NZ619924B2 - Combination als therapy - Google Patents
Combination als therapy Download PDFInfo
- Publication number
- NZ619924B2 NZ619924B2 NZ619924A NZ61992412A NZ619924B2 NZ 619924 B2 NZ619924 B2 NZ 619924B2 NZ 619924 A NZ619924 A NZ 619924A NZ 61992412 A NZ61992412 A NZ 61992412A NZ 619924 B2 NZ619924 B2 NZ 619924B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- riluzole
- subject
- effective amount
- dose
- therapeutically effective
- Prior art date
Links
- 238000002560 therapeutic procedure Methods 0.000 title description 4
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 claims abstract description 148
- 229960004181 riluzole Drugs 0.000 claims abstract description 148
- 206010002026 Amyotrophic lateral sclerosis Diseases 0.000 claims abstract description 23
- 230000003247 decreasing Effects 0.000 claims abstract description 7
- 230000036499 Half live Effects 0.000 claims abstract description 5
- -1 6-Ethynyl(pentanyl)-1H-imidazo[4,5-b]pyrazine-2(3H)- one Chemical compound 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 201000010901 lateral sclerosis Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 230000037242 Cmax Effects 0.000 abstract description 20
- RSQGZEAXODVTOL-UHFFFAOYSA-N 5-ethynyl-3-pentan-3-yl-1H-imidazo[4,5-b]pyrazin-2-one Chemical compound C#CC1=CN=C2NC(=O)N(C(CC)CC)C2=N1 RSQGZEAXODVTOL-UHFFFAOYSA-N 0.000 abstract description 2
- 229950000116 Tirasemtiv Drugs 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 26
- 239000008194 pharmaceutical composition Substances 0.000 description 12
- 239000000902 placebo Substances 0.000 description 11
- 229940068196 placebo Drugs 0.000 description 11
- 230000000694 effects Effects 0.000 description 9
- 230000036231 pharmacokinetics Effects 0.000 description 9
- 210000002381 Plasma Anatomy 0.000 description 7
- 230000036470 plasma concentration Effects 0.000 description 7
- 238000004448 titration Methods 0.000 description 7
- 230000036364 AUCinf Effects 0.000 description 6
- 230000002829 reduced Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 241000229754 Iva xanthiifolia Species 0.000 description 4
- 210000002027 Muscle, Skeletal Anatomy 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229940079593 drugs Drugs 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000000275 pharmacokinetic Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000004885 tandem mass spectrometry Methods 0.000 description 4
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 3
- 210000003205 Muscles Anatomy 0.000 description 3
- 230000036823 Plasma Levels Effects 0.000 description 3
- 230000035852 Tmax Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 230000035533 AUC Effects 0.000 description 2
- 230000035785 Cl/F Effects 0.000 description 2
- 102000008144 Cytochrome P-450 CYP1A2 Human genes 0.000 description 2
- 108010074922 Cytochrome P-450 CYP1A2 Proteins 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 208000002173 Dizziness Diseases 0.000 description 2
- 206010016256 Fatigue Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 230000035633 Metabolized Effects 0.000 description 2
- 210000002161 Motor Neurons Anatomy 0.000 description 2
- 241000233805 Phoenix Species 0.000 description 2
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 230000003111 delayed Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- 230000035498 noncompartmental analysis Effects 0.000 description 2
- 239000000546 pharmaceutic aid Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000004083 survival Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- HUTNOYOBQPAKIA-UHFFFAOYSA-N 1H-pyrazin-2-one Chemical compound OC1=CN=CC=N1 HUTNOYOBQPAKIA-UHFFFAOYSA-N 0.000 description 1
- NYNKCGWJPNZJMI-UHFFFAOYSA-N 4-amino-N-(1-benzylpiperidin-4-yl)-5-chloro-2-methoxybenzamide;2-hydroxybutanedioic acid Chemical compound [O-]C(=O)C(O)CC(O)=O.COC1=CC(N)=C(Cl)C=C1C(=O)NC1CC[NH+](CC=2C=CC=CC=2)CC1 NYNKCGWJPNZJMI-UHFFFAOYSA-N 0.000 description 1
- FTALBRSUTCGOEG-VUJIMZNRSA-N 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine Chemical compound C1=C(OC(F)(F)F)C=C2S[13C]([15NH2])=[15N]C2=C1 FTALBRSUTCGOEG-VUJIMZNRSA-N 0.000 description 1
- 230000037082 AUClast Effects 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 229960000836 Amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N Amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 108009000433 Amyotrophic lateral sclerosis (ALS) Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 210000003169 Central Nervous System Anatomy 0.000 description 1
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N Diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N Imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- 230000036917 MEAN CMAX Effects 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L Magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 230000035888 Maximum plasma concentration Effects 0.000 description 1
- 230000036740 Metabolism Effects 0.000 description 1
- 210000001589 Microsomes Anatomy 0.000 description 1
- 210000000337 Motor Cortex Anatomy 0.000 description 1
- 208000005264 Motor Neuron Disease Diseases 0.000 description 1
- 206010028003 Motor neurone disease Diseases 0.000 description 1
- YSEXMKHXIOCEJA-FVFQAYNVSA-N Nicergoline Chemical compound C([C@@H]1C[C@]2([C@H](N(C)C1)CC=1C3=C2C=CC=C3N(C)C=1)OC)OC(=O)C1=CN=CC(Br)=C1 YSEXMKHXIOCEJA-FVFQAYNVSA-N 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 229940049964 Oleate Drugs 0.000 description 1
- 229940023488 Pill Drugs 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N Propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N Saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 230000037165 Serum Concentration Effects 0.000 description 1
- 210000000587 Skeletal Muscle Fibers Anatomy 0.000 description 1
- 210000000278 Spinal Cord Anatomy 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical class [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 102000004903 Troponin Human genes 0.000 description 1
- 108090001027 Troponin Proteins 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 201000004813 bronchopneumonia Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960004606 clomipramine Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 230000003412 degenerative Effects 0.000 description 1
