Treatment method

Abstract

The present invention relates to a method for treating bacterial prostatitis, comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a human in need thereof.

Description

[Technical Field]

[0001] The project related to this application has been funded by the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No. 853976. This Joint Undertaking is supported by the European Union's Horizon 2020 research and innovation programme and EFPIA.

[0002] The present invention relates to methods of treatment, pharmaceutical compositions, or resistance-guided therapies for treating bacterial prostatitis, comprising the administration of gepotidacin or a pharmaceutically acceptable salt thereof, and / or corresponding uses thereof. [Background technology]

[0003] Prostatitis ranges from a simple clinical diagnosis in the acute phase to a complex and debilitating condition when chronic. It is often a source of frustration for treating physicians and patients. Prostatitis accounts for 8% of urology visits and up to 1% of primary care physician visits. The estimated cost of diagnosing and treating prostatitis was $84 million in 2000. Patients with chronic prostatitis often experience impaired mental and physical health-related quality of life. Acute bacterial prostatitis is estimated to account for approximately 10% of all prostatitis cases.

[0004] Treating bacterial prostatitis with antibiotics presents numerous challenges. Although the prostate is located near the bladder and urethra, it is not directly connected to the urinary tract through blood vessels. Furthermore, the prostate is not a highly vascularized organ. This can limit drug exposure to the prostate. Additionally, the anatomical location of the prostate can make it difficult to measure drug exposure in the prostate and determine whether the drug is adequately reaching the prostate. For at least these reasons, finding an effective treatment for bacterial prostatitis has been challenging.

[0005] To date, a wide variety of antibacterial agents have been developed, which have become clinically very important antimicrobial agents. Researchers at GSK have reported a new class of antibacterial agents targeting type IIA topoisomerase, which exhibits activity against a broad spectrum of Gram-positive and Gram-negative bacteria (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). International Patent Publication No. WO2008 / 128942 and U.S. Patent No. 8,389,524 (incorporated herein by reference in their entirety) disclose tricyclic nitrogen-containing compounds as antibacterial compounds, pharmaceutical compositions, and their corresponding uses. To date, gepotidacin has not been shown to be useful in treating bacterial prostatitis.

[0006] There is a need for the development of effective antibiotics for the treatment of bacterial prostatitis.The present invention is directed to overcoming these and other problems encountered in the art. Summary of the Invention

[0007] The present invention provides a method for treating bacterial prostatitis in a human, comprising administering to a human in need thereof a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof.

[0008] The present invention also provides the use of gepotidacin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of bacterial prostatitis.

[0009] The present invention also provides a kit for use in treating bacterial prostatitis, comprising gepotidacin or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0010]

Figure 1A

Figure 1B

Figure 1C

Figure 1D

[0011] In this application, the terms "antimicrobial," "antibiotic," and "antibacterial" are used interchangeably and refer to any natural or synthetic compound that kills or inhibits the growth of microorganisms.

[0012] As understood in the present invention, antibiotic resistance occurs when bacteria change in response to antibiotic use, rendering them ineffective. Antibiotic resistance is a broader term that also encompasses resistance to drugs used to treat infections caused by other microorganisms, such as parasites (e.g., malaria or helminths), viruses (e.g., HIV), and fungi (e.g., Candida).

[0013] Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic with the ability to selectively inhibit bacterial DNA replication by a means not utilized by any currently approved human therapeutics, thereby providing an opportunity to address an unmet medical need. Gepotidacin and its racemic form are disclosed in International Patent Publication No. WO 2008 / 128942, which is incorporated herein in its entirety. Gepotidacin is (2R)-2-({4-[(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione.

[0014] [ka]

[0015] 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 one embodiment, the pharmaceutically acceptable salt is gepotidacin mesylate.

[0016] International Patent Application Publication No. WO 2021 / 219637 (incorporated herein 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, comprising administering to a human in need thereof 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.

