WO2018191628A1 - Multithérapies médicamenteuses pour le traitement de la tuberculose - Google Patents

Multithérapies médicamenteuses pour le traitement de la tuberculose Download PDF

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Publication number
WO2018191628A1
WO2018191628A1 PCT/US2018/027505 US2018027505W WO2018191628A1 WO 2018191628 A1 WO2018191628 A1 WO 2018191628A1 US 2018027505 W US2018027505 W US 2018027505W WO 2018191628 A1 WO2018191628 A1 WO 2018191628A1
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Prior art keywords
opc
rifampicin
clofazimine
pyrazinamide
ethambutol
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PCT/US2018/027505
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English (en)
Inventor
Chih-Ming Ho
Marcus Aaron HORWITZ
Aleidy Marlene Silva VITE
Xianting DING
Daniel L. Clemens
Bai-Yu Lee Clemens
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The Regents Of The University Of California
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Publication of WO2018191628A1 publication Critical patent/WO2018191628A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • a pharmaceutical composition comprising, or alternatively consisting essentially of, or yet consisting of, a pharmaceutically effective amount of each drug in a drug combination, wherein the drug combination comprises, or consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide; and wherein the drug combination optionally further comprises, consists essentially of, or yet consists of, a pharmaceutically effective amount of one drug selected from OPC, A/C, or SQ109.
  • a composition comprising, or alternatively consisting essentially of, or yet consisting of, a pharmaceutically effective amount of each drug in a drug combination selected from the group of drug combinations 1-176 tabulated in Table 1.
  • Mycobacterium tuberculosis Mycobacterium bovis, Mycobacterium africanum,
  • Mycobacterium canetti or Mycobacterium microti, in a cell infected therewith, comprising, or alternatively consisting essentially of, or yet consisting of, contacting the cell with an effective amount of a pharmaceutical composition described herein.
  • TB tuberculosis
  • a method of treating tuberculosis (TB) in a subject in need thereof comprising, or alternatively consisting essentially of, or yet consisting of, administering to the subject an effective amount of a pharmaceutical composition described herein.
  • compositions as described herein for use in the treatment of tuberculosis (TB) in a subject in need thereof.
  • PRS Parabolic Response Surface
  • TB tuberculosis
  • patient demographic e.g., child, adult, pregnant, HIV-positive, and so forth.
  • the two main classifications of TB treatment are "first-line” and "second-line”.
  • First-line treatment of drug-sensitive TB is a 4-drug regimen: isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB).
  • IH isoniazid
  • RAF rifampin
  • PZA pyrazinamide
  • EMB ethambutol
  • Second-line treatments used to treat drug-resistant TB utilize 3-5 other drugs in combination:
  • FDCs used for TB treatment include Rifater [isoniazid (INH), pyrazinamide (PZA), and rifampicin (RIF)] and Rifamate [isoniazid (INH) and rifampin (RIF)].
  • MDR-TB Multi-drug resistant TB
  • MDR-TB is a categorization of strains of TB that are resistant to at least both isoniazid and rifampicin. MDR-TB arises from inappropriate treatment such as: use of poor quality medicines, administration of improper treatment regimens, and failing to ensure the patient has completed the whole course of treatment. Because MDR-TB is due to bacteria resistant to the two most powerful first-line anti-TB drugs, MDR-TB patients are then treated with first- line drugs to which the strain is sensitive plus several second-line drugs.
  • XDR-TB Extensively drug-resistant TB
  • MDR-TB is specified as MDR-TB that is additionally resistant to several other classes of anti-TB drugs including the most effective second-line anti-TB drugs. It is estimated that about 9.6% of reported MDR-TB cases are XDR-TB.
  • Embodiments of this disclosure are directed to a combination of drugs in respective doses, uses thereof and methods therewith for treating TB, and a method for determining the optimum drug doses in the combination.
  • the method for determining the optimum drug doses in the combination involves three stages. First, the optimal drug-dose combinations are determined on the basis of in vitro studies on the efficacy of various drug-dose combinations in inhibiting and in killing Mycobacterium tuberculosis, using a Parabolic Response Surface (PRS) [formerly Feedback System Control (FSC)] optimization scheme.