- 230000002939 deleterious Effects 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000002440 hepatic Effects 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000030214 innervation Effects 0.000 description 1
- 230000002452 interceptive Effects 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 230000036304 kinact Effects 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 239000011776 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000035786 metabolism Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001537 neural Effects 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 229960003642 nicergoline Drugs 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 201000008125 pain agnosia Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000750 progressive Effects 0.000 description 1
- 200000000025 progressive disease Diseases 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002685 pulmonary Effects 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000001509 sodium citrate Chemical class 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 230000000152 swallowing Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000011778 trisodium citrate Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
Provided is a method for treating ALS in a subject, comprising administering to the subject a therapeutically effective amount of riluzole and a therapeutically effective amount of CK-2017357 (Tirasemtiv). Also provided are methods of reducing the variability of riluzole exposure (e.g., Cmax and/or AUC24h) in a subject, methods of reducing the variability of riluzole exposure (e.g., Cmax and/or AUC24h) between two or more subjects, methods of decreasing the total daily dose of riluzole in a subject, methods of increasing the half-life of riluzole in a subject, methods for decreasing the frequency of riluzole dosing in the subject, and methods for reducing the incidence and/or severity of adverse events in a subject treated with riluzole. AUC24h) in a subject, methods of reducing the variability of riluzole exposure (e.g., Cmax and/or AUC24h) between two or more subjects, methods of decreasing the total daily dose of riluzole in a subject, methods of increasing the half-life of riluzole in a subject, methods for decreasing the frequency of riluzole dosing in the subject, and methods for reducing the incidence and/or severity of adverse events in a subject treated with riluzole.
Description
Combination ALS Therapy
This application claims the benefit of priority to US Appln. Nos.
61/507,381, filed July 13, 2011, 61/637,770, filed April 24, 2012, 61/544,533, filed
October 7, 2011; 61/646,699, filed May 14, 2012, and 61/637,759, filed April 24,
2012, each of which is incorporated by reference for all purposes.
Amyotrophic lateral sclerosis (ALS) is a degenerative and progressive
disorder of the nervous system. ALS is characterized by progressive loss of
motor neurons in the lateral column of the spinal cord and/or motor cortex. With
ssive loss of motor neurons, the innervation to skeletal muscle is lost which
results in an inability to ambulate, conduct daily ties and affects swallowing
and breathing. ALS is a rare and usually fatal disease; its progression can be
variable but on average patients end up dying within 3 years of diagnosis. Most
patients succumb to respiratory failure with broncho-pneumonia and pneumonia
as the main causes of death. Treatment is tive because no curative
treatment exists.
le currently is the only drug ed to treat ALS. While the
exact mechanism of action of riluzole is unknown, it is believed to act by inhibiting
the deleterious effects of an overload of ic acid and other
ransmitters in the central nervous system (see, e.g., ier et al.,
NeuroReport (1994), 5(8):1012-14; Estevez et al., Eur. J. Pharmacol. (1995),
280(1): 47-53; Rothstein et al., J. Neorochem. (1995), 65(2): 643-51). Studies
have shown that the serum and plasma concentrations of riluzole vary y
from person to person (see, e.g., Groeneveld et al., J. Neurol. Sci. , 191:
310-13). Such variability can lead to difficulties in determining and delivering a
eutically effective dose to a patient and may affect the incidence and
severity of adverse events (see, e.g., Groeneveld et al., Neurology (2003), 61:
1141-43).
6-Ethynyl(pentanyl)—1H-imidazo[4,5-b]pyrazin-2(3H)—one (also
known as CK-2017357 or ) is a selective activator of the fast skeletal
muscle troponin complex, which sensitizes fast skeletal muscle to calcium and
results in an amplification of the response to neuromuscular input, an increase in
muscle power, and a decrease in the fatigability of muscle (see, e.g., US. Patent
No. 248). The use of CK-2017357 is being studied for use in the treatment
of patients with ALS. By increasing the contractile force developed by fast
skeletal muscle fibers in response to any level of neuronal input, treatment with
CK-2017357 may improve activities of daily living (such as tion, ing
and feeding), reduce hospitalizations, and possibly prolong the survival of
patients with ALS.
CK-2017357 has been shown to be a mechanism-based inhibitor of
human CYP1A2 in vitro, with a KI ivation constant) of 1.9 uM and kinact (max
rate constant for vation) of 0.031 min'1. In humans, riluzole is primarily
metabolized by CYP1A2 (see, e.g., Sanderink et al., J. Pharmacol. & Exp. Ther.
(1997), 282(3): 1465-72). A number of other drugs have been assessed for their
ability to inhibit the metabolism of riluzole by human hepatic microsomes in vitro;
although inhibition has been observed in some cases (e.g., amitriptyline,
diclofenac, diazepam, nicergoline, clomipramine, imipramine), the high
concentrations required for inhibition make it unlikely that these drugs would
alter riluzole trations if used in combination with riluzole in the al
setting (see Bensimon et al., Expert Opin. Drug Saf. (2004), 3(6): 525-34).
Provided is a method for treating ALS in a subject, comprising
administering to the t a therapeutically effective amount of riluzole and a
therapeutically effective amount of CK-2017357.
Also provided is a method for reducing the variability of riluzole
exposure (e.g., Cmax and/or ) in a subject, comprising administering to the
subject a therapeutically effective amount of 7357.
Also provided is a method for ng the variability of riluzole
exposure (e.g., Cmax and/or AUC24h) between two or more subjects, comprising
administering to the subjects a therapeutically effective amount of CK-2017357.