[0017] As used herein, "human in need thereof" means a person who has a prostate gland and has been diagnosed with prostatitis by a physician. In one embodiment, the human in need thereof is a male.

[0018] Prostatitis is a group of prostate disorders predominantly associated with irritative or obstructive urinary symptoms and perineal pain. (Andriole, G. (2020). Prostatitis. In Merck Manual Professional Version. Merck & Co., Inc. Retrieved March 18, 2021, 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 four categories according to the NIH Consensus Classification System for Prostatitis (Krieger, JN, Nyberg, L., Nickel, JC 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, fatigue, and muscle pain. Chronic bacterial prostatitis is characterized by recurrent infections, with or without complete recovery between episodes. In this case, symptoms may persist for more than one month (e.g., symptoms persist for more than three months).

[0019] As used herein, "bacterial prostatitis" can mean that the referenced bacteria has been identified as the cause or part of the cause of the prostatitis, or that the bacteria is suspected or strongly suspected to be the cause or part of the cause of the infection due to the identification of symptoms and other factors such as patient history or local epidemiology.

[0020] Bacteria that are commonly confirmed to be the cause of bacterial prostatitis, or that are strongly suspected to be the cause or part of the cause of bacterial prostatitis, include Escherichia coli ( Escherichia coli), Pseudomonas aeruginosa ( Pseudomonas aeruginosa), Klebsiella ) species (Klebsiella pneumoniae ( Klebsiella pneumoniae ), Klebsiella oxytoca ( Klebsiella oxytoca ), Klebsiella aerogenes ( Klebsiella aerogenes ), and Klebsiella variicola ( Klebsiella variicola ), Enterococcus ( Enterococcus ) species (Enterococcus faecalis ( Enterococcus faecalis ), Enterococcus faecium ( Enterococcus faecium ), and Enterococcus cloacae ( Enterococcus cloacae ) complex), Proteus ( Proteus ) species (Proteus mirabilis ( Proteus mirabilis ), Proteus hauseri ( Proteus hauseri ), and Proteus pennellii ( Proteus peneri ), and Serratia species (spirit fungus ( Serratia marcescens Other less common causative bacteria include: Staphylococcus ( Staphylococcus ) species (saprophytic Staphylococcus ( Staphylococcus saprophyticus ), Staphylococcus lugdunensis ( Staphylococcus lugdenensis ), Staphylococcus capitis ( Staphylococcus capitis ), Staphylococcus couplera ( Staphylococcus caprae ), Staphylococcus cohnii ( Staphylococcus cohnii ), Staphylococcus epidermidis ( Staphylococcus epidermidis ), Staphylococcus haemolyticus ( Staphylococcus haemolyticus ), Staphylococcus hominis ( Staphylococcus hominis ), Staphylococcus intermedius ( Staphylococcus intermedius ), Staphylococcus simulans ( Staphylococcus simulans ), and Staphylococcus warneri ( Staphylococcus warneri ) including Streptococcus ( Streptococcus ) species (Streptococcus agalactiae ( Streptococcus agalactiae ), group F streptococcus ( Streptococcus group F ), group G streptococcus ( Streptococcus group G ), Streptococcus anginosus ( Streptococcus anginosus ), Streptococcus australis ( Streptococcus australis ), Streptococcus constellatus ( Streptococcus constellatus), Streptococcus cristatus ( Streptococcus cristatus ), Streptococcus gordonii ( Streptococcus gordonii ), Streptococcus infantarius ( Streptococcus infantarius ), Streptococcus infantis ( Streptococcus infantis ), Streptococcus intermedius ( ), Streptococcus massiliensis ( Streptococcus intermedius ), Streptococcus mitis ( Streptococcus massiliensis ), Streptococcus oralis ( Streptococcus mitis ), Streptococcus mutans ( Streptococcus oralis ), Streptococcus parasanguinis ( Streptococcus mutans ), Streptococcus salivarius, Streptococcus sanguinis ( Streptococcus parasanguinis Streptococcus sanguinis ), Streptococcus bestibularis ( Streptococcus vestibularis ), Mycoplasma genitalium ( Mycoplasma genitalium ), Neisseria gonorrhoeae ( Neisseria gonorrhea ), Salmonella species ( Salmonella spp ), and Ureaplasma urealyticum ( Ureaplasma urealyticum The in vitro efficacy of gepotidacin or a pharmaceutically acceptable salt thereof against these and other organisms is shown, for example, in International Patent Application Publication Nos. WO2008 / 128942, WO2016 / 027249, WO2020 / 201833, and WO2021 / 004910. As will be understood by those skilled in the art, it can be envisioned that gepotidacin or a pharmaceutically acceptable salt thereof can be used against bacterial prostatitis caused by any bacteria against which gepotidacin has antibiotic activity.