  • PRS Parabolic Response Surface
  • FSC Feedback System Control
  • the terms “substantially” and “about” are used to describe and account for small variations.
  • the terms can refer to instances in which the event or circumstance occurs precisely as well as instances in which the event or circumstance occurs to a close approximation.
  • the terms can refer to a range of variation of less than or equal to ⁇ 10% of that numerical value, such as less than or equal to ⁇ 5%, less than or equal to ⁇ 4%, less than or equal to ⁇ 3%, less than or equal to ⁇ 2%, less than or equal to ⁇ 1%), less than or equal to ⁇ 0.5%, less than or equal to ⁇ 0.1%, or less than or equal to ⁇ 0.05%.
  • a range of about 1 to about 200 should be understood to include the explicitly recited limits of about 1 and about 200, but also to include individual values such as about 2, about 3, and about 4, and sub-ranges such as about 10 to about 50, about 20 to about 100, and so forth.
  • clofazimine corresponds to N,5-bis(4- chlorophenyl)-3-(propan-2-ylimino)-3,5-dihydrophenazin-2-amine, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • ethambutol corresponds to (2,S',2' ) S)-2,2'-(ethane- l,2-diyldiimino)dibutan-l-ol, and is represented by the following structure, or a
  • pretomanid corresponds to (6,S)-2-nitro-6- ⁇ [4- (trifluoromethoxy)benzyl]oxy ⁇ -6,7-dihydro-5H-imidazo[2,l- ⁇ ][l,3]oxazine, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • pyrazinamide corresponds to pyrazine-2- carboxamide, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • rifampin is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • SQ109 corresponds to N-adamantan ⁇ -yl-N'- ⁇ ⁇ -S,?- dimethyl-octa-2,6-dienyl)-ethane-l,2-diamine, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • bedaquiline corresponds to (li?,2,S)-l-(6-bromo-2- methoxy-3-quinolyl)-4-dimethylamino-2-(l-naphthyl)-l-phenyl-butan-2-ol, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • amoxicillin corresponds to (2S,5R, 6R)-6- ⁇ [(2R)-2-amino- 2-(4-hydroxyphenyl)-acetyl]amino ⁇ -3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane- 24-carboxylic acid, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • clavulanic acid corresponds to (2R,5R,Z)-3-(2- hydroxyethylidene)-7-oxo-4-oxa-l-aza-bicyclo[3.2.0]heptane-2-carboxylic acid, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • delamanid corresponds to (2R)-2- methyl-6-nitro-2-[(4- ⁇ 4-[4-(trifluoromethoxy)phenoxy]-l-piperidinyl ⁇ phenoxy)methyl]-2,3- dihydroimidazo[2, l-6][l,3]oxazole, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • linear corresponds to (,S)-N-( ⁇ 3-[3-fluoro-4-(morpholin-4- yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl ⁇ methyl)acetamide and is represented by the following structure or a pharmaceutically acceptable salt thereof:
  • Tautomers refer to isomeric forms of a compound that are in equilibrium with each other.
  • concentrations of the isomeric forms will depend on an environment in which the compound is found and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.
  • pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • Stereoisomers of compounds also referred to as “optical isomers,” include all chiral, diastereomeric, and racemic forms of a chemical structure, unless the specific stereochemistry is expressly indicated.
  • compounds used in some embodiments include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions.
  • racemic and diastereomeric mixtures, as well as individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of this disclosure.
  • pharmaceutically acceptable refers to a material that is not
  • the material may be incorporated into a pharmaceutical composition administered to a patient without causing undesirable biological effects or interacting in a deleterious manner with any of other components of the
  • composition in which it is contained is contained.
  • pharmaceutically acceptable is used to refer to a pharmaceutical carrier or excipient, the carrier or excipient is one that has met standards of toxicological and manufacturing testing or that is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • extrapolation technique refers to extrapolation types including, but not limited to linear extrapolation, polynomial, conic section or French curve extrapolation.
  • Pharmacokinetic data for drugs disclosed herein includes data comprising serum levels, tissue levels, metabolism, binding affinities, and bioavailability. Pharmacokinetic data may be acquired through analytical techniques including but not limited to immunoassay, mass spectrometry, MR spectroscopy, spectrophotometry, chromatography, diode array detection, capillary electrophoresis, enzyme linked immunosorbent assay, or
  • Macrophage refers to a type of phagocytotic white blood cell of the immune system. Such machines can perceive their environment and take actions based on what is perceived.
