Gipodacin for treatment of bacterial prostatitis

Abstract

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

Description

[0001] The project leading to the present application has received funding from the Innovative Medicines Initiative 2 joint project under grant agreement n° 853976. The joint project has received support from the European Union's Horizon 2020 research and innovation programme and from EFPIA. Technical Field

[0002] The present invention relates to a method of treatment, a pharmaceutical composition or a resistance-directed therapy for treating bacterial prostatitis and / or the use thereof, comprising administering gepotidacin or a pharmaceutically acceptable salt thereof. Background Art

[0003] 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 both the treating physician and the patient. Prostatitis accounts for 8% of urologist visits and up to 1% of primary care physician visits. In 2000, the estimated cost of diagnosing and treating prostatitis was $84 million. Patients with chronic prostatitis often experience impaired quality of life related to both mental and physical health. Acute bacterial prostatitis is estimated to account for approximately 10% of all prostatitis cases.

[0004] The challenges of treating bacterial prostatitis with antibiotics are numerous. Although the prostate is located near the bladder and urethra, the prostate is not directly connected to the urinary tract via vascular connections. The prostate is also not a highly vascularized organ. Together, this can limit drug exposure to the prostate. Furthermore, due to the anatomical location of the prostate, it can be difficult to measure drug exposure in the prostate to determine if the drug is adequately reaching the prostate. For at least these reasons, finding an effective treatment for bacterial prostatitis can be challenging.

[0005] So far, a variety of antibacterial drugs have been developed, and these drugs have become extremely important clinical antibacterial drugs. GSK researchers have described a class of new antibacterial agents targeting type IIA topoisomerase [see Nature, Vol. 466, pp. 935-940 (August 19, 2010) and Gibson et al., Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcusaureus Gyrase, ACS Infectious Disease, 2019, 5, 570-581], which have shown activity against a wide spectrum of Gram-positive and Gram-negative bacteria. International Patent Publication WO 2008 / 128942 and U.S. Patent No. 8,389,524 (incorporated herein by reference in their entirety) disclose tricyclic nitrogen-containing compounds, pharmaceutical compositions and their corresponding uses as antibacterial compounds. So far, the effectiveness of Gepotacin in the treatment of bacterial prostatitis has not been confirmed.

[0006] There is a need to develop 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 of treating bacterial prostatitis in a human in need thereof, comprising administering to the human a therapeutically effective amount of gepodacin or a pharmaceutically acceptable salt thereof.

[0008] The present invention also provides the use of gepodacin or a pharmaceutically acceptable salt thereof in preparing a medicine for treating bacterial prostatitis.

[0009] The present invention also provides a kit for treating bacterial prostatitis, which comprises gepodacin or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figures 1A-1D Unbound gepodacin concentrations in blood, muscle, and prostate tissue of healthy and infected rats are shown. Points, triangles, or squares are means, and bars represent ±1 standard deviation. Figure 1A Decimal representation of unbound gepodacin concentrations in healthy rats is shown. Figure 1B A half-log representation of unbound gepodacin in healthy rats is shown. Figure 1C Decimal representation of unbound gepodacin concentrations in infected rats is shown. Figure 1D Half-log representation of unbound gepodacin in infected rats is shown. DETAILED DESCRIPTION OF THE INVENTION

[0012] The terms "antimicrobial," "antibiotic," and "antibacterial" are used interchangeably herein and refer to any natural or synthetic compound that kills or inhibits the growth of microorganisms.

[0013] As further understood in the present invention, antibiotic resistance occurs when bacteria change in response to the use of antibiotics, rendering the antibiotic ineffective; and antimicrobial resistance is a broader term that includes resistance to drugs that treat infections caused by other microorganisms, such as parasites (e.g., malaria or helminths), viruses (e.g., HIV), and fungi (e.g., Candida).

[0014] Gepodacin is a first-in-class novel triazaacenaphthene antibiotic with the ability to selectively inhibit bacterial DNA replication by means not utilized by any currently approved human therapeutic agent, thus providing an opportunity to address unmet medical needs. Gepodacin and its racemic form are disclosed in WO 2008 / 128942 (which is incorporated herein in its entirety). Gepodacin 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-triazaacenaphthene-3,8-dione:

[0015]

[0016] The methods and uses of the present invention are based on gepodacin or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of gepodacin include, but are not limited to, gepodacin hydrochloride and gepodacin mesylate. In one embodiment, the pharmaceutically acceptable salt is gepodacin mesylate.