[0021] In one aspect, the bacterium that may be identified as causing bacterial prostatitis, or that is strongly suspected of being the cause or part of the cause of bacterial prostatitis, is Escherichia coli.

[0022] In one embodiment, for any aspect of the invention, a 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 invention, gepotidacin or a pharmaceutically acceptable salt thereof is administered at 1,500 mg twice daily (bid) (total daily dose of 3,000 mg) for 5 days. In another embodiment, for any aspect of the invention, gepotidacin or a pharmaceutically acceptable salt thereof is administered at 3,000 mg twice a day, 6 to 12 hours or 10 to 12 hours apart.

[0023] Gepotidacin or a pharmaceutically acceptable salt thereof may be present in a pharmaceutical composition comprising gepotidacin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0024] In one aspect, the present invention provides a method for treating bacterial prostatitis in a human, comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof to a human in need 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 comprises administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof to a human in need thereof, wherein the human has failed one prior line of oral antibiotic treatment for bacterial prostatitis. In one embodiment, the prior oral antibiotic is a fluoroquinolone (e.g., ciciprofloxacin, norfloxacin, levofloxacin, or ofloxacin), trimethoprim-sulfamethoxazole, or doxycycline.

[0025] In another aspect, the present invention relates to a resistance-confirming therapy for treating bacterial prostatitis, comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof.

[0026] As will be understood by those skilled in the art, as used herein, "resistance-confirming therapy" refers to a course of treatment, the direction of which is determined by knowledge of the phenotypic or genotypic susceptibility of a microorganism to a given antibiotic, as described, for example, in Bradshaw et al., The Journal of Infectious Diseases, Volume 216, Issue suppl_2, 15 July 2017, Pages S412-S419. Detecting the causative agent of an infection and then detecting the resistance of the identified strain to a particular antibiotic before or during treatment has the advantage of potentially reducing the patient's exposure to ineffective antibiotics that may lead to resistance. Identification of a specific pathogen, e.g., E. coli, may be performed by any suitable genotypic or phenotypic means, such as NAAT.

[0027] Thus, in one aspect, the present invention provides a resistance-confirming therapy for treating bacterial prostatitis caused by Escherichia coli, comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof to a human in need thereof.

[0028] In one aspect, the present invention relates to a resistance confirmatory therapy for treating bacterial prostatitis caused by Escherichia coli, where bacterial prostatitis is acute bacterial prostatitis.

[0029] In one aspect, the present invention relates to a resistance confirmatory therapy for treating bacterial prostatitis caused by E. coli, where the bacterial prostatitis is chronic bacterial prostatitis.

[0030] In another aspect, the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for use in treating bacterial prostatitis in humans. In one aspect, the bacterial prostatitis is acute bacterial prostatitis. In another aspect, the bacterial prostatitis is chronic bacterial prostatitis. In one embodiment, the bacterial prostatitis is caused by Escherichia coli.