  • AI Artificial Intelligence
  • Machines with AI may display treats such as learning and memory.
  • an "effective amount” is an amount sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations or applications. Such delivery is dependent on a number of variables including the time period for which the individual composition is to be used, the bioavailability of the therapeutic agents included with the composition, the route of administration, etc. It is understood, however, that specific dose levels of the additional therapeutic agents disclosed herein for any particular subject depends upon a variety of factors including the activity of the specific compound employed, bioavailability of the compound, the route of administration, the age of the animal/subject and its body weight, general health, sex, the diet of the animal/subject, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration.
  • terapéuticaally effective amount or “pharmaceutically effective amount” is an amount sufficient to treat a specified disorder or disease or alternatively to obtain a pharmacological response such as immunosuppression, osteogenesis, bone resorption or mineralization.
  • patient refers to any animal for which treatment is desirable. Patients may be mammals, and typically, as used herein, a patient is a human individual. "Patient” and “subject” are to be understood to be interchangeable.
  • TB inhibition refers to a percentage determined via an inhibition assay, also referred to herein as a “treatment test” described in the working examples which quantifies bacteria via fluorescence or alternatively, by the quantification or colony forming unites (CFUs) as described in the working examples.
  • Administration or treatment in “combination” refers to administering two agents such that their pharmacological and/or therapeutic effects are manifest at the same time. Combination does not require administration at the same time or substantially the same time, although combination can include such administrations. Combination can include sequential administration.
  • Replication refers to the division of bacterial cells or the replication, copying, or transcription of their genetic material including deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and the like.
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • Contacting refers to introduction of a drug, agent, or
  • treating or “treatment” of a disease in a subject refers to (1) preventing the symptoms or disease from occurring in a subject that is predisposed or does not yet display symptoms of the disease; (2) inhibiting the disease or arresting its development; or (3) ameliorating or causing regression of the disease or the symptoms of the disease.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired results can include one or more, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of a condition (including a disease or trauma), stabilized (i.e., not worsening) state of a condition (including disease or trauma), delay or slowing of condition (including disease or trauma), progression, amelioration or palliation of the condition (including disease or trauma), states and remission (whether partial or total), whether detectable or undetectable.
  • inhibitors refer to attenuating, halting, reversing or attenuating the acceleration of that to which they refer. As used herein these terms may refer to attenuating, halting, reversing or attenuating the acceleration of bacterial replication or killing the bacteria.
  • administering intends local or systemic administration.
  • administration is systemic via, intracerebroventricular, intrathecal, topical, intravenous, intranasal, subcutaneous, intramuscular, or transdermal administration.
  • Local administration is surgical implantation of the compositions described herein.
  • Administration may be accomplished implanting the pharmaceutical composition directly or coating or impregnating a surgical implant or prosthesis with the pharmaceutical
  • compositions of the disclosure may be implanted anywhere throughout the body
  • Drug drugs
  • drugs and the like or “compound,” “compounds” and the like, as used herein, refers to a substance administered to a subject. Drugs of this disclosure are tabulated in Table 1 and described herein. A combination of two substances may together be referred to as a single "drug,” for example the combination of amoxicillin/clavulanic acid (A/C), is a "drug.”
  • A/C amoxicillin/clavulanic acid
  • drug-dose combination refers to a data set including a drug combination and a dose for each respective drug of the drug combination.
  • the doses for each drug in a drug dose-combination can be determined by methods described herein, for example PRS optimization scheme, in vitro, or in vivo testing.
  • a drug dose combination can be expressed in terms of a specific mass or concentration in a solution for each drug.
  • the drug dose combination can be expressed as a ratio of the drugs of a combination.
  • Various drug dose combinations are tabulated in Table 4 herein.
  • Drug combination refers to a combination of three or more drugs which together comprise the "pharmaceutical composition" of the disclosure.
  • Each row 1-176 of Table 1 discloses a "drug combination.”
  • the first row of Table 1 discloses the drug combination: ethambutol, PA824, rifampicin and OPC.
