WO2012021829A1 - Méthodes de traitement d'infections bactériennes - Google Patents

Méthodes de traitement d'infections bactériennes Download PDF

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WO2012021829A1
WO2012021829A1 PCT/US2011/047624 US2011047624W WO2012021829A1 WO 2012021829 A1 WO2012021829 A1 WO 2012021829A1 US 2011047624 W US2011047624 W US 2011047624W WO 2012021829 A1 WO2012021829 A1 WO 2012021829A1
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compound
subject
bacterial
administered
human subject
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Joyce A. Sutcliffe
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Tetraphase Pharmaceuticals Inc
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Tetraphase Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • MDR multiple-drug resistant
  • ESBL extended-spectrum ⁇ -lactamase
  • tigecycline also known as TYGACIL®
  • TYGACIL® an intravenous antibiotic with a broad spectrum of antimicrobial activity, including activity against drug- resistant bacteria such as methicillin-resistant Staphylococcus aureus
  • Tigecycline has provided physicians with an alternative to overcome the problems of resistance observed with the other antibiotics and to combat serious, resistant infections for all patients.
  • the amount of tigecycline that can be given in a single intravenous dose is limited by the drug's side effects (e.g., nausea and vomiting) requiring multiple administrations per day by parenteral means to provide an acceptable tolerability profile and to maintain therapeutic effectiveness.
  • the invention relates to a method of treating a bacterial infection in a human subject comprising intravenously administering to the subject a compound represented by the following structural formula:
  • Compound A a pharmaceutically acceptable salt thereof.
  • the compound of the above structural formula or its salt will be referred to herein as Compound A. It has been found that in comparison to tigecycline, Compound A can be administered intravenously in doses which result in a higher exposure or Area Under the Curve (AUC) providing a more efficacious drug product.
  • AUC Area Under the Curve
  • Compound A or a pharmaceutically acceptable salt thereof is administered intravenously once a day in an amount ranging from about 1- 1.5 mg/kg of the body weight of the subject. In one aspect, Compound A is administered by infusion over 30 to 120 minutes. In a more specific aspect, Compound A is administered by infusion over 30 to 60 minutes. In a most specific aspect, the concentration of the compound in the infusate administered in either of the above aspects is from about 0.2 mg/mL and 0.7 mg/mL.
  • Compound A is administered intravenously twice a day from about 0.625-1.5 mg/kg of the body weight of the subject per dose. In one aspect, Compound A is administered intravenously twice a day from about 0.625 - 1 mg/kg of the body weight of a subject per dose. In another aspect, Compound A is administered by intravenous infusion over 30 to 120 minutes per administration. In a more specific aspect, Compound A is administered by intravenous infusion over 30 to 60 minute. In a most specific aspect, the concentration of the compound in the infusate administered in either of the above aspects is from about 0.2 mg/mL and 0.7 mg/mL.
  • the infusion can be constant or intermittent. In a particular embodiment, the infusion is constant.
  • the invention also relates to a method of achieving an AUC of Compound A in a human subject that is at least 50% greater than the AUC achieved for Tygacil when the same subject is administered Tygacil at the recommended dose regimen.
  • the method comprises administering intravenously to the subject a pharmaceutical composition comprising Compound A as the sole active agent once or twice a day in a therapeutically effective amount.
  • the AUC of Compound A in the subject is at least 75% greater than the AUC achieved for Tygacil following administration of Tygacil.
  • Compound A is administered intravenously once a day in an amount equal to or greater than 1.5.mg/kg.
  • Compound A is administered intravenously twice a day in an amount equal to or greater than 0.65 mg/kg per administration.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Compound A and formulated for intravenous administration, wherein administration of the composition to a human subject results in an AUC for Compound A that is at least 50% greater than the AUC of tigecycline when tigecycline is administered to the same subject in a pharmaceutical composition comprising an amount of tigecycline that is the same as the amount of compound on a per milligram basis of active ingredient and that is administered in the same dosing regimen as Compound A.
  • the invention also relates to a method of achieving a AUC/MIC ratio for
  • Compound A in a human subject suffering from an infection by a bacterial organism that is at least 20% greater than the AUC/MIC ratio for the bacterial organism in the same subject when the subject is administered Tygacil at the recommended dose comprising administering intravenously to the subject a pharmaceutical composition comprising Compound A as the sole active agent once or twice a day in a therapeutically effective amount.