[0031] In another aspect, the present invention provides the 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 one aspect, the bacterial prostatitis is acute bacterial prostatitis. In another aspect, the bacterial prostatitis is chronic bacterial prostatitis. In one embodiment, the bacterial prostatitis is caused by Escherichia coli.

[0032] In another aspect, the present invention provides a kit comprising gepotidacin or a pharmaceutically acceptable salt thereof for use in treating bacterial prostatitis in a human. In one aspect, the bacterial prostatitis is acute bacterial prostatitis. In another aspect, the bacterial prostatitis is chronic bacterial prostatitis. In one embodiment, the bacterial prostatitis is caused by Escherichia coli.

[0033] In another aspect, the present invention relates to the use of a pharmaceutical composition as defined in the present invention for the manufacture of a medicament for the treatment of bacterial prostatitis, such as acute bacterial prostatitis or chronic bacterial prostatitis.

[0034] In another aspect, the present invention relates to the use of a pharmaceutical composition as defined herein for resistance-confirming therapy to treat bacterial prostatitis caused by Escherichia coli in a human in need thereof.

[0035] Compounds used herein International Patent Application Publication No. WO2008 / 128942 discloses the preparation of the free base and hydrochloride salt of gepotidacin.

[0036] It should 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 thereof. Thus, as a non-limiting example used herein for illustrative purposes, "gepotidacin or a pharmaceutically acceptable salt thereof" may include a pharmaceutically acceptable salt of gepotidacin that further exists as a solvate.

[0037] As used herein, gepotidacin or any pharmaceutically acceptable salt thereof may be in any physical form, including non-solid forms such as liquid or semi-solid forms, solid forms such as amorphous or crystalline forms, particular polymorphic forms, and solvates, including hydrates.

[0038] Suitable pharmaceutically acceptable salts include those described in Berge, Bighley and Monkhouse J. Pharm. Sci (1977) 66, pp 1-19.

[0039] In one embodiment, in any aspect of the invention, the gepotidacin is gepotidacin free base or gepotidacin methanesulfonate (mesylate).

[0040] The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.

[0041] Pharmaceutical Compositions and Formulations In particular, gepotidacin or a pharmaceutically acceptable salt thereof for use in the present invention may be formulated for administration for use in human or veterinary medicine, similar to other antibacterial / antitubercular compounds.

[0042] The pharmaceutical compositions used in the present invention may be formulated for administration by any route and may include pharmaceutical compositions in a form suitable for oral or parenteral use, which may be used in mammals, including humans.

[0043] The compositions may be in the form of tablets, capsules, powders, granules, troches, suppositories, creams, or liquid preparations such as oral or sterile parenteral solutions or suspensions.

[0044] In one embodiment, gepotidacin or a pharmaceutically acceptable salt thereof of the present invention is in the form of a tablet or capsule. In one embodiment, it is in the form of a tablet. In one embodiment, the tablet is a 750 mg tablet.

[0045] For parenteral administration, liquid unit dosage forms are prepared using the compound and a sterile vehicle (preferably water).The compound can be either suspended or dissolved in the vehicle depending on the vehicle and concentration used.In preparing a solution, the compound can be dissolved in water for injection and sterilized by filtration, then filled into a suitable vial or ampoule and sealed.

[0046] Furthermore, the dosage of the compounds or pharmaceutical compositions used in the present invention varies depending on the patient and the mode of administration, and can be any effective amount.

[0047] According to any of the administration methods of the present invention, the term "therapeutically effective amount," as used herein, generally includes within its meaning a non-toxic but sufficient amount of the particular drug being referred to to provide the desired therapeutic effect.

[0048] Treatment regimens for administering the compounds and / or pharmaceutical compositions used in the present invention can also be readily determined by those skilled in the art. When the composition contains dosage units, each unit preferably contains 50 to 1,000 mg of the active ingredient. Unless otherwise specified, the amount of the active ingredient (i.e., gepotidacin) refers to the amount of gepotidacin free base.