  • a " pharmaceutical composition” typically intends a combination of the active agent(s), e.g., drug(s), and a naturally-occurring or non-naturally-occurring carrier, inert (for example, a detectable agent or label) or active, such as an adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include pharmaceutically acceptable carriers.
  • active agent(s) e.g., drug(s)
  • a naturally-occurring or non-naturally-occurring carrier for example, a detectable agent or label
  • active such as an adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include pharmaceutically acceptable carriers.
  • Carriers also include pharmaceutical excipients and additives proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, tetra-oligosaccharides, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1-99.99% by weight or volume.
  • Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid/antibody
  • components which can also function in a buffering capacity, include alanine, arginine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like.
  • Carbohydrate excipients are also intended within the scope of this technology, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D- mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol.
  • monosaccharides such as fructose, maltose, galactose, glucose, D- mannose, sorbose, and the like
  • disaccharides such as lactose, sucrose
  • salts or zwitterionic forms of compounds of some embodiments which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic-response, which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
  • the salts can be prepared during a final isolation and purification of the compounds or separately by reacting an appropriate compound in the form of a free base with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, di gluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3- phen
  • basic groups in the compounds of some embodiments can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, this disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds of some embodiments and the like.
  • solvates include hydrates formed when a compound of some embodiments contains one or more bound water molecules.
  • Some embodiments of this disclosure include various combinations of known drugs.
  • the combinations show improved efficacy against TB compared with conventional treatments.
  • multiple optimal drug-dose combinations are determined on the basis of in vitro studies and PRS analysis.
  • Certain embodiments of drug combinations have been evaluated on the basis of in vitro TB treatment tests, and achieve > 60% projected TB inhibition.
  • a pharmaceutical composition comprising, or alternatively consisting essentially of, or yet consisting of, a pharmaceutically effective amount of each drug in a drug combination, wherein the drug combination comprises, or consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide; and wherein the drug combination optionally further comprises, consists essentially of, or yet consists of, a pharmaceutically effective amount of one drug selected from OPC, A/C, or SQ109.
  • the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and OPC. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and A/C. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and SQ109.
  • a drug combination is selected from one of the following drug combinations of Table 1, 1-176:
  • the pharmaceutical composition comprises, consists essentially of, or yet consists of one or more carriers.
  • the drugs are combined into a single solid dose formulation.
  • the drugs are present in the same ratio as they are in each drug-dose combination of Table 4.
  • the pharmaceutical composition comprises, consists essentially of, or yet consists a drug dose combination corresponding to a row of Table 4.
  • the drugs are in solution at a concentration according to Table 4.
  • the drugs in the pharmaceutical composition are present in a ratio of their concentrations in Table 4 relative to each other.
  • the drug combinations provide at least one of a number of benefits, including one or more of the following.
  • the drug combinations are treatment combinations that can have higher efficacy than other drug combinations used for TB treatment.
  • the drug combinations provide alternative combinations for the treatment of drug-resistant TB, and also allow faster treatment of drug-resistant TB. Since many of the drug combinations do not include INH and RTF, alternative regimens can be developed that are suitable for the treatment of many cases of MDR-TB. Surprisingly, even though many of the drug combinations do not include the two most powerful first-line anti-TB drugs, INH and RTF, those combinations are shown to be superior to the standard regimen.
  • the regimens do not include, or can omit, fluoroquinolones or aminoglycosides
  • the regimens also can be useful for treatment of many cases of XDR-TB.
  • current drug treatment regimen generally requires 6-8 months of treatment. Treatment of drug-resistant strains takes even longer, typically 24 months. Because treatment is so prolonged, patient compliance is often poor. Poor patient compliance increases the likelihood of drug resistance developing.
  • the proposed drug-dose combinations of this disclosure allow more rapid and more efficacious treatment of both drug-sensitive and drug-resistant TB and greater patient compliance.
  • a pharmaceutical composition comprising, or alternatively consisting essentially of, or yet consisting of, a pharmaceutically effective amount of each drug in a drug combination, wherein the drug combination comprises, or consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide; and wherein the drug combination optionally further comprises, consists essentially of, or yet consists of, a pharmaceutically effective amount of one drug selected from OPC, A/C, or SQ109; for use in the treatment of TB in a subject in need thereof.