[0017] International Patent Application Publication No. WO 2021 / 219637 (incorporated herein in its entirety) describes certain crystalline forms of gepodacin, including gepodacin mesylate dihydrate, gepodacin mesylate anhydrate, gepodacin mesylate monohydrate, and gepodacin anhydrate (free base). In a first aspect, the present invention provides a method for treating bacterial prostatitis in a person in need thereof, the method comprising administering to the person a therapeutically effective amount of gepodacin or a pharmaceutically acceptable salt thereof. In one embodiment, bacterial prostatitis is acute bacterial prostatitis. In another embodiment, bacterial prostatitis is chronic bacterial prostatitis.

[0018] As used herein, "a person in need thereof" refers to a person with a prostate who has been diagnosed with prostatitis by a doctor. In one embodiment, the person in need thereof is a male.

[0019] Prostatitis is a group of prostate disorders that manifest as a combination of mainly irritating 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-prost ate-disease / prostatitis). Prostatitis can be bacterial or non-bacterial. As used herein, "bacterial prostatitis" refers to prostatitis caused by bacteria. According to the NIH consensus classification system for prostatitis (Krieger, JN, Nyberg, L., Nickel, JCJAMA.1999; 282 (3): 236-237), prostatitis is divided into 4 categories-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, discomfort and myalgia. Chronic bacterial prostatitis manifests as recurrent infections with or without complete resolution between attacks; Symptoms can last for one month or longer (e.g., symptoms last>3 months).

[0020] As used herein, "prostatitis caused by bacteria" can mean that the referenced bacteria has been identified as the cause or part of the cause of the prostatitis, or it can mean that due to identification of symptoms and other factors (e.g., patient history or local epidemiology), the bacteria is suspected or strongly suspected to be the cause or part of the cause of the infection.

[0021] Bacteria that are commonly identified as the cause of, or strongly suspected of being the cause of, or part of the cause of bacterial prostatitis include Escherichia coli, Pseudomonas aeruginosa, Klebsiella (including Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella aerogenes, and Klebsiella variegata), Enterococcus (including Enterococcus faecalis, Enterococcus faecium, and Enterococcus cloacae complex), Proteus (including Proteus mirabilis, Proteus hauseri, and Proteus peneri), and Serratia (including Serratia marcescens). Other less common pathogens include: Staphylococcus (including Staphylococcus saprophyticus, Staphylococcus lugdenensis, Staphylococcus capitis, Staphylococcus capitis, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, and Staphylococcus woerneri), Streptococcus (including Streptococcus agalactiae, group F Streptococcus, group G Streptococcus, Streptococcus anginosus, Streptococcus australis, Streptococcus constellatus, Streptococcus ridgeis, Streptococcus garrettii, Streptococcus infantarius, Streptococcus infantis, Streptococcus spp. infantis), Streptococcus intermedius, Streptococcus massiliensis, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus vestibularis), Mycoplasma genitalium, Neisseria gonorrhoea, Salmonella and Ureaplasma urealyticum. For example, International Patent Application Publication Nos. WO2008 / 128942, WO2016 / 027249, WO2020 / 201833 and WO2021 / 004910 show the in vitro efficacy of gepodaxin or its pharmaceutically acceptable salt to these and other organisms. As will be appreciated by the technician, it is envisioned that gepodaxin or its pharmaceutically acceptable salt can be used to combat bacterial prostatitis caused by any bacteria to which gepodaxin has antibiotic activity.

[0022] In one aspect, the bacterium that can be identified as a cause of bacterial prostatitis, or is strongly suspected of being a cause of bacterial prostatitis, or a part of a cause of bacterial prostatitis is Escherichia coli.

[0023] In one embodiment, for any aspect of the invention, gepodacin or a pharmaceutically acceptable salt thereof is administered to a human 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, gepodacin or a pharmaceutically acceptable salt thereof is administered at 1500 mg bid (total daily dose of 3000 mg) for 5 days. In another embodiment, for any aspect of the invention, gepodacin or a pharmaceutically acceptable salt thereof is administered at two doses of 3000 mg each, 6-12 or 10-12 hours apart.