[0049] Depending on the treatment being performed, the compounds and / or compositions of the present invention may be administered orally, intravenously, intraperitoneally, subcutaneously, or intramuscularly. Preferably, the compositions are suitable for oral administration. In any of the above aspects of the present invention, in one embodiment, gepotidacin or a pharmaceutically acceptable salt thereof is administered orally.

[0050] It is to be understood that the present invention is not limited to the above-exemplified aspects or embodiments, and that the rights are reserved to all modifications within the scope of the exemplified aspects or embodiments and the following claims.

[0051] The various references to journals, patents, and other publications cited herein contain the state of the art and are incorporated herein by reference as if set forth in their entirety.

[0052] The examples presented below are illustrative of the present invention and are not intended to limit the scope of the invention in any way. [Example]

[0053] Example 1 The Examples herein describe microdialysis experiments in E. coli-infected rats to measure the tissue distribution of unbound gepotidacin. In in vivo microdialysis experiments, the concentrations of unbound gepotidacin in the rat prostate, muscle, and blood were simultaneously determined. Because gepotidacin must diffuse across capillary membranes to reach the prostate, it is important to understand the tissue distribution of unbound gepotidacin, particularly in the target prostate tissue. The assumption that gepotidacin plasma concentrations are a good proxy for prostate concentrations without prostate tissue confirmation may lead to erroneous conclusions, especially since the pathogen is localized in the prostate.

[0054] The concentrations of unbound gepotidacin in blood, muscle, and prostate were similar in all tissues, indicating that gepotidacin was delivered sufficiently to the prostate, supporting the conclusion that gepotidacin is effective in treating bacterial prostatitis.

[0055] method In vivo microdialysis in rats The rat model of E. coli prostatitis was obtained as follows: Four days before microdialysis, rats (n=11) were treated with an inoculum of 10 7 E. coli prostatitis was induced by infecting the prostatic urethra with E. coli ATCC 13441 at 1 CFU / rat. Healthy rats (n=9) were not infected with E. coli as a control.

[0056] The day before the experiment, two CMA / 20 probes (10 mm membrane length, Harvard Apparatus, Courtaboeuf, France) were inserted into the right jugular vein and right hindlimb muscle of healthy and infected rats under anesthesia and analgesia. Concurrently, catheters were inserted into the femoral vein and artery, respectively, to administer gepotidacin intravenously (IV) and collect blood samples to determine the total plasma gepotidacin concentration. The rats were then allowed to regain consciousness and were deprived of food for 12 hours.

[0057] On the day of the experiment, healthy control rats and infected rats were anesthetized again, and a CMA / 20 Elite probe (4 mm in length) was inserted into the prostate. All probes were connected to an infusion pump, and Ringer's solution containing a calibrator (((R)-1-((4-(((2,3-dihydro-[1,4]oxathiino[2,3-c]pyridin-7-yl)methyl)amino)piperidin-1-yl)methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione; 1,500 n / mL) was infused at a flow rate of 0.5 mL. The blood was perfused at a rate of 1 μL / min. After an equilibration period, gepotidacin was administered intravenously as a bolus at a dose of 20 mg / kg. Blood, muscle, and prostate dialysates were collected every 10 min for 90 min, then every 30 min for 300 min (6 h). Seven blood samples were also collected to analyze the pharmacokinetics of gepotidacin in total plasma. Gepotidacin concentrations were measured in the dialysate and plasma by LC-MS / MS.