  • the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and OPC. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and A/C. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and SQ109.
  • the pharmaceutical composition comprises, consists essentially of, or yet further consists of a drug combination that has been evaluated on the basis of in vitro treatment tests, and achieves greater than or equal to 60% projected TB inhibition.
  • treatment comprises, consists essentially of, or yet further consists of administering two or more drugs of the drug combination sequentially. In some embodiments, treatment comprises, consists essentially of, or yet further consists of administering two or more drugs of the drug combination concurrently.
  • the subject is a mammal, including, for example, farm animals, sheep, pigs, cows, horses, pets, dogs, cats; laboratory animals, rats, mice and rabbits.
  • the mammal is a bovine, a feline, a canine, a murine, an equine, or a human .
  • the mammal is a human.
  • TB that is treated is caused by Mycobacterium
  • tuberculosis In other embodiments, the tuberculosis treated is caused by other species in the Mycobacterium tuberculosis complex. In some embodiments, the tuberculosis (TB) is caused by Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, or
  • TB is drug-sensitive TB or MDR-TB or XDR-TB. In some embodiments the TB is active TB. In some embodiments the TB is miliary TB. In some embodiments, the TB is pulmonary TB. In some embodiments the TB is latent TB.
  • the drugs are each independently administered once a day, twice a day or three times a day. In some embodiments, each drug's administration is independently continued for 2 or 4 or 6 or 8 weeks or more, or one, two, three, four or five months or more, or any value therein between. In some embodiments each drug's administration is independently continued for less than 6 months, or less than 9, 12, 15, 18, 21 or 24 months.
  • Some embodiments of this disclosure include methods of treating TB in a patient or other subject in need thereof, comprising, or alternatively consisting essentially of, or yet further consisting of, administering to the patient a pharmaceutically effective amount of a pharmaceutical composition or drug combination described herein.
  • the drug combination has been evaluated on the basis of in vitro treatment tests, and achieves greater than or equal to 60% projected TB inhibition.
  • the combination comprises, or alternatively consists essentially of, or yet further consists of one of the drug combinations selected from drug combinations 1-176 in Table 1.
  • Drugs in a drug combination used in the methods of some embodiments are administered sequentially or concurrently. In some embodiments, one, two, three, or four of drugs of a selected drug combination are administered sequentially. In some embodiments, one or two or three or four of the drugs of the selected drug combination are administered concurrently.
  • An administration schedule of the methods of some embodiments may be in a manner that provides a desirable therapeutic effect. For example, in some embodiments, a combination is administered once a day, twice a day or three times a day. In some embodiments, administration is continued for 2 or 4 or 6 or 8 weeks or more, or one, two, three, four or five months or more, or any value therein between. In some embodiments, the duration of treatment is less than 6 months of treatment, or less than 9, 12, 15, 18, 21 or 24 months.
  • a subject in need thereof is a mammal.
  • the mammal can be any mammal, including, for example, farm animals, sheep, pigs, cows, horses, pets, dogs, cats; laboratory animals, rats, mice and rabbits.
  • the mammal is a bovine, a feline, a canine, a murine, an equine, or a human .
  • the mammal is a human.
  • TB that is treated is caused by Mycobacterium
  • tuberculosis In other embodiments, the tuberculosis treated is caused by other species in the Mycobacterium tuberculosis complex. In some embodiments, the tuberculosis (TB) is caused by Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, or
  • TB is drug-sensitive TB or MDR-TB or XDR-TB. In some embodiments the TB is active TB. In some embodiments the TB is miliary TB. In some embodiments the TB is latent TB. In some embodiments the TB is latent TB.
  • a method of treating MDR-TB in a subject in need thereof comprising determining if a subject is infected with MDR-TB, and administering to the subject identified as infected with MDR-TB a pharmaceutical composition herein.
  • a method for treating MDR-TB in a subject in need thereof comprising administering a pharmaceutical composition herein, to the subject identified as being infected with MDR-TB.
  • a method of treating XDR-TB in a subject in need thereof comprising determining if a subject is infected with XDR-TB, and administering to the subject identified as infected with XDR-TB a pharmaceutical composition herein.