[0024] Gepodacin or a pharmaceutically acceptable salt thereof may be present in a pharmaceutical composition comprising gepodacin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0025] In one aspect, the present invention provides a method for treating bacterial prostatitis in a person in need thereof, the method comprising administering to the person a therapeutically effective amount of gepodaxin or a pharmaceutically acceptable salt thereof, wherein the person has failed at least one prior line of bacterial prostatitis treatment. In one embodiment, the method for treating bacterial prostatitis in a person in need thereof comprises administering to the person a therapeutically effective amount of gepodaxin or a pharmaceutically acceptable salt thereof, wherein the person has failed a prior oral antibiotic treatment for bacterial prostatitis. In one embodiment, the prior oral antibiotic is a fluoroquinolone (e.g., ciprofloxacin, norfloxacin, levofloxacin, or ofloxacin), trimethoprim-sulfamethoxazole, or doxycycline.

[0026] In another aspect, the present invention relates to a resistance-directed therapy for treating bacterial prostatitis comprising administering a therapeutically effective amount of gepodacin or a pharmaceutically acceptable salt thereof.

[0027] As will be appreciated by the skilled artisan, as used herein, "resistance-guided therapy" means a course of therapy whose direction is guided by knowledge of the phenotypic or genotypic susceptibility of a microorganism to a given antibiotic, e.g., as described in Bradshaw et al., The Journal of Infectious Diseases, Volume 216, Issue suppl_2, July 15, 2017, pp. S412-S419. Detecting pathogenic bacteria in an infection and then testing the identified strains for resistance to certain antibiotics in advance or during the course of treatment has the advantage of potentially reducing patient exposure to ineffective antibiotics that may cause resistance. Identification of a specific pathogen (e.g., E. coli) can be performed by any suitable genotypic or phenotypic means (e.g., by NAAT).

[0028] Thus, in one aspect, the present invention provides a resistance-directed therapy for treating bacterial prostatitis caused by Escherichia coli, comprising administering to a human in need thereof a therapeutically effective amount of gepodacin or a pharmaceutically acceptable salt thereof.

[0029] In one aspect, the present invention relates to a resistance-directed therapy for treating bacterial prostatitis caused by Escherichia coli, wherein the bacterial prostatitis is acute bacterial prostatitis.

[0030] In one aspect, the present invention relates to a resistance-directed therapy for treating bacterial prostatitis caused by Escherichia coli, wherein the bacterial prostatitis is chronic bacterial prostatitis.

[0031] In another aspect, the present invention provides gepodaxin 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.

[0032] In another aspect, the present invention provides the use of gepodacin or a pharmaceutically acceptable salt thereof in the preparation of a medicament for 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 provides a kit comprising gepodaxin 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.

[0034] 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.

[0035] In another aspect, the present invention relates to the use of a pharmaceutical composition as defined in the present invention for resistance-directed therapy for the treatment of bacterial prostatitis caused by Escherichia coli in a human in need thereof.

[0036] Compounds used in the present invention

[0037] WO2008 / 128942 discloses the preparation of the free base and the hydrochloride salt of gepodacin.

[0038] It should be understood that the phrase "gepodacin or a pharmaceutically acceptable salt thereof" is intended to encompass gepodacin, a pharmaceutically acceptable salt of gepodacin, a solvate of gepodacin, or any pharmaceutically acceptable combination of these. Thus, by way of non-limiting example for purposes of illustration herein, "gepodacin or a pharmaceutically acceptable salt thereof" may include a pharmaceutically acceptable salt of gepodacin that further exists as a solvate.

[0039] As used herein, gepodacin 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, particular polymorphic forms, and solvates including hydrates.

[0040] Suitable pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse J. Pharm. Sci (1977) 66, pp 1-19.

[0041] In one embodiment, in any aspect of the invention, gepodacin is gepodacin free base or gepodacin methanesulphonate (mesylate).

[0042] The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.

[0043] Pharmaceutical compositions and preparations

[0044] In particular, by analogy with other antibacterial / anti-tuberculosis compounds, the gepodacin or pharmaceutically acceptable salts used in the present invention may be formulated for human or veterinary administration.

