WO2024068524A1 - Gepotidacin for use in the treatment of bacterial prostatitis - Google Patents
Gepotidacin for use in the treatment of bacterial prostatitis Download PDFInfo
- Publication number
- WO2024068524A1 WO2024068524A1 PCT/EP2023/076355 EP2023076355W WO2024068524A1 WO 2024068524 A1 WO2024068524 A1 WO 2024068524A1 EP 2023076355 W EP2023076355 W EP 2023076355W WO 2024068524 A1 WO2024068524 A1 WO 2024068524A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- gepotidacin
- streptococcus
- staphylococcus
- bacterial prostatitis
- prostatitis
- Prior art date
Links
- PZFAZQUREQIODZ-LJQANCHMSA-N dvf0pr037d Chemical compound C1CCOC(C=N2)=C1C=C2CNC(CC1)CCN1C[C@H]1N2C(=O)C=NC(C=CC3=O)=C2N3C1 PZFAZQUREQIODZ-LJQANCHMSA-N 0.000 title claims abstract description 89
- 229950010739 gepotidacin Drugs 0.000 title claims abstract description 89
- 206010069918 Bacterial prostatitis Diseases 0.000 title claims abstract description 55
- 238000011282 treatment Methods 0.000 title claims description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 21
- 201000007094 prostatitis Diseases 0.000 claims description 39
- 239000003814 drug Substances 0.000 claims description 15
- 241000588722 Escherichia Species 0.000 claims description 14
- 241000894006 Bacteria Species 0.000 claims description 13
- MTLHHQWYERWLIX-RGFWRHHQSA-N gepotidacin mesylate Chemical compound O.O.CS(O)(=O)=O.C1CCOC(C=N2)=C1C=C2CNC(CC1)CCN1C[C@H]1N2C(=O)C=NC(C=CC3=O)=C2N3C1 MTLHHQWYERWLIX-RGFWRHHQSA-N 0.000 claims description 7
- 241000588769 Proteus <enterobacteria> Species 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 241000194033 Enterococcus Species 0.000 claims description 3
- 241000191940 Staphylococcus Species 0.000 claims description 3
- 241000194017 Streptococcus Species 0.000 claims description 3
- 208000013507 chronic prostatitis Diseases 0.000 claims description 3
- 241000194032 Enterococcus faecalis Species 0.000 claims description 2
- 241000194031 Enterococcus faecium Species 0.000 claims description 2
- 206010018612 Gonorrhoea Diseases 0.000 claims description 2
- 241000588915 Klebsiella aerogenes Species 0.000 claims description 2
- 241000588749 Klebsiella oxytoca Species 0.000 claims description 2
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 2
- 241001014264 Klebsiella variicola Species 0.000 claims description 2
- 241000204051 Mycoplasma genitalium Species 0.000 claims description 2
- 241000588653 Neisseria Species 0.000 claims description 2
- 241001076189 Proteus hauseri Species 0.000 claims description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 2
- 241000607142 Salmonella Species 0.000 claims description 2
- 241000607715 Serratia marcescens Species 0.000 claims description 2
- 241001147736 Staphylococcus capitis Species 0.000 claims description 2
- 241001147695 Staphylococcus caprae Species 0.000 claims description 2
- 241001147698 Staphylococcus cohnii Species 0.000 claims description 2
- 241000191963 Staphylococcus epidermidis Species 0.000 claims description 2
- 241000191984 Staphylococcus haemolyticus Species 0.000 claims description 2
- 241000192087 Staphylococcus hominis Species 0.000 claims description 2
- 241000191980 Staphylococcus intermedius Species 0.000 claims description 2
- 241001147691 Staphylococcus saprophyticus Species 0.000 claims description 2
- 241000191978 Staphylococcus simulans Species 0.000 claims description 2
- 241000192086 Staphylococcus warneri Species 0.000 claims description 2
- 241000193985 Streptococcus agalactiae Species 0.000 claims description 2
- 241000194008 Streptococcus anginosus Species 0.000 claims description 2
- 241000176094 Streptococcus australis Species 0.000 claims description 2
- 241001291896 Streptococcus constellatus Species 0.000 claims description 2
- 241000191981 Streptococcus cristatus Species 0.000 claims description 2
- 241000194026 Streptococcus gordonii Species 0.000 claims description 2
- 241001473878 Streptococcus infantarius Species 0.000 claims description 2
- 241000960363 Streptococcus infantis Species 0.000 claims description 2
- 241000194046 Streptococcus intermedius Species 0.000 claims description 2
- 241001256220 Streptococcus massiliensis Species 0.000 claims description 2
- 241001134658 Streptococcus mitis Species 0.000 claims description 2
- 241000194019 Streptococcus mutans Species 0.000 claims description 2
- 241000194025 Streptococcus oralis Species 0.000 claims description 2
- 241000193991 Streptococcus parasanguinis Species 0.000 claims description 2
- 241000194024 Streptococcus salivarius Species 0.000 claims description 2
- 241000194023 Streptococcus sanguinis Species 0.000 claims description 2
- 241000194005 Streptococcus sp. 'group G' Species 0.000 claims description 2
- 241000194051 Streptococcus vestibularis Species 0.000 claims description 2
- 241000202921 Ureaplasma urealyticum Species 0.000 claims description 2
- 229940032049 enterococcus faecalis Drugs 0.000 claims description 2
- 229940037649 staphylococcus haemolyticus Drugs 0.000 claims description 2
- 229940037648 staphylococcus simulans Drugs 0.000 claims description 2
- 241000588770 Proteus mirabilis Species 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 description 35
- 210000004369 blood Anatomy 0.000 description 24
- 239000008280 blood Substances 0.000 description 24
- 241000700159 Rattus Species 0.000 description 21
- 210000001519 tissue Anatomy 0.000 description 18
- 238000001690 micro-dialysis Methods 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 10
- 210000003205 muscle Anatomy 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 238000011472 radical prostatectomy Methods 0.000 description 10
- 238000007483 tonsillectomy Methods 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- 238000011471 prostatectomy Methods 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- 239000003242 anti bacterial agent Substances 0.000 description 6
- 229940088710 antibiotic agent Drugs 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 238000001647 drug administration Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 210000002741 palatine tonsil Anatomy 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000002051 biphasic effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 239000000385 dialysis solution Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 229940127249 oral antibiotic Drugs 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 208000017497 prostate disease Diseases 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 210000003708 urethra Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OPQFKYZLJABARW-UHFFFAOYSA-N 1,4,7-triazatricyclo[6.3.1.04,12]dodeca-2,6,8(12),9-tetraene-5,11-dione Chemical compound N1=CC(=O)N2C=CN3C(=O)C=CC1=C32 OPQFKYZLJABARW-UHFFFAOYSA-N 0.000 description 1
- DPAHPKBTWARMFG-FSRHSHDFSA-N 30z5b7acv6 Chemical compound Cl.C1CCOC(C=N2)=C1C=C2CNC(CC1)CCN1C[C@H]1N2C(=O)C=NC(C=CC3=O)=C2N3C1 DPAHPKBTWARMFG-FSRHSHDFSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000250507 Gigaspora candida Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 208000000450 Pelvic Pain Diseases 0.000 description 1
- 206010061339 Perineal pain Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000001793 Wilcoxon signed-rank test Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 210000001601 blood-air barrier Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 229940047766 co-trimoxazole Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 244000000013 helminth Species 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to methods of treatment, pharmaceutical compositions, or resistance guided therapies and/or corresponding uses thereof for treating bacterial prostatitis, which comprises administration of gepotidacin or pharmaceutically acceptable salts thereof.
