., 6 mg
• daily doses of more than 0.1 mg of Compound A e.g., 0.2 to 2 mg
• full HSD-1 inhibition throughout the course of treatment could be achieved by a fixed dose combination of a corticosteroid with an amount (N) of a HSD-1 inhibitor wherein 6N is sufficient to achieve full HSD-1 inhibition concurrently with the first corticosteroid dose.
• a fixed dose combination such that the amount of Compound A in six dosage forms is more than 4 mg (e.g., 0.7 to 1 mg) could be selected.
• an intramuscular dose of 40 to 240 mg methylprednisolone or an intralesional dose of 20 to 160 mg methylprednisolone can be expected to have substantial pharmacologic effect for at least 5 to 10 days.
• a single oral dose of more than 4 mg of Compound A (e.g., 6 mg) could be expected to rapidly achieve full HSD-1 inhibition and maintain substantial HSD-1 inhibition for at least 5 to 10 days.
• Example 8 Dosage Formulation for Tablets with 1 mg Compound A

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