[0045] The pharmaceutical compositions used in the present invention may be formulated for administration by any route, and include those in forms suitable for oral or parenteral use, and may be used in mammals including humans.

[0046] The composition 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.

[0047] In one embodiment, the gepodacin 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.

[0048] For parenteral administration, a fluid unit dosage form is prepared using the compound and a sterile vehicle (preferably water). Depending on the vehicle and concentration used, the compound can be suspended or dissolved in the vehicle. In preparing a solution, the compound can be dissolved in water for injection and sterilized by filtration before being filled into a suitable vial or ampoule and sealed.

[0049] Furthermore, the administration amount of the compound or pharmaceutical composition used in the present invention will vary depending on the patient and the mode of administration, and may be any effective amount.

[0050] As used herein, the term "therapeutically effective amount" generally includes within its meaning a non-toxic but sufficient amount of the specific drug to which it refers to provide the desired therapeutic effect, according to any administration method of the present invention.

[0051] Those skilled in the art can also easily determine the treatment regimen for administering the compounds and / or pharmaceutical compositions used in the present invention. When the composition comprises dosage units, each unit will preferably contain 50-1000 mg of active ingredient. Unless otherwise indicated, the amount of active ingredient (i.e., gepodaxin) refers to the amount of gepodaxin free base.

[0052] Depending on the treatment achieved, the compounds and / or compositions of the invention may be administered orally, intravascularly, intraperitoneally, subcutaneously or intramuscularly. Preferably, the composition is suitable for oral administration. In any of the above aspects of the invention, in one embodiment, gepodacin or a pharmaceutically acceptable salt thereof is administered orally.

[0053] It will be understood that the invention is not limited to the aspects or embodiments shown above and that the rights are reserved to the aspects or embodiments shown and all modifications coming within the scope of the following claims.

[0054] Various references to journals, patents, and other publications cited herein comprise the prior art and are incorporated herein by reference as if fully set forth.

[0055] The following examples are given to illustrate the present invention but are not intended to limit the scope of the present invention in any way.

[0056] Example 1

[0057] The examples herein describe microdialysis experiments performed in rats infected with E. coli to measure the tissue distribution of unbound gepodaxin. In vivo microdialysis experiments simultaneously determined the concentration of unbound gepodaxin in the rat prostate, muscle, and blood. Understanding the tissue distribution of unbound gepodaxin is very important, especially in the target prostate tissue, because gepodaxin must diffuse through the capillary membrane to reach the prostate. In the absence of prostate tissue confirmation, assuming that the plasma concentration of gepodaxin represents a suitable surrogate for prostate concentrations may lead to erroneous conclusions, especially because the pathogen is located in the prostate.

[0058] Unbound gepodacin concentrations in blood, muscle, and prostate were found to be similar in all tissues, thus indicating that gepodacin was adequately delivered to the prostate and supporting the conclusion that gepodacin is effective in treating bacterial prostatitis.

[0059] method

[0060] In vivo microdialysis in rats

[0061] The E. coli prostatitis model in rats was obtained as follows. Four days before microdialysis, rats (n=11) were infected with E. coli ATCC 13441 in the prostatic urethra at a rate of 10 7 Inoculation amount of CFU / rat to induce E. coli prostatitis. Healthy rats (n=9) not infected with E. coli were used as controls.

[0062] One day before the experiment, two CMA / 20 probes (membrane length 10 mm, Harvard Apparatus, CourtaboeufFrance) were inserted into the right jugular vein and right hind leg muscle of healthy and infected rats under anesthesia and analgesia. In parallel, catheters were inserted into the femoral vein and artery to administer gepodaxin intravenously (IV) and collect blood samples to determine the total plasma gepodaxin concentration, respectively. The rats were allowed to regain consciousness and were deprived of food for 12 hours.

[0063] On the day of the experiment, healthy control and infected rats were re-anesthetized and a CMA / 20Elite probe (membrane length 4 mm) was inserted into the prostate. All probes were connected to an infusion pump and infused with a Ringer 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; 1500 n / mL) at a flow rate of 0.5 μL / min. er perfusion.After the equilibrium period, gepodacin was administered by IV push injection with a dosage of 20mg / kg.Blood, muscle and prostate dialysate were collected every 10 minutes for 90 minutes, and then blood, muscle and prostate dialysate were collected every 30 minutes for 300 minutes (6 hours).Seven blood samples were also collected for analyzing the pharmacokinetics of gepodacin in total plasma.The concentration of gepodacin in dialysate and plasma was measured by LC-MS / MS.