- Prostatitis ranges from a straightforward clinical diagnosis in its acute form to a complex, debilitating condition when chronic. It is often a source of frustration for the treating physician and patient. Prostatitis accounts for 8% of visits to urologists, and up to 1% of visits to primary care physicians. In 2000, the estimated cost to diagnose and treat prostatitis was $84 million. Patients with chronic prostatitis often experience impaired mental and physical health-related quality of life. Acute bacterial prostatitis is estimated to comprise approximately 10% of all prostatitis cases.
- the challenges of treating bacterial prostatitis with antibiotics are myriad. While the prostate is located near the bladder and urethra, the prostate is not directly connected to the urinary tract through vascular connections. The prostate is also not a highly vascularized organ. Together, this can limit drug exposure to the prostate. Additionally, due to the prostate's anatomical location, it can be difficult to measure drug exposure in the prostate to determine if a drug is adequately reaching the prostate. For at least these reasons, finding effective treatments for bacterial prostatitis can be challenging.
- the present invention provides a method for treating bacterial prostatitis in a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof.
- the present invention also provides use of gepotidacin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of bacterial prostatitis.
- the present invention also provides a kit comprising gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of bacterial prostatitis.
- FIGs. 1A-1D show unbound gepotidacin concentrations in blood, muscle, and prostate tissue in healthy and infected rats. Dots, triangles or squares are means, bars represent ⁇ 1 standard deviation.
- FIG. 1A shows decimal representation of unbound gepotidacin concentrations in healthy rats.
- FIG. IB shows semi-log representation of unbound gepotidacin in healthy rats.
- FIG. 1C shows decimal representation of unbound gepotidacin concentrations in infected rats.
- FIG. ID shows semilog representation of unbound gepotidacin in infected rats.
- antimicrobial refers to any natural or synthetic compound which kills or inhibits the growth of a microorganism.
- antibiotic resistance occurs when bacteria change in response to the use of antibiotics, making them ineffective; and antimicrobial resistance is a broader term, encompassing resistance to drugs that treat infections caused by other microbes as well, such as parasites (e.g. malaria or helminths), viruses (e.g. HIV) and fungi (e.g. Candida).
- parasites e.g. malaria or helminths
- viruses e.g. HIV
- fungi e.g. Candida
- Gepotidacin is a first-in-class, novel triazaacenaphthylene antibiotic with the ability to selectively inhibit bacterial DNA replication by a means not utilized by any currently approved human therapeutic agent, therefore providing the opportunity to address an unmet medical need.
- Gepotidacin and its racemic form is disclosed in WO 2008/128942 (herein incorporated in its entirety).
- Gepotidacin is (2 )-2-( ⁇ -[(3, -dihydro-2/ -pyrano[2,3-c]pyridin-6-ylmethyl)amino]-l-piperidinyl ⁇ methyl)-l,2- dihydro-3//, 8H-2a, 5, 8a-triazaacenaphthylene-3, 8-dione:
- gepotidacin or a pharmaceutically acceptable salt thereof.
- Pharmaceutically acceptable salts of gepotidacin include, but are not limited to gepotidacin hydrochloride and gepotidacin mesylate.
- the pharmaceutically acceptable salt is gepotidacin mesylate.
- the present invention provides a method for treating bacterial prostatitis in a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof.
- the bacterial prostatitis is acute bacterial prostatitis.
- the bacterial prostatitis is chronic bacterial prostatitis.
- a "human in need thereof” means a person having a prostate, who is diagnosed with prostatitis by a doctor. In one embodiment, the human in need thereof is a male.
- Prostatitis is a group of prostate disorders that manifests with a combination of predominantly irritative or obstructive urinary symptoms and perineal pain. (Andriole, G. (2020). Prostatitis. In Merck Manal Professional Version. Merck & Co., Inc. Retrieved March 18, 2021, from https://www.merckmanuals.com/professional/genitourinary-disorders/benign-prostate- disease/prostatitis). Prostatitis can be bacterial or non-bacterial. As used herein, "bacterial prostatitis" refers to prostatitis caused by bacteria.
- Prostatitis is classified into 4 categories according to the NIH Consensus Classification System for Prostatitis (Krieger, IN., Nyberg, L., Nickel, 1C. JAMA. 1999;282(3):236-237) - acute bacterial prostatitis, chronic bacterial prostatitis, chronic prostatitis/chronic pelvic pain syndrome; and asymptomatic inflammatory prostatitis.
- Patients with acute bacterial prostatitis often experience systemic symptoms such as fever, chills, malaise, and myalgias.
- Chronic bacterial prostatitis manifests with recurrent episodes of infection with or without complete resolution between bouts; symptoms can last for a month or more (e.g., symptoms lasting > 3 months).
- prostatitis caused by a bacterium may mean that the cited bacterium has been identified as being the cause or part of the cause of the prostatitis, or it may mean that the bacterium is suspected or strongly suspected to be the cause or part of the cause of the infection, due to identification of symptoms and other factors such as patient history or local epidemiology.
- Bacteria which are commonly identified as being the cause of bacterial prostatitis, or strongly suspected to be the cause of bacterial prostatitis, or part of the cause of bacterial prostatitis include Escherichia coll, Pseudomonas aeruginosa, Klebsiella spp. (including Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella aerogenes, and Klebsiella variicola), Enterococcus spp. (including Enterococcus faecalis, Enterococcus faecium, and Enterococcus cloacae complex , Proteus spp.
- Serratia spp including Serratia marcescens .
- Other less common causative bacteria include: Staphylococcus spp.
- Streptococcus spp including Staphylococcus saprophyticus, Staphylococcus lugdenensis, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans and Staphylococcus warneri), Streptococcus spp.
- Streptococcus agalactiae including Streptococcus agalactiae, Streptococcus group F, Streptococcus group G, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus vestibularis), Mycoplasma genitalium, Neisseria gonorrhoea, Salmonella spp, and Ureaplasma urealyticum.
- gepotidacin or pharmaceutically acceptable salt thereof against these and other organisms is shown in, for example, international patent application publication nos. W02008/ 128942, WO2016/027249, W02020/201833 and W02021/004910.
- gepotidacin or a pharmaceutically acceptable salt could be used against bacterial prostatitis caused by any bacterium against which gepotidacin has antibiotic activity.
- the bacteria which can be identified as being the cause of bacterial prostatitis, or strongly suspected to be the cause of bacterial prostatitis, or part of the cause of bacterial prostatitis is Escherichia coll.
- the human is administered gepotidacin or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days.
- the gepotidacin or a pharmaceutically acceptable salt thereof is administered at 1500 mg, b.i.d. (total daily dose 3000 mg) for 5 days.
- the gepotidacin or a pharmaceutically acceptable salt thereof is administered at two doses of 3000 mg each, 6-12 or 10- 12 hours apart.
- gepotidacin or a pharmaceutically acceptable salt thereof may be present in a pharmaceutical composition which comprises gepotidacin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient(s).
- the present invention provides a method for treating bacterial prostatitis in a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, wherein the human has failed at least one prior line of treatment for the bacterial prostatitis.