[0058] Data analysis Pharmacokinetic (PK) parameters were determined for each individual rat using a noncompartmental approach with Phoenix WinNonLin 7 software (Certara, Princeton, NJ) according to standard procedures. Total unbound clearance (CL) was determined. u ) is CL u = dose / AUC u,血液 where AUC u,血液is the sum of the unbound blood concentration and time area under the curve from zero to infinity, and the area under the curve from zero to the final measured concentration, AUC 0-last,u,血液 , the area under the curve from the final measured concentration to infinity, AUC last-infinity,u,血液 AUC is the sum of the two. 0-last,u,血液 was calculated by the log-linear trapezoidal method. The final measured concentration C(last) u,血液 Area under the curve (AUC) last-infinity,u,血液 C(last) u,血液 / ke 血液 The excretion rate constant (ke 血液 ) and the corresponding half-life (t 1 / 2,血液 ) was estimated by the least-squares method of the data points (log concentration-time). The linear-log trapezoidal method was used to calculate the unbound blood concentration versus time moment curves A UMC from zero to the final measured concentration. 0-last,u,血液 The area under the curve remaining after the final concentration measurement, AUMC, was calculated. last-infinity,u,血液 tlast×C(last) u,血液 / ke 血液 +C(last) u,血液 / ke 血液 2 The mean residence time (MRT) from zero to infinity was determined from 0-infinity ,AUMC 0-infinity,u,血液 / AUC 0-infinity,u,血液 The distribution volume (Vss u ) and MRT 0-infinity ×CL u The AUC in tissue u and t 1 / 2,u was also estimated using the same procedure.

[0059] result The unbound gepotidacin concentrations are illustrated in Figures 1A and 1B for healthy controls across different tissue types (blood, muscle, and prostate). The time profile of unbound gepotidacin in blood was biphasic, and the concentration profiles in prostate and muscle were nearly overlapping with the blood concentration, except for the first time point (Figure 1A). In prostatitis (i.e., infected) rats, the unbound gepotidacin concentration-time profile in blood was also biphasic, and the gepotidacin concentration in the prostate appeared slightly lower than the blood concentration (Figures 1C-1D). The pharmacokinetic parameter values ​​obtained for the healthy and infected groups are shown in Tables 1 and 2. The half-life and C of gepotidacin in blood, muscle, and prostate of healthy control rats. max,u were similar (Table 1). This comparability was confirmed by the AUC u This is supported by the ratio of approximately 1 (Table 2). max The half-life of gepotidacin was similar among blood, muscle, and prostate, although the AUC of gepotidacin was slightly lower than that of healthy rats (Table 1). u The ratios were not significantly different from those obtained in healthy rats (p>0.05, Wilcoxon test, statistical software R) (Table 2).

[0060] [Table 1]

[0061] [Table 2]

[0062] In parallel with microdialysis, total PK parameters were determined from total plasma concentrations, which are shown in Table 3. The total plasma results are similar to those obtained with microdialysis.

[0063] [Table 3]

[0064] Example 2 This study (NCT04484740) will determine the concentrations of gepotidacin in plasma, prostate, and tonsil tissue from patients undergoing radical prostatectomy (RPE) for localized prostate enlargement, simple prostatectomy (PE) for benign prostate hyperplasia (BPH), or tonsillectomy (TE).

[0065] Patients undergoing radical prostatectomy (RPE) or simple prostatectomy (PE) and patients undergoing tonsillectomy (TE) will receive a single oral dose of 1,500 mg gepotidacin. The individual time points for gepotidacin administration will be selected so that the time of tissue removal coincides as closely as possible with one of six different sampling time points. After study drug administration, RPE or TE will be performed according to clinical routine.

[0066] A microdialysis (MD) probe is then inserted ex-vivo into the excised tissue (tonsil tissue or prostate tissue), and MD is performed to determine the unbound drug concentration in the tissue.

[0067] Plasma PK samples are collected immediately prior to study drug administration and up to 48 hours after gepotidacin administration.

[0068] Since the MD provides the concentration of the unbound fraction of gepotidacin, the unbound fraction of the concentration value obtained from the blood draw is calculated for comparison. To do this, protein binding is determined for each subject using ultrafiltration at the time point closest to Cmax. The individual protein binding values ​​can then be used to calculate the unbound plasma fraction of gepotidacin. This allows the plasma PK data to be converted to the same scale as the microdialysis data.