  • the subject is suffering from a bacterial infection characterized by the presence of an organism with a MIC to compound of less than or equal to 2 ⁇ .
  • a MIC to compound of less than or equal to 2 ⁇ g/mL means the organism has a MIC of less than or equal to 2 ⁇ g/mL to Compound A.
  • the "same subject" can be administered Tygacil and Compound A at different times after a sufficient wash-out period between administrations.
  • the present invention further relates to a method of treating hospital- acquired or community-acquired bacterial pneumonia in a human subject comprising the step of administering intravenously to the subject a therapeutically effective amount of Compound A.
  • the community-acquired bacterial pneumonia is characterized by the presence of two or more CABP pathogens selected from:
  • Streptococcus pneumoniae Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Streptococcus pyogenes, Legionella pneumophila,
  • Chlamydia pneumoniae, and Mycoplasma pneumoniae are Chlamydia pneumoniae, and Mycoplasma pneumoniae.
  • the invention also relates to a method of treating CABP in a human subject comprising the step of administering intravenously to the subject an effective amount of Compound A, wherein the community-acquired bacterial pneumonia is characterized by the presence of Legionella pneumophila.
  • the invention also relates to a method of treating hospital-acquired bacterial pneumonia in a human subject in need of treatment comprising the step of administering intravenously to the subject a therapeutically effective amount of Compound A, wherein the hospital-acquired bacterial pneumonia is characterized by the present of two or more of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Escherichia coli and Klebsiella pneumonia.
  • the invention also relates to a method of causing a 2 log 10 reduction in the amount of a bacterial strain selected from MRSA and S. pneumoniae present in a human subject comprising the step of administering intravenously to the subject a pharmaceutical composition comprising a therapeutically effective amount of Compound A as the sole active ingredient.
  • the bacterial strain is selected from the clonal lineage of methicillin-resistant Staphylococcus aureus USA 300.
  • the invention also relates to a method of treating complicated urinary tract infections including pyelonephritis in a human subject comprising the step of administering intravenously to the subject a therapeutically effective amount of Compound A, wherein the urinary pathogens can be effectively treated.
  • the urinary pathogens are selected from: Escherichia coli and Klebsiella pneumoniae, including strains producing extended -spectrum ⁇ - lactamases and/or carbapenem-resistant strains; other Enterobacteriaceae species ⁇ Proteus mirabilis, Proteus vulgaris, Citrobacter freundii, etc.) and Acinetobacter baumannii and other gram-negative species as detailed in Table 15, including by extraction other species of any of the genera tested.
  • the urinary tract infection is characterized by two or more urinary pathogens selected from: Escherichia coli and Klebsiella pneumoniae, including strains producing extended -spectrum ⁇ -lactamases and/or carbapenem-resistant strains; other Enterobacteriaceae species ⁇ Proteus mirabilis, Proteus vulgaris, Citrobacter freundii, etc.); Acinetobacter baumannii; and other gram-negative species as detailed in Table 15, including by extraction other species of any of the genera tested;
  • the invention relates to a method of treating complicated urinary tract infections including pyelonephritis in a human subject comprising the step of administering intravenously to the subject a therapeutically effective amount of Compound A, wherein the urinary pathogens can be effectively treated and the urinary tract infection is characterized by two or more urinary pathogens selected from Escherichia coli and Klebsiella pneumoniae, including strains producing extended -spectrum ⁇ -lactama
  • Anaerobic bacteria are most often seen in intra-abdominal infections and wounds (e.g., diabetic foot).
  • Compound A and multiple comparators are shown in Table 16 for many anaerobic species. Compound A is overall the most potent agent.
  • FIG. 1 shows the Area Under the Curve (AUC) and incidence of
  • FIG. 2 shows the results of testing Compound A in a murine model of lung infection challenged with either a multidrug-resistant Streptococcus pneumoniae or methicillin-resistant Staphylococcus aureus (MRSA).
  • MRSA methicillin-resistant Staphylococcus aureus
  • FIG. 3 shows the results of testing Compound A in a model of
  • Compound A The compound of the above structural formula or its salts is referred to herein as Compound A. Suitable methods for making this compound are described in published International Application No. WO 2010/017470.
  • TYGACIL is a tetracycline derivative (a glycylcycline) for intravenous infusion.