- the method for treating bacterial prostatitis in a human in need thereof comprises administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, wherein the human has failed one prior oral antibiotic treatment for the bacterial prostatitis.
- the prior oral antibiotic is a fluoroquinolone (e.g. ciprofloxacin, norfloxacin, levofloxacin or ofloxacin), trimethoprim-sulfamethoxazole or doxycycline.
- the present invention relates to resistance guided therapy for treating bacterial prostatitis, comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof.
- resistance guided therapy means a course of therapy, the direction of which is guided by knowledge of the phenotypic or genotypic susceptibility of the microorganism to a given antibiotic, for example as described in Bradshaw et al, The Journal of Infectious Diseases, Volume 216, Issue suppl_2, 15 July 2017, Pages S412-S419. Detecting the causative bacteria in an infection, then detecting resistance of the identified strain to certain antibiotics, in advance or during the course of treatment, has the advantage of potentially reducing the patient's exposure to ineffective antibiotics that may lead to resistance. Identification of a particular pathogen, for example Escherichia coii, may be performed by any suitable genotypic or phenotypic means, such as by NAAT.
- the present invention provides a resistance guided therapy for treating bacterial prostatitis caused by Escherichia coii comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, to a human in need thereof.
- the present invention relates to resistance guided therapy for treating bacterial prostatitis caused by Escherichia coii, where the bacterial prostatitis is acute bacterial prostatitis.
- the present invention relates to resistance guided therapy for treating bacterial prostatitis caused by Escherichia coii, where the bacterial prostatitis is chronic bacterial prostatitis.
- the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of bacterial prostatitis in a human.
- the bacterial prostatitis is acute bacterial prostatitis.
- the bacterial prostatitis is chronic bacterial prostatitis.
- the bacterial prostatitis is caused by Escherichia coil
- the present invention provides use of gepotidacin or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of bacterial prostatitis in a human.
- the bacterial prostatitis is acute bacterial prostatitis.
- the bacterial prostatitis is chronic bacterial prostatitis.
- the bacterial prostatitis is caused by Escherichia coil
- the present invention provides a kit comprising gepotidacin or a pharmaceutically acceptable salt thereof, for use in the treatment of bacterial prostatitis in a human.
- the bacterial prostatitis is acute bacterial prostatitis.
- the bacterial prostatitis is chronic bacterial prostatitis.
- the bacterial prostatitis is caused by Escherichia coil
- the present invention relates to a use of a pharmaceutical composition as defined in the present invention for the manufacture of a medicament for treating bacterial prostatitis, such as acute bacterial prostatitis or chronic bacterial prostatitis.
- the present invention relates to a use of a pharmaceutical composition as defined in the present invention for resistance guided therapy for treating bacterial prostatitis caused by Escherichia coii, in a human in need thereof.
- WO2008/128942 discloses the preparation of the free base and the hydrochloride salt of gepotidacin.
- gepotidacin or a pharmaceutically acceptable salt thereof is intended to encompass gepotidacin, a pharmaceutically acceptable salt of gepotidacin, a solvate of gepotidacin, or any pharmaceutically acceptable combination of these.
- gepotidacin or a pharmaceutically acceptable salt thereof may include a pharmaceutically acceptable salt of gepotidacin that is further present as a solvate.
- gepotidacin or any pharmaceutically acceptable salt thereof may be in any physical form thereof, including non-solid forms such as liquid or semi-solid forms, solid forms such as amorphous or crystalline forms, specific polymorphic forms and solvates including hydrates.
- Suitable pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse IPharm.Sci (1977) 66, pp 1-19.
- the gepotidacin is gepotidacin free base or is gepotidacin methanesulphonate (mesylate).
- the present invention includes within its scope all possible stoichiometric and non- stoich iometric salt forms.
- gepotidacin or pharmaceutically acceptable salts used in the present invention may be formulated for administration for use in human or veterinary medicine, by analogy with other antibacterials/antitubercular compounds.
- compositions used in the present invention may be formulated for administration by any route and include those in a form adapted for oral or parenteral use and may be used in mammals including humans.
- compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
- the gepotidacin or pharmaceutically acceptable saltthereof of the present invention is in a tablet or a capsule form. In one embodiment, it is in a tablet form. In one embodiment, the tablet is a 750mg tablet.
- fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
- the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
- the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
- the quantity of the compound or pharmaceutical composition used in the present invention administered will vary depending on the patient and the mode of administration and can be any effective amount.
- a "therapeutically effective amount" generally includes within its meaning a non-toxic but sufficient amount of the particular drug to which it is referring to provide the desired therapeutic effect.
- compositions comprise dosage units, each unit will preferably contain from 50-1000 mg of the active ingredient.
- amount of the active ingredient refers to that of gepotidacin free base.
- the compounds, and/or compositions of the present invention can be administered orally, intravascularly, intraperitoneally, subcutaneously, or intramuscularly.
- the composition is adapted for oral administration.
- the gepotidacin or a pharmaceutically acceptable salt thereof is administered orally.
- the example herein describes microdialysis experiments in E coli infected rats to measure tissue distribution of unbound gepotidacin.
- In vivo microdialysis experiments simultaneously determined unbound gepotidacin concentrations in rat prostate, muscle, and blood. It is important to understand the tissue distribution of unbound gepotidacin, especially in the target prostate tissue, since gepotidacin must diffuse through capillary membranes to reach the prostate. An assumption that the plasma concentration of gepotidacin represents a suitable surrogate of prostate concentrations, without prostate tissue confirmation, may lead to erroneous conclusions, especially since the pathogen is localized in the prostate.
- Blood, muscle, and prostate dialysates were collected every 10 minutes for 90 minutes, and then every 30 minutes for 300 minutes (6 hours). Seven blood samples were also collected for analysis of gepotidacin pharmacokinetics in total plasma. Gepotidacin concentrations were measured in dialysates and in plasma by LC-MS/MS.
- PK Pharmacokinetic
- AUC u ,biood is the total area under the unbound blood concentration-versus-time curve from zero to infinity, equal to the area under the curve from zero to the last measured concentration
- AUCo-iast,u,biood added to the area under the curve from the last measured concentration to infinity
- AUCiast-infinity,u,biood was calculated by linear-logarithmic trapezoidal method.
- AUCiast-infinity,u blood the area remaining under the curve after the last measured concentration, C(last) u , blood was determined from C(last) u ,biood/kebiood.
- the linear-logarithmic trapezoidal method was used to compute the area under the unbound blood concentration-versus-time moment curve AUMCo-iast,u,biood from zero to the last measured concentration.
- AUMCiast -infinity, u blood the area remaining under the curve after the last measured concentration was determined from: tlast x C(last) u ,biood/kebiood + C(last) u ,biood/kebiood 2 .
- the mean residence time from zero to infinity, MRTo-infinity was determined from AUMCo-infinity,u,biood/AUCo- infinity,u, blood.
- the volume of distribution (Vss u ) was obtained from MRTo-infinity x CL U .
- the AUCu and ti/z,u in tissues were also estimated by the same procedure.
- Unbound concentrations of gepotidacin are illustrated in healthy control across different tissue types (blood, muscle, and prostate) in FIG. 1A, IB.
- the unbound concentration time profile in blood was biphasic and the concentration profiles in prostate and muscle were almost superimposed with blood concentrations with the exception of the first time point (FIG 1A).