Also provided is a method of increasing the exposure of riluzole (e.g.,
Cmax and/or AUC24h) in a subject, comprising administering to the subject a
therapeutically effective amount of 7357.
Also provided is a method of increasing the half-life of riluzole in a
subject, comprising administering to the subject a therapeutically effective
amount of CK-2017357.
Also provided is a method for decreasing the frequency of riluzole
dosing in the subject, comprising administering to the subject a eutically
effective amount of CK-2017357.
Also provided is a method for decreasing the total daily dose of riluzole
in a t, comprising administering to the subject a therapeutically effective
amount of CK-2017357.
Also provided is a method for reducing the incidence and/or ty of
adverse events in a subject treated with riluzole, comprising administering to the
subject treated with le a therapeutically effective amount of CK-2017357.
Also provided is a pharmaceutical composition comprising a
therapeutically effective amount of riluzole and a therapeutically effective amount
of CK-2017357.
Also provided is a method for treating ALS in a subject, comprising
administering to the subject at least two doses daily of CK-2017357.
DESCRIPTION OF FIGURES
Figure 1 provides mean riluzole plasma concentration as a function of
time for riluzole alone (50 mg single dose) and le (50 mg single dose) and
CK-2017357 (250 mg daily x 11 days in healthy subjects.
Figure 2 rates the effect of steady-state CK-2017357 on riluzole
pharmacokinetics in healthy subjects. Panel A provides Cmax for riluzole alone
(50 mg single dose) and riluzole (50 mg single dose) + CK-2017357 (250 mg
daily for 11 days). Panel B provides AUCime for riluzole alone (50 mg single dose)
and riluzole (50 mg single dose) + CK-2017357 (250 mg daily for 11 days). The
figure shows that in healthy subjects, the inter-subject variability of Cmax of riluzole
has been reduced through co-administration of CK-2017357.
Figure 3 provides mean riluzole plasma concentration as a function of
time for 50 mg riluzole administered BID and CK-2017357 administered at either
250 or 500 mg single dose in ALS ts.
Figure 4 shows a study flow diagram for a clinical study investigating a
daily dose titration regimen of CK-2017357 in patients with ALS.
As used herein, the following abbreviations, words and phrases are
generally intended to have the gs as set forth below, except to the extent
that the context in which they are used tes othenNise.
As used herein, AUCz4h is the area under the plasma concentrationtime
curve from hour 0 to the last measurable plasma concentration (e.g., 24
, calculated by the linear trapezoidal rule.
As used herein, ALS or amyotrophic lateral sclerosis refers to the motor
neuron disease commonly known as Lou Gehrig's Disease, and in some
embodiments, ophic lateral sclerosis with early bulbar involvement or the
bulbar form of the disease, and in some ments, "limb-onset" ALS.
As used herein, QD refers to once a day.
As used herein, BID refers to twice a day.
As used herein, Cmax refers to maximum plasma concentration
As used herein, fm refers to fraction metabolized.
Provided is a method for treating ALS in a subject, comprising
administering to the subject a therapeutically ive amount of riluzole and a
therapeutically effective amount of 7357.
In some embodiments, administering the riluzole in combination with
CK-2017357 extends survival and/or time to tracheostomy.
In some embodiments, the eutically ive amount of riluzole
administered in combination with CK-2017357 is a smaller dose than the
therapeutically effective amount of riluzole when administered singly (i.e., without
CK-2017357 treatment). In some embodiments, both the therapeutically effective
amount of riluzole and the therapeutically effective amount of CK-2017357 when
administered in combination are smaller doses than the therapeutically effective
amount of riluzole and the therapeutically effective amount of CK-2017357 when
each is administered singly.
In some embodiments, the stration of riluzole is BID. In some
embodiments, the administration of le is OD.
In some embodiments, the administration of CK-2017357 is BID. In
some embodiments, the administration is OD.
In some embodiments, the administration of riluzole is OD and the
administration of CK-2017357 is BID. In some embodiments, the administration
of riluzole is BID and the administration of CK-2017357 is BID.
In some embodiments, the administration of riluzole is OD and the
stration of CK-2017357 is QD. In some embodiments, the administration
of riluzole is BID and the administration of CK-2017357 is OD.
In some embodiments, the CK-2017357 is administered in two or more
doses at different times (e.g., once in the morning and once in the evening). In
some embodiments, the CK-2017357 is administered in two or more equal doses.
In some embodiments, the CK-2017357 is administered in two or more different
doses. In some embodiments, the dose of CK-2107357 is titrated over time to a
different (e.g., higher) daily dose level.
In some embodiments, single daily dose of 50 mg riluzole is
administered in combination with a eutically effective amount of CK-
2017357. In some embodiments, a single daily dose of 50 mg riluzole is
administered in combination with a total daily dose of between about 125 mg and
2000 mg of CK-2017357. In some embodiments, a single daily dose of 50 mg
riluzole is administered in combination with a total daily dose of 125, 250, 375, or
500 mg of CK-2017357.
In some embodiments, a twice daily dose of 25 mg riluzole is
administered in combination with a therapeutically effective amount of CK-
2017357. In some embodiments, a twice daily dose of 25 mg riluzole is
administered in combination a total daily dose of between about 125 mg and
2000 mg of CK-2017357. In some embodiments, a twice daily dose of 25 mg
riluzole is administered in ation with a total daily dose of 125, 250, 375, or
500 mg of CK-2017357.
In some ments, a single daily dose of 25 mg le is
administered in combination with a therapeutically effective amount of CK-
2017357. In some embodiments, a single daily dose of 25 mg riluzole is
administered in ation with a total daily dose of between about 125 mg and
2000 mg of 7357. In some embodiments, a single daily dose of 25 mg
riluzole is administered in combination with a total daily dose of 125, 250, 375, or
500 mg of CK-2017357.