[0064] Data analysis

[0065] Pharmacokinetic (PK) parameters were determined in each individual rat by noncompartmental methods according to standard procedures and using the software Phoenix WinNonLin 7 (Certara, Princeton, NJ). Total unbound body clearance (CL u ) is calculated as CL u =Dose / AUC u,血液 , where AUC u,血液 is the total area under the unbound blood concentration-versus-time curve from zero to infinity and is equal to the area under the curve from zero to the last measured concentration, AUC 0-最后,u,血液 Add the area under the curve (AUC) from the last measured concentration to infinity 最后-无穷大,u,血液 AUC 0-最后,u,血液 AUC was calculated by the linear-log trapezoidal method. 最后-无穷大,u,血液 At the final measurement concentration C(final) u,血液 The remaining area under the curve after is given by C(final) u,血液 / ke 血液 The elimination rate constant (ke) was estimated by least squares fitting of the data points (log concentration-time). 血液 ) and its corresponding half-life (t 1 / 2,血液 The area under the unbound blood concentration-versus-time moment curve (AUC) from zero to the last measured concentration was calculated using the linear-log trapezoidal method. 0-最后,u,血液 AUMC 最后-无穷大,u,血液 The area under the curve remaining after the last concentration measurement is given by tLast xC(Last) u,血液 / ke 血液+C(last) u,血液 / ke 血液 2 OK. The mean residence time MRT from zero to infinity 0-无穷大 By AUMC 0-无穷大,u,血液 / AUC 0-最后,u,血液 OK. From MRT 0-无穷大 ×CL u Obtain the distribution volume (Vss u ). AUC in tissue u and t 1 / 2,u is also estimated by the same procedure.

[0066] result

[0067] Figure 1A , 1B The unbound concentrations of gepodacin in different tissue types (blood, muscle and prostate) in healthy controls are shown. The unbound concentration-time curve in blood is biphasic, and the concentration curves in prostate and muscle almost overlap with the blood concentration except for the first time point ( Figure 1A In prostatitis (i.e., infected) rats, the unbound gepodacin concentration-time curve in the blood was also biphasic, and the concentration of gepodacin in the prostate was slightly lower than that in the blood ( Figure 1C-1D The pharmacokinetic parameter values ​​obtained in the healthy and infected groups are presented in Tables 1 and 2. The half-life and C of gepodacin in the blood, muscle and prostate of healthy control rats max,u similar (Table 1), and this comparability is confirmed by an AUC of approximately 1 u The ratio supports (Table 2). In infected rats, C in the prostate was higher than that in healthy rats. max Slightly lower, but the half-life of gepodacin was the same between blood, muscle, and prostate. (Table 1). Muscle / blood and prostate / blood AUC in infected animals u The ratios were not significantly different from the muscle / blood and prostate / blood AUCu ratios obtained in healthy rats (p>0.05, Wilcoxon test, R software) (Table 2).

[0068] Table 1

[0069]

[0070] Table 2

[0071] <![CDATA[AUC u肌肉 / 血液 ]]> <![CDATA[AUC u前列腺 / 血液 ]]> Healthy rats (n=9) 1.06±0.17 0.89±0.17 Infected rats (n=11) 1.03±0.13 0.78±0.21

[0072] In parallel with microdialysis, overall PK parameters were obtained from total plasma concentrations and are presented in Table 3. Total plasma results were similar to those of microdialysis.

[0073] Table 3

[0074]

[0075] Example 2

[0076] This study (NCT04484740) was designed to determine gepodacin concentrations in plasma, prostate, and tonsillar tissue in patients undergoing radical prostatectomy (RPE) for localized prostate, simple prostatectomy (PE) for benign prostatic hyperplasia (BPH), or tonsillectomy (TE).