- the prostatitis (i.e., infected) rats the unbound gepotidacin concentration time profile in blood was also biphasic and gepotidacin concentrations in prostate appear slightly lower than in blood (FIG. 1C-1D).
- Pharmacokinetic parameter values obtained in the healthy and infected groups are presented in Tables 1 and 2.
- NCT04484740 The present study (NCT04484740) is to determine concentrations of gepotidacin in plasma, prostate and tonsillar tissue of patients undergoing radical prostatectomy (RPE) for localized prostate, simple prostatectomy (PE) for benign prostate hyperplasia (BPH) or tonsillectomy (TE).
- RPE radical prostatectomy
- PE simple prostatectomy
- BPH benign prostate hyperplasia
- TE tonsillectomy
- a single oral dose of 1500 mg gepotidacin will be administered to patients who will undergo radical prostatectomy (RPE) or simple prostatectomy (PE) and patients undergoing tonsillectomy (TE).
- RPE radical prostatectomy
- PE simple prostatectomy
- TE tonsillectomy
- the individual time-points of gepotidacin administration will be chosen to ensure that the time-point of tissue removal corresponds with one of six different sampling time-points, as closely as possible.
- RPE or TE will be performed according to clinical routine.
- microdialysis (MD) probes will be inserted in the removed tissue (tonsillar or prostate tissue) ex-vivo and MD will be performed to determine unbound drug concentrations in the tissue.
- Plasma PK samples will be collected just before study drug administration and up to 48h after administration of gepotidacin.
- MD provides the concentration of the unbound fraction of gepotidacin
- NCA non-compartmental analysis
- PopPK population pharmacokinetic models
- NCT04484740 determined concentrations of gepotidacin in plasma, prostate and tonsillar tissue of patients undergoing radical prostatectomy (RPE) for localized prostate, simple prostatectomy (PE) for benign prostate hyperplasia (BPH) or tonsillectomy (TE).
- RPE radical prostatectomy
- PE simple prostatectomy
- BPH benign prostate hyperplasia
- TE tonsillectomy
- a single oral dose of 1500 mg gepotidacin was administered to patients who were scheduled to undergo radical prostatectomy (RPE) or simple prostatectomy (PE) and patients undergoing tonsillectomy (TE).
- RPE radical prostatectomy
- PE simple prostatectomy
- TE tonsillectomy
- the individual time-points of gepotidacin administration were chosen to ensure that the time-point of tissue removal corresponds with one of six different sampling time-points up to 24h, as closely as possible.
- RPE or TE was performed according to clinical routine.
- MD microdialysis
- Plasma PK Blood samples for plasma PK were collected just before study drug administration and up to 48h after administration of gepotidacin. Since MD samples provided the unbound gepotidacin concentrations, for comparison plasma PK was adjusted based on the measured in vitro unbound fraction.
- Plasma PK parameters were obtained using non-compartmental analysis (NCA), whereas tissue PK parameters were obtained using a population pharmacokinetic modeling approach (PopPK) that incorporated plasma and tissue concentrations.
- NCA non-compartmental analysis
- PopPK population pharmacokinetic modeling approach
Abstract
The present invention relates to methods for treating bacterial prostatitis, which comprises administration of gepotidacin or pharmaceutically acceptable salts thereof to a human in need thereof.
Description
GEPOTIDACIN FOR USE IN THE TREATMENT OF BACTERIAL PROSTATITIS
The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement n° 853976. This Joint Undertaking receives the support from the European Union's Horizon 2020 research and innovation programme and EFPIA.
FIELD OF THE INVENTION
The present invention relates to methods of treatment, pharmaceutical compositions, or resistance guided therapies and/or corresponding uses thereof for treating bacterial prostatitis, which comprises administration of gepotidacin or pharmaceutically acceptable salts thereof.
BACKGROUND TO THE INVENTION
Prostatitis ranges from a straightforward clinical diagnosis in its acute form to a complex, debilitating condition when chronic. It is often a source of frustration for the treating physician and patient. Prostatitis accounts for 8% of visits to urologists, and up to 1% of visits to primary care physicians. In 2000, the estimated cost to diagnose and treat prostatitis was $84 million. Patients with chronic prostatitis often experience impaired mental and physical health-related quality of life. Acute bacterial prostatitis is estimated to comprise approximately 10% of all prostatitis cases.
The challenges of treating bacterial prostatitis with antibiotics are myriad. While the prostate is located near the bladder and urethra, the prostate is not directly connected to the urinary tract through vascular connections. The prostate is also not a highly vascularized organ. Together, this can limit drug exposure to the prostate. Additionally, due to the prostate's anatomical location, it can be difficult to measure drug exposure in the prostate to determine if a drug is adequately reaching the prostate. For at least these reasons, finding effective treatments for bacterial prostatitis can be challenging.
To date, a variety of antibacterial drugs have been developed which have become clinically extremely important antimicrobial drugs. Researchers at GSK described a novel class of antibacterial agents that target type IIA topoisomerases [see Nature, Volume 466, pages 935-940 (19 August 2010) and Gibson et al. Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase, ACS Infectious Disease, 2019, 5, 570-581] that has shown activity against a broad spectrum of gram-positive and gram-negative bacteria. International Patent Publication WO 2008/128942 and U.S. Patent No. 8,389,524, hereby incorporated by reference in their entirety, disclose tricyclic nitrogen containing compounds as antibacterial compounds, pharmaceutical compositions and corresponding uses thereof. To date, the utility of gepotidacin in the treatment of bacterial prostatitis has not been shown.
There is a demand for development of effective antibiotics for treating bacterial prostatitis. The present invention is directed to overcoming these and other problems encountered in the art.
SUMMARY OF THE INVENTION
The present invention provides a method for treating bacterial prostatitis in a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof.
The present invention also provides use of gepotidacin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of bacterial prostatitis.
The present invention also provides a kit comprising gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of bacterial prostatitis.
DESCRIPTION OF DRAWINGS/FIGURES
FIGs. 1A-1D show unbound gepotidacin concentrations in blood, muscle, and prostate tissue in healthy and infected rats. Dots, triangles or squares are means, bars represent ± 1 standard deviation. FIG. 1A shows decimal representation of unbound gepotidacin concentrations in healthy rats. FIG. IB shows semi-log representation of unbound gepotidacin in healthy rats. FIG. 1C shows decimal representation of unbound gepotidacin concentrations in infected rats. FIG. ID shows semilog representation of unbound gepotidacin in infected rats.
DETAILED DESCRIPTION OF THE INVENTION
The terms "antimicrobial", "antibiotic" and "antibacterial" are used interchangeably in the present application, and refer to any natural or synthetic compound which kills or inhibits the growth of a microorganism.
Further as understood in the present invention, antibiotic resistance occurs when bacteria change in response to the use of antibiotics, making them ineffective; and antimicrobial resistance is a broader term, encompassing resistance to drugs that treat infections caused by other microbes as well, such as parasites (e.g. malaria or helminths), viruses (e.g. HIV) and fungi (e.g. Candida).