In some embodiments, a twice daily dose of 12.5 mg riluzole is
stered in combination with a therapeutically effective amount of CK-
2017357. In some embodiments, a twice daily dose of 12.5 mg riluzole is
administered in combination with a total daily dose of between about 125 mg and
2000 mg of CK-2017357. In some embodiments, a twice daily dose of 12.5 mg
riluzole is administered in combination with 125, 250, 375, or 500 mg of CK-
Also disclosed is a method for increasing the half-life of riluzole in a
t, comprising administering to the subject a therapeutically effective
amount of CK-2017357.
Also disclosed is a method for sing the frequency of riluzole
dosing in a subject (e.g., from twice-daily to once-daily) or ng the dose of
riluzole stered to the subject (e.g., from 200 mg daily to 100 mg daily, or
from 100 mg daily to 50 mg daily, or from 50 mg daily to 25 mg daily).
Also disclosed is a method for reducing the inter-subject variability of
le exposure (e.g., Cmax and/or AUC24h) between two or more subjects,
comprising administering to the subjects a therapeutically effective amount of CK-
2017357.
Also disclosed is a method for reducing the intra-subject ility of
riluzole exposure (e.g., Cmax and/or AUC24h), comprising administering to the
subject a therapeutically effective amount of CK-2017357.
Also disclosed is a method for reducing the incidence and/or severity of
adverse events in a subject treated with riluzole, comprising administering to the
subject a therapeutically effective amount of CK-2017357. In some
embodiments, the adverse event is a CNS-related adverse event (see, e.g.,
o et al., Anesthesia & Analgesia (2007), 104:1415-21).
In some embodiments, CK-2017357 is administered to the subject
concurrently with riluzole administration, i.e., CK-2017357 and le are
stered simultaneously, essentially simultaneously or within the same
treatment protocol. In some instances of concurrent administration,
administration of CK-2017357 and riluzole begin and end at the same time (i.e.,
on the same day or within the same treatment protocol). In other instances of
concurrent administration, only one of CK-2017357 and riluzole is stered
for a first period of time, followed by co-administration of the 7357 and
riluzole for a second period of time. For example, the subject may receive
riluzole for a first period of time, then receive both CK-2017357 and riluzole for a
second period of time. Administration of either CK-2017357 or riluzole may then
continue for a third period of time. In another example, the subject may receive
7357 for a first period of time, then receive both CK-2017357 and riluzole
for a second period of time. Administration of either CK-2017357 or riluzole may
then ue for a third period of time. In other instances of concurrent
administration, CK-2017357 and riluzole are co-administered for a first period of
time, followed by stration of only one of CK-2017357 and riluzole for a
second period of time. For example, the subject may receive both 7357
and riluzole for a first period of time, then receive CK-2017357 for a second
period of time. In another example, the subject may receive both 7357
and riluzole for a first period of time, then receive riluzole for a second period of
time. In all instances, alternate administration may be repeated during a single
treatment protocol. The ination of the order of administration and the
number of repetitions of administration of each therapy during a treatment
ol is within the knowledge of the skilled physician after evaluation of the
condition of the patient.
In some embodiments, riluzole and CK-2017357 are administered
sequentially. In some instances of sequential administration, CK-2017357 is
administered to the subject after riluzole administration has ended. The
administration of CK-2017357 may begin immediately following ation of
riluzole administration, or there may be a time interval (e.g., one day, one week,
one month, six months, one year, etc.) between the end of riluzole administration
and the beginning of CK-2017357 administration. In other instances of sequential
administration, riluzole is administered to the subject after CK-2017357
administration has ended. The administration of riluzole may begin immediately
following termination of CK-2017357 administration, or there may be a time
al (e.g., one day, one week, one month, six months, one year, etc.) between
the end of CK-2017357 administration and the ing of riluzole
administration. In each instance, alternate administration may be repeated during
a single ent protocol. The determination of the order of stration and
the number of repetitions of administration of each therapy during a treatment
protocol is within the knowledge of the d physician after evaluation of the
condition of the patient.
In some embodiments, CK-2017357 and riluzole are administered in a
single pharmaceutical composition. The single pharmaceutical composition may
be administered via any of the accepted modes of administration for therapeutic
agents including, but not d to, , sublingually, subcutaneously,
intravenously, intranasally, topically, transdermally, intraperitoneally,
intramuscularly, intrapulmonarily, vaginally, rectally, or intraocularly. In some
embodiments, the single ceutical composition is administered . In
some embodiments, the single pharmaceutical composition is formulated to
administer both CK-2017357 and riluzole at the same time or rate. In some
embodiments, the single pharmaceutical composition is formulated to administer
both CK-2017357 and riluzole at different times or rates. For example, the single
pharmaceutical composition may deliver riluzole at a slower rate the CK-
2017357, or CK-2017357 at a slower rate than le. In another example, the
single pharmaceutical composition may deliver CK-2017357 first followed by
riluzole (i.e., delayed release of riluzole), or riluzole first followed by CK-2017357
(i.e., delayed release of CK-2017357).
In some embodiments, 7357 and riluzole are stered in
separate pharmaceutical compositions. Each agent may, because of different
physical and chemical characteristics, be stered by different . For
example, one agent can be administered orally, while the other is administered
intravenously. Alternatively, each agent may be administered by the same route.
For example, both CK-2017357 and riluzole may be administered orally (i.e., in
the form of two separate pills or capsules). The determination of the mode of
stration and the advisability of administration, in the same pharmaceutical
composition (if le) is within the dge of the skilled clinician. The initial
administration can be made according to established ols known in the art,
and then, based upon the observed effects, the dosage, modes of administration
and times of administration can be modified by the skilled clinician.