  • a method for treating XDR-TB in a subject in need thereof comprising administering a pharmaceutical composition herein to the subject identified as being infected with XDR-TB.
  • kits of drug combinations or as fixed dose combinations (FDCs) along with a pharmaceutically acceptable carrier or excipient.
  • FDCs fixed dose combinations
  • drugs in drug combinations can be combined into a single solid dose formulation for treating TB.
  • liquid or solid dose formulations may be used.
  • oral dose formulations include tablets, gelatin capsules, pills, troches, elixirs, suspensions, syrups, wafers, chewing gum and the like.
  • the compounds of some embodiments can be mixed with a suitable pharmaceutical carrier (vehicle) or excipient as understood by practitioners in the art.
  • suitable pharmaceutical carrier include starch, milk, sugar, certain types of clay, gelatin, lactic acid, stearic acid or salts thereof, including magnesium or calcium stearate, talc, vegetable fats or oils, gums and glycols.
  • formulations of the compounds useful in the methods of some embodiments may utilize conventional diluents, carriers, or excipients, which can be employed to deliver the compounds.
  • the formulations may comprise one or more of the following: a stabilizer, a surfactant (such as a nonionic, ionic, anionic, or zwitterionic surfactant), and optionally a salt and/or a buffering agent.
  • the compounds may be administered in the form of a solution, suspension, or in a reconstituted lyophilized form.
  • a stabilizer may be, for example, an amino acid, such as glycine; or an oligosaccharide, such as sucrose, trehalose, lactose or a dextran.
  • the stabilizer may be a sugar alcohol, such as mannitol; or a combination thereof.
  • Other stabilizers may include Beeswax, butylated hydroxytoluene, citric acid, ethyl vanillin, gelatin, glycerin, iron oxide, lecithin, p-methoxy acetophenone, parabens, plant oils, and propylene glycol.
  • the stabilizer or combination of stabilizers constitutes from about 0.1% to about 10% by weight/weight of a formulation.
  • a surfactant is a nonionic surfactant, such as a polysorbate.
  • suitable surfactants include polysorbates (e.g., Tween20, Tween80); a polyethylene glycol or a polyoxyethylene polyoxypropylene glycol, such as Pluronic F-68 at from about 0.001%) by weight/volume (w/v) to about 10%> (w/v).
  • a salt or buffering agent may be any suitable salt or buffering agent, such as sodium chloride, or sodium/potassium phosphate, respectively.
  • the buffering agent maintains the pH of the pharmaceutical composition in the range of about 5.5 to about 7.5.
  • the salt and/or buffering agent is also useful to maintain the osmolality at a level suitable for administration to a human or other animal.
  • the salt or buffering agent is present at a roughly isotonic concentration of about 150 mM to about 300 mM.
  • the formulations of the compounds useful in the methods of this disclosure may additionally comprise one or more conventional additives.
  • additives include a solubilizer such as glycerol or hydroxypropyl-cyclodextrin; an antioxidant such as benzalkonium chloride (a mixture of quaternary ammonium compounds, referred to as "quats"), benzyl alcohol, chloretone or chlorobutanol; anesthetic agent such as a morphine derivative; or an isotonic agent.
  • a solubilizer such as glycerol or hydroxypropyl-cyclodextrin
  • an antioxidant such as benzalkonium chloride (a mixture of quaternary ammonium compounds, referred to as "quats"), benzyl alcohol, chloretone or chlorobutanol
  • anesthetic agent such as a morphine derivative
  • the formulations of the compounds useful in the methods of this disclosure are contained in a single vehicle (e.g., a single oral dose form).
  • a single oral dose formulation e.g., a single tablet, gelatin capsule, pill, troche, elixir, suspension, and so forth.
  • Stimulations can be applied to direct a complex system towards a desired state, such as applying drugs to treat a patient.
  • the types and the amplitudes (e.g., doses) of applying these stimulations are part of input parameters that can affect the efficiency in bringing the system towards the desired state.
  • N types of different drugs with different drug-doses for each drug will result in A f possible "drug-dose combinations.”
  • To identify an optimized or even near optimized combination by multiple tests of all possible drug-dose combinations is prohibitive in practice. For example, it is not practical to perform all the possible drug-dose combinations in in vitro or in vivo tests for finding an effective drug-dose combination as the number of drugs and dosages increase.