Gepotidacin is a first-in-class, novel triazaacenaphthylene antibiotic with the ability to selectively inhibit bacterial DNA replication by a means not utilized by any currently approved human therapeutic agent, therefore providing the opportunity to address an unmet medical need. Gepotidacin and its racemic form is disclosed in WO 2008/128942 (herein incorporated in its entirety). Gepotidacin is (2 )-2-({ -[(3, -dihydro-2/ -pyrano[2,3-c]pyridin-6-ylmethyl)amino]-l-piperidinyl}methyl)-l,2- dihydro-3//, 8H-2a, 5, 8a-triazaacenaphthylene-3, 8-dione:
The methods and uses of the present invention are based on gepotidacin or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of gepotidacin include, but are not limited to gepotidacin hydrochloride and gepotidacin mesylate. In an embodiment, the pharmaceutically acceptable salt is gepotidacin mesylate.
International Patent Application Publication No. WO 2021/219637 (herein incorporated in its entirety) describes certain crystalline forms of gepotidacin, including gepotidacin mesylate dihydrate, gepotidacin mesylate anhydrate, gepotidacin mesylate monohydrate and gepotidacin anhydrate (free base). In a first aspect, the present invention provides a method for treating bacterial prostatitis in a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof. In one embodiment, the bacterial prostatitis is acute bacterial prostatitis. In another embodiment, the bacterial prostatitis is chronic bacterial prostatitis.
As used herein, a "human in need thereof" means a person having a prostate, who is diagnosed with prostatitis by a doctor. In one embodiment, the human in need thereof is a male.
Prostatitis is a group of prostate disorders that manifests with a combination of predominantly irritative or obstructive urinary symptoms and perineal pain. (Andriole, G. (2020). Prostatitis. In Merck Manal Professional Version. Merck & Co., Inc. Retrieved March 18, 2021, from https://www.merckmanuals.com/professional/genitourinary-disorders/benign-prostate- disease/prostatitis). Prostatitis can be bacterial or non-bacterial. As used herein, "bacterial prostatitis" refers to prostatitis caused by bacteria. Prostatitis is classified into 4 categories according to the NIH Consensus Classification System for Prostatitis (Krieger, IN., Nyberg, L., Nickel, 1C. JAMA. 1999;282(3):236-237) - acute bacterial prostatitis, chronic bacterial prostatitis, chronic prostatitis/chronic pelvic pain syndrome; and asymptomatic inflammatory prostatitis. Patients with acute bacterial prostatitis often experience systemic symptoms such as fever, chills, malaise, and myalgias. Chronic bacterial prostatitis manifests with recurrent episodes of infection with or without complete resolution between bouts; symptoms can last for a month or more (e.g., symptoms lasting > 3 months).
As used herein, "prostatitis caused by a bacterium" may mean that the cited bacterium has been identified as being the cause or part of the cause of the prostatitis, or it may mean that the bacterium is suspected or strongly suspected to be the cause or part of the cause of the infection, due to identification of symptoms and other factors such as patient history or local epidemiology.
Bacteria which are commonly identified as being the cause of bacterial prostatitis, or strongly suspected to be the cause of bacterial prostatitis, or part of the cause of bacterial prostatitis, include Escherichia coll, Pseudomonas aeruginosa, Klebsiella spp. (including Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella aerogenes, and Klebsiella variicola), Enterococcus spp. (including Enterococcus faecalis, Enterococcus faecium, and Enterococcus cloacae complex , Proteus spp. (including Proteus mirabih's, Proteus hauseri and Proteus peneri), and Serratia spp. (including Serratia marcescens . Other less common causative bacteria include: Staphylococcus spp. (including Staphylococcus saprophyticus, Staphylococcus lugdenensis, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans and Staphylococcus warneri), Streptococcus spp. (including Streptococcus agalactiae, Streptococcus group F, Streptococcus group G, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus vestibularis), Mycoplasma genitalium, Neisseria gonorrhoea, Salmonella spp, and Ureaplasma urealyticum. The in vitro efficacy of gepotidacin or pharmaceutically acceptable salt thereof against these and other organisms is shown in, for example, international patent application publication nos. W02008/ 128942, WO2016/027249, W02020/201833 and W02021/004910. As would be understood by the skilled person, it is envisaged that gepotidacin or a pharmaceutically acceptable salt could be used against bacterial prostatitis caused by any bacterium against which gepotidacin has antibiotic activity.
In an aspect, the bacteria which can be identified as being the cause of bacterial prostatitis, or strongly suspected to be the cause of bacterial prostatitis, or part of the cause of bacterial prostatitis is Escherichia coll.
In one embodiment, for any aspect of the present invention, the human is administered gepotidacin or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days. In one embodiment, for any aspect of the present invention, the gepotidacin or a pharmaceutically acceptable salt thereof is administered at 1500 mg, b.i.d. (total daily dose 3000 mg) for 5 days. In another embodiment, for any aspect of the present invention, the gepotidacin or a
pharmaceutically acceptable salt thereof is administered at two doses of 3000 mg each, 6-12 or 10- 12 hours apart.
The gepotidacin or a pharmaceutically acceptable salt thereof may be present in a pharmaceutical composition which comprises gepotidacin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient(s).
In one aspect, the present invention provides a method for treating bacterial prostatitis in a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, wherein the human has failed at least one prior line of treatment for the bacterial prostatitis. In one embodiment, the method for treating bacterial prostatitis in a human in need thereof comprises administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, wherein the human has failed one prior oral antibiotic treatment for the bacterial prostatitis. In one embodiment, the prior oral antibiotic is a fluoroquinolone (e.g. ciprofloxacin, norfloxacin, levofloxacin or ofloxacin), trimethoprim-sulfamethoxazole or doxycycline.
In another aspect, the present invention relates to resistance guided therapy for treating bacterial prostatitis, comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof.
As would be understood by the skilled person, as used herein, "resistance guided therapy" means a course of therapy, the direction of which is guided by knowledge of the phenotypic or genotypic susceptibility of the microorganism to a given antibiotic, for example as described in Bradshaw et al, The Journal of Infectious Diseases, Volume 216, Issue suppl_2, 15 July 2017, Pages S412-S419. Detecting the causative bacteria in an infection, then detecting resistance of the identified strain to certain antibiotics, in advance or during the course of treatment, has the advantage of potentially reducing the patient's exposure to ineffective antibiotics that may lead to resistance. Identification of a particular pathogen, for example Escherichia coii, may be performed by any suitable genotypic or phenotypic means, such as by NAAT.
Thus in one aspect, the present invention provides a resistance guided therapy for treating bacterial prostatitis caused by Escherichia coii comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, to a human in need thereof.
In one aspect, the present invention relates to resistance guided therapy for treating bacterial prostatitis caused by Escherichia coii, where the bacterial prostatitis is acute bacterial prostatitis.
In one aspect, the present invention relates to resistance guided therapy for treating bacterial prostatitis caused by Escherichia coii, where the bacterial prostatitis is chronic bacterial prostatitis.