Also provided is a method for treating ALS by administering to a patient
at least two doses daily of CK-2017357. In some embodiments, two doses of
CK-2017357 are administered at different times (e.g., once in the morning and
once in the evening). In some embodiments, the total daily dose is at least about
250 mg, or at least about 300 mg, or at least about 350 mg, or at least about 400
mg, or at least about 450 mg, or at least about 500 mg. In some embodiments, at
least one of the doses is equal to or greater than about 125 mg, or equal to or
r than about 150 mg, or equal to or greater than about 200 mg, or equal to
or r than about 250 mg. In some embodiments, at least two of the doses
are equal to or greater than about 125 mg, or equal to or greater than about 150
mg, or equal to or greater than about 200 mg, or equal to or greater than about
250 mg. In some embodiments, the CK-2017357 is administered in two or more
equal doses (e.g., two equal doses of 125 mg or two equal doses of 250 mg). In
some embodiments, the CK-2017357 is administered in two or more different
doses (e.g., 125mg/250mg or 250mg/125mg). In some embodiments, the dose
of CK-2107357 is titrated over time to a different (e.g., higher) daily dose level.
Administration of CK-2017357 can be via any of the accepted modes of
administration for therapeutic agents including, but not limited to, orally,
gually, subcutaneously, intravenously, intranasally, topically, transdermally,
intraperitoneally, intramuscularly, intrapulmonarily, lly, rectally, or
intraocularly. In some embodiments, CK-2017357 is administered orally. In other
embodiments, CK-2017357 is administered intravenously. In still other
embodiments, CK-2017357 is administered into the lungs by inhalation or
spraying of a dry powder, sion, solution or aerosol sing CK-
2017357.
Pharmaceutically acceptable compositions include solid, semi-solid,
liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders,
liquids, suspensions, itories, aerosols or the like. CK-2017357 can also
be administered in sustained or controlled release dosage forms, including depot
injections, osmotic pumps, pills, transdermal (including electrotransport) patches,
and the like, for ged and/or timed, pulsed administration at a predetermined
rate. In certain ments, the compositions are provided in unit dosage forms
suitable for single administration of a precise dose.
7357 can be administered either alone or in combination with a
conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose,
, magnesium stearate, sodium saccharine, talcum, cellulose, sodium
crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like).
If d, the pharmaceutical composition can also contain minor amounts of
nontoxic auxiliary substances such as wetting agents, emulsifying agents,
solubilizing agents, pH buffering agents and the like (e.g., sodium acetate,
sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, anolamine
acetate, anolamine oleate, and the like). Generally, depending on the
intended mode of administration, the pharmaceutical composition will contain
about 0.005% to 95% or, in certain ments, about 0.5% to 50% by weight
of CK-2017357. Actual methods of preparing such dosage forms are known, or
will be nt, to those skilled in this art; for example, see Remington’s
Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
In n embodiments, the itions will take the form of a pill or
tablet and thus the composition may contain, along with the active ingredient, a
diluent such as lactose, sucrose, ium phosphate, or the like; a lubricant
such as magnesium stearate or the like; and a binder such as starch, gum
acacia, polyvinylpyrrolidine, gelatin, ose, cellulose derivatives or the like. In
certain embodiments of a solid dosage form, a powder, marume, solution or
suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) is
encapsulated in a gelatin capsule.
Liquid pharmaceutically administrable itions can, for example,
be prepared by dissolving, dispersing, etc. the active ient and optional
pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous se,
glycerol, glycols, ethanol or the like) to form a solution or suspension. lnjectables
can be prepared in conventional forms, either as liquid solutions or suspensions,
as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior
to ion. The percentage of CK-2017357 contained in such parenteral
compositions is dependent on the specific nature of the compound, as well as the
activity of CK-2017357 and the needs of the subject. In some embodiments,
percentages of active ingredient of 0.01% to 10% in solution are employable, and
may be higher if the composition is a solid which will be subsequently diluted.
ceutical compositions of CK-2017357 may also be
administered to the respiratory tract as an aerosol or solution for a zer, or
as a microfine powder for insufflation, alone or in combination with an inert carrier
such as lactose. In some embodiments, the particles of the pharmaceutical
composition have diameters of less than 50 microns, in certain embodiments,
less than 10 microns.
Example 1: Effect of multiple daily doses of CK-2017357 on the PK of a
single dose of riluzole in healthy subjects
The primary ive of this study was to evaluate the effect of multiple
daily doses of CK-2017357 on the pharmacokinetics (PK) of a single dose of
riluzole in healthy subjects. On Day 1, 12 subjects (7 males and 5 females)
received a single 50 mg oral dose of riluzole. On Day 6, all subjects began 11
days of oral dosing with 250 mg CK-2017357 QD (through Day 16). On Day 13,
11 of the 12 subjects received another single 50 mg oral dose of riluzole.
Following each dose of riluzole, plasma samples were collected at pre-dose, 0.5,
1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post-dose. Plasma
concentrations of riluzole were determined using a validated HPLC/MS/MS
method with a quantitation range of 5.00 to 2,000 ng/mL. Samples were
analyzed using a 50.0 uL aliquot volume and a n-precipitation extraction
procedure ed by HPLC/MS/MS. Riluzole concentrations were calculated
with a 1/x2 linear regression over a concentration range of 5.00 to 2,000 using
riluzole-130,15N2 as an al standard. Separately, another set of plasma
samples were collected at pre-dose of CK-2017357 on days 11, 12, and 13.
These plasma samples were ed using a ted LC/MS/MS method for
trough CK-2017357 levels to determine the attainment of steady-state
pharmacokinetics of CK-2017357.
Plasma concentration data of riluzole were analyzed by non-
compartmental methods to ine pharmacokinetic parameters of riluzole.