[0077] A single oral dose of 1500mg gepodacin will be administered to patients who will undergo radical prostatectomy (RPE) or simple prostatectomy (PE) and patients who will undergo tonsillectomy (TE). Each time point of gepodacin administration will be selected to ensure that the time point of tissue excision corresponds as closely as possible to one of six different sampling time points. After the study drug is administered, RPE or TE will be performed according to clinical routine.

[0078] Subsequently, a microdialysis (MD) probe will be inserted into the ex vivo removed tissue (tonsil or prostate tissue), and MD will be performed to determine the unbound drug concentration in the tissue.

[0079] Plasma PK samples will be collected prior to study drug administration and up to 48 h after gepodacin administration.

[0080] Since MD provides the concentration of the unbound fraction of gepodacin, for comparison, we will calculate the unbound fraction for the concentration values ​​obtained by blood sampling. For this purpose, we will determine the protein binding for each subject using ultrafiltration at the time point closest to Cmax. The individual protein binding can then be used to calculate the unbound plasma fraction of gepodacin. This will allow the plasma PK data to be converted to the same scale as the microdialysis data.

[0081] Samples will be analyzed for plasma concentrations using non-compartmental analysis (NCA), and tissue concentrations combined with plasma concentrations will be analyzed using a population pharmacokinetic model (PopPK).

[0082] Example 3

[0083] This study (NCT04484740) determined gepodacin concentrations in plasma, prostate, and tonsil tissue in patients undergoing radical prostatectomy (RPE) for localized prostate, simple prostatectomy (PE) for benign prostatic hyperplasia (BPH), or tonsillectomy (TE).

[0084] Patients undergoing radical prostatectomy (RPE) or simple prostatectomy (PE) and patients undergoing tonsillectomy (TE) were administered a single oral dose of 1500 mg gepodacin. Each time point for administration of gepodacin was selected to ensure that the time point of tissue excision was as close as possible to one of the six different sampling time points until 24 h. After the study drug was administered, RPE or TE was performed according to clinical routine.

[0085] Subsequently, a microdialysis (MD) probe is inserted into the ex vivo removed tissue (tonsil or prostate tissue), and MD is performed to obtain a sample for determination of the unbound drug concentration in the tissue.

[0086] Blood samples for plasma PK were collected just before study drug administration and 48 h after gepodacin administration. As MD samples provide unbound gepodacin concentrations, for comparison, plasma PK was adjusted based on the measured in vitro unbound fraction.

[0087] Plasma PK parameters were derived using noncompartmental analysis (NCA), while tissue PK parameters were derived using a population pharmacokinetic modeling approach (PopPK) incorporating plasma and tissue concentrations.

[0088] Data analysis

[0089] Available data

[0090] 47 patients had measurable plasma concentrations, 29 from the prostate group, and 18 from the tonsil group. 24 patients from the prostate group had at least 1 measurable tissue sample, and 11 patients from the tonsil group had at least 1 measurable tissue sample. Of a total of 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 gepodacin or a pharmaceutically acceptable salt thereof.

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

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

4. The method of any one of claims 1 to 3, wherein the bacterial prostatitis is caused by a bacterium selected from the group consisting of Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella aerogenes, Klebsiella variegata, Enterococcus faecalis, Enterococcus faecium, Enterococcus cloacae complex, Proteus mirabilis, Proteus houernensis, Proteus penningsi, Serratia marcescens, Staphylococcus saprophyticus, Staphylococcus lugdunensis, Staphylococcus capitis, Staphylococcus capitis, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus simulans, Staphylococcus worteri, Streptococcus agalactiae, Group F Streptococcus, Group G Streptococcus, Streptococcus anginosus, Streptococcus australia, Streptococcus constellatus, Streptococcus ridge, Streptococcus garneri, Streptococcus infantis, Streptococcus intermedius, Streptococcus marseilles, Streptococcus mitis, Streptococcus oralis, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus vestibularis, Mycoplasma genitalium, Neisseria gonorrhoeae, Salmonella spp., and Ureaplasma urealyticum.

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

6. The method of any one of claims 1-5, wherein the gepodacin is gepodacin mesylate.

7. The method of any one of claims 6, wherein the gepodacin is gepodacin mesylate dihydrate.

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

9. The method of any one of claims 1-8, wherein the human has failed at least one prior line of treatment for bacterial prostatitis.

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

11. Use of gepodacin or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating bacterial prostatitis in humans.

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

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