In another aspect, the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of bacterial prostatitis in a human. In an aspect, the
bacterial prostatitis is acute bacterial prostatitis. In another aspect, the bacterial prostatitis is chronic bacterial prostatitis. In an embodiment, the bacterial prostatitis is caused by Escherichia coil
In another aspect, the present invention provides use of gepotidacin or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of bacterial prostatitis in a human. In an aspect, the bacterial prostatitis is acute bacterial prostatitis. In another aspect, the bacterial prostatitis is chronic bacterial prostatitis. In an embodiment, the bacterial prostatitis is caused by Escherichia coil
In another aspect, the present invention provides a kit comprising gepotidacin or a pharmaceutically acceptable salt thereof, for use in the treatment of bacterial prostatitis in a human. In an aspect, the bacterial prostatitis is acute bacterial prostatitis. In another aspect, the bacterial prostatitis is chronic bacterial prostatitis. In an embodiment, the bacterial prostatitis is caused by Escherichia coil
In another aspect, the present invention relates to a use of a pharmaceutical composition as defined in the present invention for the manufacture of a medicament for treating bacterial prostatitis, such as acute bacterial prostatitis or chronic bacterial prostatitis.
In another aspect, the present invention relates to a use of a pharmaceutical composition as defined in the present invention for resistance guided therapy for treating bacterial prostatitis caused by Escherichia coii, in a human in need thereof.
Compounds Used In The Present Invention
WO2008/128942 discloses the preparation of the free base and the hydrochloride salt of gepotidacin.
It will be understood that the phrase "gepotidacin or a pharmaceutically acceptable salt thereof" is intended to encompass gepotidacin, a pharmaceutically acceptable salt of gepotidacin, a solvate of gepotidacin, or any pharmaceutically acceptable combination of these. Thus by way of non-limiting example used here for illustrative purpose, "gepotidacin or a pharmaceutically acceptable salt thereof" may include a pharmaceutically acceptable salt of gepotidacin that is further present as a solvate.
As used herein, gepotidacin or any pharmaceutically acceptable salt thereof may be in any physical form thereof, including non-solid forms such as liquid or semi-solid forms, solid forms such as amorphous or crystalline forms, specific polymorphic forms and solvates including hydrates.
Suitable pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse IPharm.Sci (1977) 66, pp 1-19.
In one embodiment, in any aspect of the invention, the gepotidacin is gepotidacin free base or is gepotidacin methanesulphonate (mesylate).
The present invention includes within its scope all possible stoichiometric and non- stoich iometric salt forms.
Pharmaceutical Compositions And Formulations
In particular, gepotidacin or pharmaceutically acceptable salts, used in the present invention may be formulated for administration for use in human or veterinary medicine, by analogy with other antibacterials/antitubercular compounds.
The pharmaceutical compositions used in the present invention may be formulated for administration by any route and include those in a form adapted for oral or parenteral use and may be used in mammals including humans.
The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
In one embodiment, the gepotidacin or pharmaceutically acceptable saltthereof of the present invention is in a tablet or a capsule form. In one embodiment, it is in a tablet form. In one embodiment, the tablet is a 750mg tablet.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Moreover, the quantity of the compound or pharmaceutical composition used in the present invention administered will vary depending on the patient and the mode of administration and can be any effective amount.
In accordance with any of the methods of administration of the present invention, the term a "therapeutically effective amount", as used herein, generally includes within its meaning a non-toxic but sufficient amount of the particular drug to which it is referring to provide the desired therapeutic effect.
Treatment regimens for the administration of the compounds and/or pharmaceutical compositions used in the present invention can also be determined readily by those with ordinary skill in art. Where the compositions comprise dosage units, each unit will preferably contain from 50-1000 mg of the active ingredient. Unless otherwise noted, the amount of the active ingredient (i.e., gepotidacin) refers to that of gepotidacin free base.
Depending upon the treatment being effected, the compounds, and/or compositions of the present invention can be administered orally, intravascularly, intraperitoneally, subcutaneously, or intramuscularly. Preferably, the composition is adapted for oral administration. In any of the above
aspects of the present invention, in one embodiment, the gepotidacin or a pharmaceutically acceptable salt thereof is administered orally.
It is to be understood that the invention is not limited to the aspects or embodiments illustrated hereinabove and the right is reserved to the illustrated aspects or embodiments and all modifications coming within the scope of the following claims.
The various references to journals, patents, and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.
The Examples set forth below are illustrative of the present invention and are not intended to limit, in any way, the scope of the present invention.
EXAMPLE 1
The example herein describes microdialysis experiments in E coli infected rats to measure tissue distribution of unbound gepotidacin. In vivo microdialysis experiments simultaneously determined unbound gepotidacin concentrations in rat prostate, muscle, and blood. It is important to understand the tissue distribution of unbound gepotidacin, especially in the target prostate tissue, since gepotidacin must diffuse through capillary membranes to reach the prostate. An assumption that the plasma concentration of gepotidacin represents a suitable surrogate of prostate concentrations, without prostate tissue confirmation, may lead to erroneous conclusions, especially since the pathogen is localized in the prostate.
Unbound gepotidacin concentrations in blood, muscle, and prostate were found to be similar across all tissues, thus indicating that gepotidacin is sufficiently delivered to the prostate and supports the conclusion that gepotidacin is effective in treating bacterial prostatitis.
Methods
In vivo microdialysis in rats
An Escherichia coii prostatitis model in rats was obtained as follows. Four days before microdialysis, rats (n= 11) were infected with Escherichia coii ATCC 13441 in the prostatic urethra, to induce E. coii prostatitis, at an inoculum of 107 CFU/rat. Healthy rats (n=9) were not infected with E. coii as control.
The day before the experiment, two CMA/20 probes (membrane length 10mm, Harvard Apparatus, Courtaboeuf France) were inserted into right jugular vein and the right hind leg muscle of healthy and infected rats under anesthesia and analgesic treatment. In parallel, catheters were inserted into the femoral vein and artery to administer gepotidacin intravenously (IV) and to collect blood samples for determination of total plasma gepotidacin concentrations, respectively. The rats were allowed to recover consciousness, and food was withdrawn for 12 hours.
On the day of the experiment, healthy control and infected rats were re-anesthetized and a CMA/20 Elite probe (membrane length 4mm) was inserted into the prostate. All probes were connected to infusion pumps and perfused with Ringer containing a calibrator (((R)-l-((4-(((2,3- dihydro-[l,4]oxathiino[2,3-c]pyridin-7-yl)methyl)amino)piperidin-l-yl)methyl)-l,2-dihydro-3H,8l-l- 2a, 5, 8a-triazaacenaphthylene-3, 8-dione; 1500 n/mL) at a flow rate of 0.5 pL/min with Ringer. After an equilibration period, gepotidacin was administered by IV bolus at a dose of 20 mg/kg. Blood, muscle, and prostate dialysates were collected every 10 minutes for 90 minutes, and then every 30 minutes for 300 minutes (6 hours). Seven blood samples were also collected for analysis of gepotidacin pharmacokinetics in total plasma. Gepotidacin concentrations were measured in dialysates and in plasma by LC-MS/MS.