Descriptive pharmacokinetic parameters such as Cmax, Tmax, AUC, t1/2, Cl/F,
and V/F were ated using Phoenix WinNonlin 6.1 ight, in View,
CA). All concentrations < LLOQ were set to zero for the purpose of calculating
descriptive statistics and noncompartmental analysis. Summary PK parameters
of riluzole are presented in Tables 1A and 18 below.
Table 1A: Summary cokinetic parameters of riluzole in healthy subjects
Tmax AUClast AUCinf t1/2 CL/F
hr hr*no/ml hr*no/ml hr ml/hr
N 12 12 12
Mean 190 1.1 845 8.0 86258
so 113 0.5 416 440 2.5 75198
CV% 59.6 46.9 87.2
Table 13: Summary pharmacokinetic parameters of riluzole + CK2017357 (250
mg QD) in healthy subjects
AU Clast AU Cinf t1/2
hr*no/ml hr*no/ml hr
N 11 11 11 11 11
Min 191 0.5 1309 1412 9.6
Median 324 1.0 2443 2559 14.9
Max 482 2.0 6613 7019 23.2
CV% 27.0 46.0 55.6 54.7 32.2
The extent of drug-drug interaction was assessed by comparing AUCinf
values from Period 1 (riluzole alone) to values from Period 2 (riluzole + CK-
2017357). Results of this study are ted in Table 2 below. Mean plasma
concentration-time es are presented graphically in Figure 1, and Cmax and
AUCinf data for Periods 1 and 2 are represented in Figure 2.
Table 2: Individual and Summary of AUCinf-fold increase of riluzole in the
presence of steady-state CK-2015375 (250mg) in y ts
AUCinf AUCinf
Fold increase
Period 1 Period 2
(hr*ng/ml) (hr*ng/ml)
1 1335.38
2 813.03 1622.66
3 619.77 1931.23
4 162.75 1951.67
883.12 2608.46
6 1189.32 9
7 1674.53 3577.29
8 1263.88 7018.50
9 630.27 3
573.21 2559.42
11 378.92 1412.02
12 612.18 2540.58
N 12 11
844.70 2929.00
440.32 1600.93
162.75 1412.02
721.65 2559.42
1674.53 7018.50
52.1 54.7
This study showed that -state CK-2017357 ) raised the
mean Cmax of riluzole approximately 1.7-fold, and its mean AUCinf approximately
4.4-fold compared with riluzole alone. The mean tug of riluzole increased from
8.0 hours to 15.5 hours in the presence of steady-state CK-2017357. As
illustrated in Figure 2, co—administration of CK-2017357 generally reduced the
inter-subject variability of riluzole pharmacokinetics in these healthy subjects.
Example 2: Drug-drug interaction (DDI) between riluzole and CK-2017357 in
ALS patients
This was a placebo controlled, three-period crossover study. Each
t received 50 mg riluzole BID and single doses of placebo, 250 mg CK-
2017357, and 500 mg CK-2017357 in random order, separated by 6-10 days.
Duplicate PK samples were collected from each t in the clinical study. One
set was analyzed for CK-2017357, and the other analyzed for riluzole using a
validated LC/MS/MS . Riluzole exposure (AUC24h) was calculated for
each patient and each treatment of CK-2015357 (placebo, 250mg, and 500 mg).
le AUC-fold increase over CK-2017357 placebo period was used to assess
the extent of drug-drug interaction.
Plasma concentrations of riluzole were determined using a validated
HPLC/MS/MS method with a quantitation range of 5.00 to 2,000 ng/mL. Samples
were analyzed using a 50.0 uL aliquot volume and a protein-precipitation
extraction procedure followed by HPLC/MS/MS. Riluzole concentrations were
calculated with a 1/x2 linear regression over a concentration range of 5.00 to
2,000 using riluzole-13C,15N2 as an internal standard. ptive
pharmacokinetic parameters such as Cmax, Tmax, AUC, t1/2, Cl/F, and VIP were
calculated using Phoenix WinNonlin 6.1 (Pharsight, Mountain View, CA). All
concentrations < LLOQ were set to zero for the purpose of calculating descriptive
statistics and noncompartmental analysis. Since the time of dosing for riluzole
was not ed, time elapsed was ated based on nominal time points of
7357, and used to calculate riluzole .
The results of this experiment are summarized in Table 3 below and
mean plasma concentration-time profiles are presented in Figure 3.
Table 3: Individual and summary riluzole AUC24h and AUC24hr-fold se
following oral le at 50mg b.i.d.