  • Embodiments of this disclosure apply a technique that allows a rapid search for optimized combinations of input parameters to guide multi-dimensional (or multivariate) systems with multiple input parameters toward their desired states.
  • the technique is comprised of a multi-dimensional complex system whose state is affected by input parameters along respective dimensions of a multi-dimensional parameter space.
  • the technique can efficiently operate on a large pool of input parameters (e.g., a drug pool), where the input parameters can involve complex interactions both among the parameters and with the complex system.
  • a search technique can be used to identify at least a subset, or all, optimized combinations or sub-combinations of input parameters that produce desired states of the complex system.
  • a parameter space sampling technique e.g., an experimental design methodology
  • a parameter space sampling technique can guide the selection of a minimal or reduced number of tests to expose salient features of the complex system being evaluated, and to reveal a combination or subcombination of input parameters of greater significance or impact in affecting a state of the complex system.
  • the is within Mycobacterium tuberculosis a macrophage.
  • the PRS optimization scheme is an Artificial Intelligence (AI) based PRS optimization scheme.
  • testing in step b) is done to reoptimize the in vivo doses.
  • an output (or a cost function) ⁇ is specified for a complex biological system being evaluated.
  • the output can be a function of X, which is a vector of input parameters in an input parameter space (e.g., a combination of doses of drugs sampled according to an experimental design methodology), and can be specified as an efficacy of a combinatorial drug or a percentage of inhibition.
  • Other outputs can be defined, such as a therapeutic window based on a viability of healthy control cells subjected to X and a viability of diseased cells subjected to X, where the former corresponds to safety of X, and the latter corresponds to efficacy of X, or including an interaction effect among drugs of X, to account for whether the drugs interact synergistically, antagonistically, or when the effect of the drugs is additive.
  • the output ⁇ represents an overall therapeutic outcome or response to be optimized (e.g., enhanced or maximized), and includes a combination (e.g., a weighted sum) of phenotypic contributions or responses, including either, or both, safety or toxicity when Xis applied to healthy control cells, and efficacy when Xis applied to diseased cells.
  • the output ⁇ can be represented as a response surface that is a function of input parameters within a multidimensional input parameter space.
  • Other relevant phenotypic contributions can be included in the output ⁇ by applying proper transformations to adjust a range and scale of the phenotypic contributions, such as those related to improved tolerance, enlarged therapeutic window, reduced drug dosages, and broad reduction of side effects.
  • phenotypic responses are desirable, such as drug efficacy or drug safety, while other phenotypic responses are undesirable, such as drug toxicity or drug side effects.
  • their weighting factors serve as penalty factors in the optimization of combinatorial drugs.
  • a response of a complex system to multiple input parameters can be represented by a low order function, such as a second order (or quadratic) equation, although a first order (or linear) equation as well as a third order (or cubic) equation are also contemplated as possible low order equations. Also, higher order functions are contemplated for other embodiments.
  • a low order function such as a second order (or quadratic) equation
  • a first order (or linear) equation as well as a third order (or cubic) equation are also contemplated as possible low order equations.
  • higher order functions are contemplated for other embodiments.
  • X is a dose of an z 'th drug from the pool of N drugs being evaluated
  • ⁇ is a coefficient representing a baseline response
  • ? is a coefficient representing a single drug response contribution
  • a coefficient is a coefficient.
  • i ⁇ j the terms represent drug-drug interaction contributions.
  • a total number of parameters m is 1 + 2N+ (N(N - l))/2. If one drug dose is kept constant in the evaluation, the number of parameters m can be further reduced to 1 + 2(TV- 1) +((N- l)(N- 2))/2, for TV > 1.
  • Table 2 sets forth a total number of coefficients in a quadratic cost function with respect to a total number drugs in a pool of drugs being evaluated.
  • An experimental design methodology is used to guide the selection of tests to sample an input parameter space.
  • the experimental design methodology can allow exposure of salient features of a complex system being evaluated, and can reveal a combination or subcombination of input parameters of greater significance or impact in affecting a state of the complex system. Selection of the experimental design methodology can be according to a particular cost function of the complex system being evaluated. Examples of experimental design methodologies include Latin hypercube sampling, central composite design, d-optimal design, orthogonal array design, full factorial design, and fractional factorial design, among others.