Data Analysis
Pharmacokinetic (PK) parameters were determined in each individual rat by a noncompartmental approach according to standard procedures and with the software Phoenix WinNonLin 7. (Certara, Princeton, NJ) Total unbound body clearance (CLU) was calculated as CLU = dose/AUCu, blood, where AUCu,biood is the total area under the unbound blood concentration-versus-time curve from zero to infinity, equal to the area under the curve from zero to the last measured concentration AUCo-iast,u,biood added to the area under the curve from the last measured concentration to infinity AUCiast-infinity,u,biood. AUCo-iast,u, blood was calculated by linear-logarithmic trapezoidal method. AUCiast-infinity,u, blood the area remaining under the curve after the last measured concentration, C(last)u, blood was determined from C(last)u,biood/kebiood. The elimination rate constant (kebiood) and its corresponding half-life (ti/z,biood) were estimated by least squares fit of the data points (log concentration-time). The linear-logarithmic trapezoidal method was used to compute the area under the unbound blood concentration-versus-time moment curve AUMCo-iast,u,biood from zero to the last measured concentration. AUMCiast -infinity, u, blood the area remaining under the curve after the last measured concentration was determined from: tlast x C(last)u,biood/kebiood + C(last)u,biood/kebiood2. The mean residence time from zero to infinity, MRTo-infinity was determined from AUMCo-infinity,u,biood/AUCo- infinity,u, blood. The volume of distribution (Vssu) was obtained from MRTo-infinity x CLU. The AUCu and ti/z,u in tissues were also estimated by the same procedure.
Results
Unbound concentrations of gepotidacin are illustrated in healthy control across different tissue types (blood, muscle, and prostate) in FIG. 1A, IB. The unbound concentration time profile in blood was biphasic and the concentration profiles in prostate and muscle were almost superimposed with blood concentrations with the exception of the first time point (FIG 1A). In the prostatitis (i.e.,
infected) rats, the unbound gepotidacin concentration time profile in blood was also biphasic and gepotidacin concentrations in prostate appear slightly lower than in blood (FIG. 1C-1D). Pharmacokinetic parameter values obtained in the healthy and infected groups are presented in Tables 1 and 2. Gepotidacin half-life and Cmax,u in blood, muscle, and prostate of healthy control rats were similar (Table 1) and this comparability is supported with AUCu ratios of approximately 1 (Table 2). In infected rats, Cmax in prostate were slightly lower compared to healthy rats but gepotidacin half-lives were the same between blood, muscle, and prostate. (Table 1). The muscle/blood and prostate/blood AUCu ratios in infected animals were not significantly different than those obtained in healthy rats (p>0.05, Wilcoxon test, R software) (Table 2). Table 1
In parallel to microdialysis, total PK parameters were obtained from total plasma concentrations and are presented in Table 3. The total plasma results are similar to microdialysis.
EXAMPLE 2
The present study (NCT04484740) is to determine concentrations of gepotidacin in plasma, prostate and tonsillar tissue of patients undergoing radical prostatectomy (RPE) for localized prostate, simple prostatectomy (PE) for benign prostate hyperplasia (BPH) or tonsillectomy (TE).
A single oral dose of 1500 mg gepotidacin will be administered to patients who will undergo radical prostatectomy (RPE) or simple prostatectomy (PE) and patients undergoing tonsillectomy (TE). The individual time-points of gepotidacin administration will be chosen to ensure that the time-point of tissue removal corresponds with one of six different sampling time-points, as closely as possible. After study drug administration RPE or TE will be performed according to clinical routine.
Subsequently, microdialysis (MD) probes will be inserted in the removed tissue (tonsillar or prostate tissue) ex-vivo and MD will be performed to determine unbound drug concentrations in the tissue.
Plasma PK samples will be collected just before study drug administration and up to 48h after administration of gepotidacin.
Since MD provides the concentration of the unbound fraction of gepotidacin, for comparison we will calculate the unbound fraction of the concentration values obtained through blood sampling. To this end, we will determine the protein binding using ultrafiltration for each subject at the timepoint closest to the Cmax. The individual protein binding can then be used to calculate the unbound plasma fraction of gepotidacin. This will allow to transform the plasma PK data to the same scale as the microdialysis data.
Samples will be analysed using non-compartmental analysis (NCA) for plasma concentrations and population pharmacokinetic models (PopPK) for tissue concentrations pooled with plasma concentrations.
EXAMPLE 3
The present study (NCT04484740) determined concentrations of gepotidacin in plasma, prostate and tonsillar tissue of patients undergoing radical prostatectomy (RPE) for localized prostate, simple prostatectomy (PE) for benign prostate hyperplasia (BPH) or tonsillectomy (TE).
A single oral dose of 1500 mg gepotidacin was administered to patients who were scheduled to undergo radical prostatectomy (RPE) or simple prostatectomy (PE) and patients undergoing tonsillectomy (TE). The individual time-points of gepotidacin administration were chosen to ensure that the time-point of tissue removal corresponds with one of six different sampling time-points up to 24h, as closely as possible. After study drug administration RPE or TE was performed according to clinical routine.
Subsequently, microdialysis (MD) probes were inserted in the removed tissue (tonsillar or prostate tissue) ex-vivo and MD was performed to obtain samples for the determination of unbound drug concentrations in the tissue.
Blood samples for plasma PK were collected just before study drug administration and up to 48h after administration of gepotidacin. Since MD samples provided the unbound gepotidacin concentrations, for comparison plasma PK was adjusted based on the measured in vitro unbound fraction.
Plasma PK parameters were obtained using non-compartmental analysis (NCA), whereas tissue PK parameters were obtained using a population pharmacokinetic modeling approach (PopPK) that incorporated plasma and tissue concentrations.
Data Analysis
Available data
47 patients had assayable plasma concentrations, 29 were from the prostate cohort and 18 from the tonsil cohort. 24 patients from the prostate cohort had at least 1 assayable tissue sample, 11 patients from the tonsil cohort had at least 1 assayable tissue sample. In total 522 plasma samples, 94 prostate samples and 25 tonsil samples were collected.
Claims
1. A method for treating bacterial prostatitis in a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof.
2. The method as claimed in claim 1, wherein the bacterial prostatitis is acute prostatitis.
3. The method as claimed in claim 1, wherein the bacterial prostatitis is chronic prostatitis.
4. The method as claimed in any one of claims 1-3 wherein the bacterial prostatitis is caused by bacteria selected from the group consisting of Escherichia coll, Pseudomonas aeruginosa, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella aerogenes, Klebsiella variicola, Enterococcus faecalis, Enterococcus faecium, Enterococcus cloacae complex, Proteus mirabilis, Proteus hauseri, Proteus peneri, Serratia marcescens, Staphylococcus saprophyticus, Staphylococcus lugdenensis, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans Staphylococcus warneri, Streptococcus agalactiae, Streptococcus group F, Streptococcus group G, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus cristatus, Streptococcus gordonii, Streptococcus infantarius, Streptococcus infantis, Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus vestibularis, Mycoplasma genitalium, Neisseria gonorrhoea, Salmonella spp, and Urea plasma urealyticum.
5. The method as claimed in any of claims 1-4, wherein the bacteria is Escherichia coll.
6. The method as claimed in any of claims 1-5, wherein the gepotidacin is gepotidacin mesylate.
7. The method as claimed in any of claim 6, wherein the gepotidacin is gepotidacin mesylate di hydrate.
8. The method as claimed in any of claims 1-7, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered orally.
9. The method as claimed in any of claims 1-8, wherein the human has failed at least one prior line of treatment for the bacterial prostatitis.
10. Gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of bacterial prostatitis in a human.
11. Use of gepotidacin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of bacterial prostatitis in a human.
12. A kit comprising gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of bacterial prostatitis in a human.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202263377064P | 2022-09-26 | 2022-09-26 | |
US63/377,064 | 2022-09-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024068524A1 true WO2024068524A1 (en) | 2024-04-04 |
Family
ID=88204074
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2023/076355 WO2024068524A1 (en) | 2022-09-26 | 2023-09-25 | Gepotidacin for use in the treatment of bacterial prostatitis |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024068524A1 (en) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008128942A1 (en) | 2007-04-20 | 2008-10-30 | Glaxo Group Limited | Tricyclic nitrogen containing compounds as antibacterial agents |
WO2016027249A1 (en) | 2014-08-22 | 2016-02-25 | Glaxosmithkline Intellectual Property Development Limited | Tricyclic nitrogen containing compounds for treating neisseria gonorrhoea infection |
WO2020201833A1 (en) | 2019-04-03 | 2020-10-08 | Glaxomithkline Intellectual Property Development Limited | Gepotidacin for use in the treatment of bacterial urinary tract infections |
WO2021004910A1 (en) | 2019-07-05 | 2021-01-14 | Glaxosmithkline Intellectual Property Development Limited | Combination for the treatment of infections caused by mycoplasma genitalium |
WO2021198715A1 (en) * | 2020-04-02 | 2021-10-07 | Glaxosmithkline Intellectual Property Development Limited | Regimen for treating a neisseria gonorrhoeae infection with gepotidacin |
WO2021219637A1 (en) | 2020-04-29 | 2021-11-04 | Glaxosmithkline Intellectual Property Development Limited | Crystalline forms of gepotidacin |
-
2023
- 2023-09-25 WO PCT/EP2023/076355 patent/WO2024068524A1/en unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008128942A1 (en) | 2007-04-20 | 2008-10-30 | Glaxo Group Limited | Tricyclic nitrogen containing compounds as antibacterial agents |
US8389524B2 (en) | 2007-04-20 | 2013-03-05 | Glaxo Group Limited | Tricyclic nitrogen containing compounds as antibacterial agents |
WO2016027249A1 (en) | 2014-08-22 | 2016-02-25 | Glaxosmithkline Intellectual Property Development Limited | Tricyclic nitrogen containing compounds for treating neisseria gonorrhoea infection |
WO2020201833A1 (en) | 2019-04-03 | 2020-10-08 | Glaxomithkline Intellectual Property Development Limited | Gepotidacin for use in the treatment of bacterial urinary tract infections |
WO2021004910A1 (en) | 2019-07-05 | 2021-01-14 | Glaxosmithkline Intellectual Property Development Limited | Combination for the treatment of infections caused by mycoplasma genitalium |
WO2021198715A1 (en) * | 2020-04-02 | 2021-10-07 | Glaxosmithkline Intellectual Property Development Limited | Regimen for treating a neisseria gonorrhoeae infection with gepotidacin |
WO2021219637A1 (en) | 2020-04-29 | 2021-11-04 | Glaxosmithkline Intellectual Property Development Limited | Crystalline forms of gepotidacin |
Non-Patent Citations (8)
Title |
---|
ANDRIOLE, G.: "Prostatitis", 2020, MERCK & CO., INC., article "Merck Manal Professional Version" |
BERGEBIGHLEYMONKHOUSE, J.PHARM.SCI, vol. 66, 1977, pages 1 - 19 |
BRADSHAW ET AL., THE JOURNAL OF INFECTIOUS DISEASES, vol. 216, no. 2, 15 July 2017 (2017-07-15), pages S412 - S419 |
GIBSON ET AL.: "Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase", ACS INFECTIOUS DISEASE, vol. 5, 2019, pages 570 - 581, XP055715568, DOI: 10.1021/acsinfecdis.8b00315 |
JENSEN JØRGEN SKOV ET AL: "In vitro activity of the first-in-class triazaacenaphthylene gepotidacin alone and in combination with doxycycline against drug-resistant and -susceptible Mycoplasma genitalium", EMERGING MICROBES & INFECTIONS, vol. 9, no. 1, 1 January 2020 (2020-01-01), pages 1388 - 1392, XP093100657, DOI: 10.1080/22221751.2020.1775498 * |
KRIEGER, J.N.NYBERG, L.NICKEL, J.C., JAMA, vol. 282, no. 3, 1999, pages 236 - 237 |
MARQUEZ-ALGABA ESTER ET AL: "Pharmacotherapeutic interventions for the treatment of bacterial prostatitis", EXPERT OPIN PHARMACOTHER, vol. 23, no. 9, 13 June 2022 (2022-06-13), London, UK, pages 1091 - 1101, XP093100745, ISSN: 1465-6566, DOI: 10.1080/14656566.2022.2077101 * |
NATURE, vol. 466, 19 August 2010 (2010-08-19), pages 935 - 940 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Nix et al. | Effect of multiple dose oral ciprofloxacin on the pharmacokinetics of theophylline and indocyanine green | |
MX2007000713A (en) | Memantine as adjunctive treatment to atypical antipsychotics in schizophrenia patients. | |
US20120157472A1 (en) | Method for treating colorectal cancer | |
RU2540513C2 (en) | Method of treating hepatic encephalopathy | |
WO2020201833A1 (en) | Gepotidacin for use in the treatment of bacterial urinary tract infections | |
Vidyavathi et al. | A review on ciprofloxacin: dosage form perspective | |
WO2023207398A1 (en) | Use of anti-idiopathic pulmonary fibrosis drug nintedanib in treatment of tuberculosis | |
JP2022539583A (en) | Combinations for the treatment of infections caused by Mycoplasma genitalium | |
Fischman et al. | Pharmacokinetics of [18F] fleroxacin in patients with acute exacerbations of chronic bronchitis and complicated urinary tract infection studied by positron emission tomography | |
WO2024068524A1 (en) | Gepotidacin for use in the treatment of bacterial prostatitis | |
Taneja et al. | Stable, compounded bedaquiline suspensions to support practical implementation of pediatric dosing in the field | |
Vincent et al. | The pharmacokinetic effects of coadministration of morphine and trovafloxacin in healthy subjects | |
Li et al. | Prospective audit of aminoglycoside usage in a general hospital with assessments of clinical processes and adverse clinical outcomes | |
ES2779762T3 (en) | Treatment of alopecia areata | |
Pittman et al. | Randomized double-blind trial of high-and low-dose fleroxacin versus norfloxacin for complicated urinary tract infection | |
Khan et al. | Assessment of bioequivalence of ciprofloxacin in healthy male subjects using HPLC. | |
Inoshita et al. | A randomized prospective study of oral levofloxacin vs intravenous flomoxef prophylaxis in postoperative infection after endoscopic sinus surgery | |
US20220184071A1 (en) | Gepotidacin for use in the treatment of bacterial urinary tract infections | |
RU2508106C2 (en) | Methods and compositions for treating schizophrenia with using atypical neuroleptic combined therapy | |
KR20240006600A (en) | dosing regimen | |
US20030105127A1 (en) | Methods of use of gemifloxacin compounds against fluoroquinolone resistant streptococcus pneumoniae bacteria | |
US20030073695A1 (en) | Methods of use of gemifloxacin compounds against fluoroquinolone resistant Streptococcus pneumoniae bacteria | |
TWI532494B (en) | Method for reducing side effects of colistin injection | |
Preston et al. | A new fluoroquinolone for use in community-acquired pneumonia and other infections. | |
US20020086868A1 (en) | Methods of use of gemifloxacin compounds against fluoroquinolone resistant Streptococcus pneumoniae bacteria |