CK357 = CK357 = CK357 = Auc24hr-fold AUC24hr-fold
0mg 250mg 500mg Increase Increase
(CK'357 = (CK357 =
(hr*ng/ml) (hr*ng/ml) (hr*ng/ml)
1 2831.49 7 4062.97 1.57 1.43
2 1093.68 7 2346.72 2.25 2.15
3 4778.27
4 2492.82 3767.26 4082.12 1.51 1.64
307.49
6 829.77 9 4510.3 6.07 5.44
7 747.85 1828.87 2623.22 2.45 3.51
8 2540.48 1841.12 5652.57 0.72 2.23
9 945.95 1761.84 4024.18 1.86 4.25
1400.63 2509.68 7921.64 1.79 5.66
11 1263.74 4464.6 3.53
12 992.23 2194.64 3132.45 2.21 3.16
13 2172.04 4805.42 5410.5 2.21 2.49
14 2220.49 3939.67 5655.82 1.77 2.55
2647.84 1850.43 2055.75 0.70 0.78
16 1125.41 2947.04 3972.68 2.62 3.53
17 4 1564.05 5600.95 0.85 3.05
18 3047.02 7371.82 7084.32 2.42 2.33
19 1155.09 4366.21 3438.4 3.78 2.98
2699.12 3939.62 4753.02 1.46 1.76
21 683.16 4034.31 4295.43 5.91 6.29
22 1511.98 2 2986.23 3.18 1.98
23 2087.11 3828.63 2197.83 1.83 1.05
24 1384.24
2003.85 2644.38 2773.55 1.32 1.38
26 1477.45 2971.36 5 2.01 2.67
27 4116.82 4620.8 5 1.12 1.28
28 1460.67 2136.77 3992.31 1.46 2.73
29 2344.66 2437.78 7 1.04 1.66
2083.63 1598.71 5707.86 0.77 2.74
31 996.99 1250.21 830.83 1.25 0.83
32 2569.22 3265.26 4360.36 1.27 1.70
33 4171.45 3685.49
34 4841.83 5862.48 9116.2 1.21 1.88
1163.34 4568.86 3138.61 3.93 2.70
36 838.09 2295.37 7 2.74 4.30
37 2812.13 4350.55 4292.15 1.55 1.53
38 1438.58 1 4386.6 2.59 3.05
39 3547.69
40 1158.27 1575.61 1817.17 1.36 1.57
41 1387.18 887.4 3869.44 0.64 2.79
42 536.67 1448.56 849.78 2.70 1.58
43 1379.36
N 39 38 40
Mean 1775.54 3252.18 4025.65
SD 969.09 1462.15 1721.25
Min 307.49 887.4 830.83
Median 7 3118.31 3982.49
Max 4841.83 7371.82 9116.2
CV% 54.6 45 42.8
Analysis of riluzole AUC24h following 50 mg BID showed a general
trend of increasing riluzole trations in CK-2017357 active periods (250 and
500 mg vs. 0 mg). Compared to the CK-2017357 placebo period, mean riluzole
AUC24h increased approximately 2.1- and 2.6-fold for the 250- and 500-mg CK-
7 dose, respectively. As illustrated in Figure 3, the mean riluzole Cmax
roughly doubled in the presence of steady-state concentrations of CK-2017357. .
Example 3: Pharmacokinetics and Interactive Effects of the Fast Skeletal Muscle
Activator CK-2017357 and Riluzole
The ive of this study was to determine the cokinetics of
repeated doses of CK-2017357 both in the presence and absence of riluzole, and
to determine the effects of CK-2017357 at g doses on plasma le
serum levels.
In this study, 49 patients with ALS were treated; 24 patients were not
taking riluzole and the remainder took a stable but reduced dose of le (50
mg daily). Patients (n = off/on riluzole) ed single daily doses of placebo (n
= 6/7), 125, 250, or 375 mg of CK-357 (n = 6/6 for all 3 CK-2017357 groups) for
14 days. CK-2017357 and riluzole levels were ed on Days 1, 2, 8 and 15.
Plasma levels of CK-2017357 achieved steady state by Day 8; levels
four hours after dosing on Day 8 were approximately 70% higher than four hours
after the first dose on Day 1. CK-2017357 Cmax increased proportionally by dose
with no apparent effect of riluzole, as shown in Table 4.
Table 4: CK-2017357 Cmax levels with and without riluzole
—CK-2017357 Cmax mc/mL
CK-2017357 Daily Dose No Riluzole On Riluzole
———m_
CK-2017357 approximately doubled riluzole levels across all dose
groups as shown in Table 5 below Adverse event frequencies were not altered
by the presence of riluzole at any dose of CK-2017357.
Table 5: Riluzole Cmax levels with various doses of CK-2017357
Dose Group Cmax (ng/mL) AUCIast (hr*pg/mL)
Median 1 SD Median 1 SD
125 mg once daily 243 i 89 42.6 1r 14.8
250 mg once daily 143 1r 125 30.0 1r 21.7
375 mg once daily 228 1r 169 46.3 1r 18.2
CK-2017357 had predictable linear kinetics at the repeated doses used
in the current study, reaching steady state within 1 week. CK- 2017357 plasma
levels were not affected by the presence of le. Riluzole levels were
increased by CK-2017357 with plasma levels increasing approximately 2-fold
across all dose levels of CK-2017357. r, no adverse events were
reported during this study attributable to higher riluzole levels with the daily
riluzole dose reduced to 50 mg daily. These results suggest that 7357
and riluzole may be given safely in combination.
Example 4: Investigation of Twice-daily Dose Titration Regimen of CK-2017357
in Patients with ALS
In previous clinical ments, 1-(ethy|propyl)ethynylimidazo[4,5-
b]pyrazinol (CK-2017357) has been administered once a day in the morning.
While improvements in patient and investigator global assessments, muscle
fatigability and pulmonary on have been observed in these studies,
dizziness has been a dose-limiting adverse event in both healthy volunteers and
in patients with ALS. This e examines whether the maximum tolerable
total daily dose of 7357 can be increased by dividing the daily dose into
two portions (morning and evening), and beginning treatment with a low dose and
titrating upward to a target of 250 mg twice daily.
ts enrolled in this clinical study were randomized, double-blind,
and placebo-controlled. There was a 7-day stabilization period for le at a
reduced dose of 50 mg OD. The patients were then randomized 3:1 to CK-
2017357 or placebo for 14 days.
The CK-2017357 titration regimen was as follows: dosing ted at
125 mg twice daily for 7 days (250 mg total daily dose); on Day 8, up titration to
125 mg in the morning and 250 mg in the evening (375 mg total daily dose); on
Day 15, up titration to 250 mg twice daily (500 mg total daily dose) continued
through the morning dose on Day 22. Patients who did not tolerate a dose
escalation returned to the previous ted dose level and remained at that
dose level to complete the study. Placebo patients underwent a similar dummy
dose titration to maintain the blind. Figure 4 illustrates the study design.