  • an experimental design methodology can be used to guide the selection of drug dosages for in vitro tests. In connection with the experimental design methodology, possible doses can be narrowed down into a few discrete levels.
  • therapeutic outcomes e.g., phenotypic responses
  • therapeutic outcomes are measured by testing each combination of input parameters sampled according to the experimental design methodology, such as by applying each combination of drug doses in vitro.
  • a representation of the cost function is fitted using values of the cost function measured or derived from the test results. Fitting of the cost function can be carried out by linear regression, Gaussian process regression, support vector machine regression, Bayesian regression, or another suitable technique. Based on the fitting performance between the test results and the fitted representation of the cost function, additional tests can be conducted to improve the accuracy of the fitted representation.
  • a globally or locally optimized combination of input parameters is determined or predicted using the fitted representation, such as by locating extrema using a stochastic or a deterministic optimization technique. Examples of stochastic techniques include simulated annealing, Markov chain Monte Carlo (MCMC), genetic optimization, differential evolution, and Gur game, among others. Examples of deterministic techniques include steepest descent and conjugate gradient, among others.
  • An optimized combination of input parameters predicted from a fitted representation can be experimentally verified, such as by applying the optimized combination in vitro, in vivo, or in clinical/human tests.
  • the significance of each input parameter and its synergistic effect with other input parameters can be identified.
  • Non-significant input parameters that have little or no impact in affecting a state of a complex system can be dropped or omitted from an initial pool of input parameters, thereby effectively converting an initial multi-dimensional system to a refined system with a lower dimensionality.
  • non-significant drugs can be identified as having low or negative values of the constants ?, ⁇ , ⁇ , and ⁇ , and can be dropped from an initial pool of drugs for subsequent evaluation.
  • Mtb-iGFP M tuberculosis Erdman inducible GFPuv strain
  • a pool of 15 drugs are evaluated, including the First-line drugs, Second-line Drugs, and Experimental TB drugs as follows:
  • Drug combinations are determined by experimental design methodology according to the PRS scheme. Monolayers are imaged with a high throughput
  • Table 3 PRS-projected inhibition of 3- and 4-drug combinations.
  • Table 4 tabulates the drug-dose combinations with their respective calculated inhibition.
  • Table 4 PRS-projected inhibition of 3- and 4-drug, drug dose combinations (including doses).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques comprenant diverses combinaisons de médicaments. L'invention concerne également des méthodes d'inhibition de la réplication des bactéries provoquant la tuberculose (TB) dans une cellule. Et des méthodes de traitement de la TB. L'invention concerne également des procédés de détermination d'une dose optimale de chaque médicament dans une combinaison de médicaments de l'invention.
PCT/US2018/027505 2017-04-14 2018-04-13 Multithérapies médicamenteuses pour le traitement de la tuberculose WO2018191628A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015107482A1 (fr) * 2014-01-17 2015-07-23 Piramal Enterprises Limited Association pharmaceutique pour traiter la tuberculose
WO2016073524A1 (fr) * 2014-11-03 2016-05-12 The Regents Of The University Of California Multithérapies médicamenteuses pour le traitement de la tuberculose
US20160220578A1 (en) * 2008-09-03 2016-08-04 Pfizer Inc. Combination Therapy for Tuberculosis
WO2017059411A1 (fr) * 2015-10-01 2017-04-06 Memorial Sloan-Kettering Cancer Center Inhibiteurs de la biosynthèse de la ménaquinone

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160220578A1 (en) * 2008-09-03 2016-08-04 Pfizer Inc. Combination Therapy for Tuberculosis
WO2015107482A1 (fr) * 2014-01-17 2015-07-23 Piramal Enterprises Limited Association pharmaceutique pour traiter la tuberculose
WO2016073524A1 (fr) * 2014-11-03 2016-05-12 The Regents Of The University Of California Multithérapies médicamenteuses pour le traitement de la tuberculose
WO2017059411A1 (fr) * 2015-10-01 2017-04-06 Memorial Sloan-Kettering Cancer Center Inhibiteurs de la biosynthèse de la ménaquinone

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