[0069] Samples will be analyzed using non-compartmental analysis (NCA) for plasma concentrations and a population pharmacokinetic model (PopPK) for plasma and pooled tissue concentrations.

[0070] Example 3 This study (NCT04484740) determined gepotidacin concentrations in plasma, prostate, and tonsil tissue from patients who underwent radical prostatectomy (RPE) for localized prostate gland, simple prostatectomy (PE) for benign prostatic hyperplasia (BPH), or tonsillectomy (TE).

[0071] Patients scheduled for radical prostatectomy (RPE) or simple prostatectomy (PE) and patients undergoing tonsillectomy (TE) received a single oral dose of 1,500 mg of gepotidacin. The individual time points for gepotidacin administration were selected so that the time of tissue removal coincided as closely as possible with one of six different sampling time points over a maximum 24-hour period. After study drug administration, RPE or TE was performed according to clinical routine.

[0072] Then, a microdialysis (MD) probe was inserted ex-vivo into the excised tissue (tonsil or prostate tissue), and MD was performed to obtain samples for determining the unbound drug concentration in the tissue.

[0073] Blood samples for plasma PK were collected immediately before study drug administration and up to 48 hours after gepotidacin administration. Because MD samples provided unbound gepotidacin concentrations, plasma PK was adjusted based on the unbound fraction measured in vitro for comparison.

[0074] Plasma PK parameters were determined using non-compartmental analysis (NCA), while tissue PK parameters were determined using a population pharmacokinetic modeling approach (PopPK) incorporating plasma and tissue concentrations.

[0075] Data analysis Available Data Plasma concentrations were evaluable in 47 patients, 29 from the prostate cohort and 18 from the tonsil cohort. 24 patients from the prostate cohort had at least one evaluable tissue sample, and 11 patients from the tonsil cohort had at least one evaluable tissue sample. A total of 522 plasma samples, 94 prostate samples, and 25 tonsil samples were collected.

Claims

1. 1. A method for treating bacterial prostatitis in a human, comprising administering to a human in need thereof a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof.

2. 2. The method of claim 1, wherein the bacterial prostatitis is acute prostatitis.

3. 2. The method of claim 1, wherein the bacterial prostatitis is chronic prostatitis.

4. The bacterial prostatitis may be caused by Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella aerogenes, Klebsiella variicola, Enterococcus faecalis, Enterococcus faecium, Enterococcus cloacae complex, Proteus mirabilis, Proteus hauseri, Proteus pennellii, Serratia marcescens, Staphylococcus aureus, Staphylococcus lugdunensis, Staphylococcus aureus, Staphylococcus purpura, Staphylococcus purpurea, Staphylococcus purpurea, Staphylococcus purpura ... Staphylococcus capitis, Staphylococcus capra, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, Staphylococcus warneri, Streptococcus agalactiae, Group F streptococci, Group G streptococci, Streptococcus 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 bestibularis, Mycoplasma genitalium, Neisseria gonorrhoeae, Salmonella spp., and Ureaplasma urealyticum.

5. The method according to any one of claims 1 to 4, wherein the bacterium is Escherichia coli.

6. The method according to any one of claims 1 to 5, wherein the gepotidacin is gepotidacin mesylate.

7. 7. The method of claim 6, wherein the gepotidacin is gepotidacin mesylate dihydrate.

8. The method of any one of claims 1 to 7, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered orally.

9. 9. The method of any one of claims 1 to 8, wherein the human has failed at least one previously selected treatment for bacterial prostatitis.

10. 10. Gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of said bacterial prostatitis in humans.

11. 10. Use of gepotidacin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of bacterial prostatitis in humans.

12. A kit for use in treating bacterial prostatitis in humans, comprising gepotidacin or a pharmaceutically acceptable salt thereof.

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