Twenty-seven patients were treated in this study. All six patients
randomized to placebo completed three weeks of dosing. Of the 21 patients
randomized to treatment with CK-2017357, 14 were escalated to the t total
daily dose of 500 mg and completed three weeks of . The most commonly
reported treatment-emergent adverse event was dizziness, which was mild in 10
of the 12 patients in whom it occurred and only te in the other two.
ess was self-limited in 6 of 12 ts in whom it occurred. Encouraging
trends toward increases in the ALSFRS-R score and MVV were observed on CK-
2017357 relative to placebo. Thus, this study suggests that CK-2017357
administered in a twice-daily, dose titration regimen is safe and well tolerated.
While the present invention has been described with reference to the
specific embodiments described herein, it should be understood by those skilled in
the art that various changes may be made and equivalents may be substituted
without departing from the true spirit and scope of the invention. In addition,
modifications may be made to adapt a particular situation, material, composition of
matter and/or process to the objective, spirit and scope of the present invention.
All such modifications are intended to be within the scope of the claims appended
The reference in this specification to any prior publication (or
information derived from it), or to any matter which is known, is not, and should not
be taken as an acknowledgment or admission or any form of suggestion that that
prior publication (or information d from it) or known matter forms part of the
common general knowledge in the field of endeavour to which this specification
relates.
Throughout this ication and the claims which follow, unless the
context requires otherwise, the word "comprise", and variations such as
"comprises" and "comprising", will be understood to imply the ion of a stated
integer or step or group of integers or steps but not the exclusion of any other
integer or step or group of integers or steps.
Claims (6)
1. Use of a therapeutically effective amount of riluzole and a eutically effective amount of 6-Ethynyl(pentanyl)-1H-imidazo[4,5-b]pyrazine-2(3H)- one, in the manufacture of a medicament for treating amyotrophic l sclerosis in a subject.
2. Use according to claim 1, wherein the therapeutically effective amount of riluzole to administered in combination with 6-Ethynyl(pentanyl)-1H- imidazo[4,5-b]pyrazine-2(3H)-one is a smaller dose than the therapeutically effective amount of riluzole when intended to be administered singly.
3. Use of a therapeutically effective amount of 6-Ethynyl(pentanyl)-1H- imidazo[4,5-b]pyrazine-2(3H)-one, in the manufacture of a medicament for reducing the variability of riluzole exposure in a subject with amyotrophic lateral sclerosis.
4. Use of a therapeutically effective amount of 6-Ethynyl(pentanyl)-1H- imidazo[4,5-b]pyrazine-2(3H)-one, in the manufacture of a medicament for reducing the total daily dose of riluzole in a subject with amyotrophic lateral sclerosis.
5. Use of a therapeutically effective amount of 6-Ethynyl(pentanyl)-1H- imidazo[4,5-b]pyrazine-2(3H)-one, in the manufacture of a medicament for sing the half-life of le in a subject with ophic lateral sclerosis.
6. Use of a therapeutically effective amount of 6-Ethynyl(pentanyl)-1H- imidazo[4,5-b]pyrazine-2(3H)-one, in the manufacture of a medicament for decreasing the frequency of riluzole dosing in a subject with amyotrophic l sclerosis. H:\ACG\Interwoven\NRPortbl\DCC\ACG\9411033_1.docx-
Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161507381P | 2011-07-13 | 2011-07-13 | |
US61/507,381 | 2011-07-13 | ||
US201161544533P | 2011-10-07 | 2011-10-07 | |
US61/544,533 | 2011-10-07 | ||
US201261637759P | 2012-04-24 | 2012-04-24 | |
US201261637770P | 2012-04-24 | 2012-04-24 | |
US61/637,770 | 2012-04-24 | ||
US61/637,759 | 2012-04-24 | ||
US201261646699P | 2012-05-14 | 2012-05-14 | |
US61/646,699 | 2012-05-14 | ||
PCT/US2012/046523 WO2013010015A2 (en) | 2011-07-13 | 2012-07-12 | Combination als therapy |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ619924A NZ619924A (en) | 2016-02-26 |
NZ619924B2 true NZ619924B2 (en) | 2016-05-27 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2012281042B2 (en) | Combination ALS therapy | |
US10912744B2 (en) | Therapeutic formulation for reduced drug side effects | |
JP4938905B2 (en) | Administration method of selective S1P1 receptor agonist | |
EA020193B1 (en) | Combinations comprising methotrexate and dhodh inhibitors | |
EP2722045B1 (en) | Compositions for treating centrally mediated nausea and vomiting | |
JP2023171776A (en) | Synthetic transdermal cannabidiol for treatment of focal epilepsy in adults | |
US20170105983A1 (en) | Compositions for reduction of side effects | |
US9066949B2 (en) | Compositions and methods for the treatment of catatonia | |
EA009935B1 (en) | New synergistic combination comprising roflumilast and formoterol | |
NZ619924B2 (en) | Combination als therapy | |
JP6420923B1 (en) | Medicine | |
US10258617B2 (en) | Dosing regimens for fast onset of antidepressant effect | |
JP6860984B2 (en) | Administration regimen for ataxia in spinocerebellar degeneration | |
MX2014000455A (en) | Combination als therapy. | |
US20230172895A1 (en) | Methods of treating or preventing organophosphorus poisoning | |
AU2013205648B2 (en) | Combination treatment | |
EP2482658B1 (en) | Methods and compositions for treatment of raynaud's phenomenon | |
WO2016208045A1 (en) | Dosing regimen of therapeutic agent for ataxia associated with spinocerebellar degeneration | |
Cole | American Academy of Neurology 64th Annual Meeting, New Orleans, Louisiana, USA-April 21-28, 2012 |