  • the chemical name of tigecycline is (4S,4aS,5aR,12aS)-9-[2- (tert-butylamino)acetamido]-4,7bis(dimethylamino)-l,4,4a,5,5a,6,l l,12a-octan ⁇ 3,10,12,12a-tetrahydroxy-l,l l-dioxo-2naphthacenecarboxamide.
  • the empirical formula is C2 H39N 5 O8 and the molecular weight is 585.65.
  • the recommended dose regimen for TYGACIL is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous infusions of TYGACIL should be administered over approximately 30 to 60 minutes every 12 hours. Adverse effects, such as a high incidence of nausea and vomiting have been reported at the recommended doses (-26% nausea, ⁇ 18%vomiting, and -12% diarrhea).
  • the recommended duration of treatment with TYGACIL for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5 to 14 days.
  • the recommended duration of treatment with TYGACIL for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5 to 14 days.
  • the recommended duration of treatment with TYGACIL for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5 to 14 days.
  • community-acquired bacterial pneumonia is 7 to 14 days.
  • the duration of therapy should be guided by the severity and site of the infection and the patient's clinical and bacteriological progress.
  • AUC as used herein is the area under the concentration-time curve at steady-state over 24 hours. The AUC is reported as Concentration x time (e.g., ng'h/L or ⁇ g ⁇ h/mL.
  • MIC is the Minimum Inhibitory Concentration or the lowest concentration to inhibit the growth of a bacterial isolate.
  • MIC90 is the concentration required to inhibit the growth of 90% of a collection of microorganisms.
  • MIC 5 0 IS the concentration required to inhibit the growth of 50% of a collection of microorganisms.
  • MIC range as used herein is the lowest and higher MIC concentrations observed in a collection of microorganisms.
  • a MIC to compound of less than or equal to 2 ⁇ g/ml means that the MIC for an organism treated with Compound A is less than or equal to a MIC of 2 ⁇ g/ml.
  • a PK/PD index is the quantitative relationship between a pharmacokinetic parameter (such as AUC, peak level, or percentage of time over MIC) and a microbiological parameter (such as MIC).
  • a pharmacokinetic parameter such as AUC, peak level, or percentage of time over MIC
  • a microbiological parameter such as MIC
  • the recommended dose of tigecycline is an initial dose of 100 mg, followed by 50 mg every 12 hours by Intravenous (IV) infusions over approximately 30 to 60 minutes.
  • Undersirable side effects refer to a side effects following administration of drug which would require termination of treatment or prevent initiation of treatment due to the severity of the side effect.
  • the undesirable side effect can be nausea/vomiting.
  • This application also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a unit dose of Compound A or a pharmaceutically acceptable salt thereof, wherein the unit dose is from about 1-1.5 mg/kg subject body weight and a pharmaceutically acceptable carrier.
  • the unit dose of Compound A is provided in dry powder form and reconstituted in a pharmaceutically acceptable carrier, such as a sterile aqueous formulation prior to administration to a subject.
  • Such pharmaceutical compositions are administered by parenteral routes (e.g., intravenous or intramuscular).
  • “Pharmaceutically acceptable carrier” means non-therapeutic components that are of sufficient purity and quality for use in the formulation of a composition of the invention that, when appropriately administered to typically do not produce an adverse reaction, and that are used as a vehicle for a drug substance (i.e., Compound A).
  • an acid salt can be obtained by reacting the compound with a suitable organic or inorganic acid, resulting in pharmaceutically acceptable anionic salt forms.
  • anionic salts include (but are not limited to) the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate,
  • phosphate/diphosphate polygalacturonate
  • salicylate stearate, subacetate
  • succinate sulfate
  • tannate tartrate
  • teoclate tosylate
  • triethiodide salts triethiodide salts.
  • Salts of the compound of the present invention can be prepared by reacting with a suitable base.
  • a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium.
  • Compound A can be used to prevent or treat important mammalian and veterinary diseases.
  • diseases include, but are not limited to, skin infections, GI infections, urinary tract infections, genito-urinary infections, respiratory tract infections, sinuses infections, middle ear infections, systemic infections, intraabdominal infections, pyelonephritis, pneumonia, bacterial vaginosis, streptococcal sore throat, chronic bacterial prostatitis, gynecological and pelvic infections, sexually transmitted bacterial diseases, ocular and otic infections, cholera, influenza, bronchitis, acne, psoriasis, rosacea, impetigo, malaria, sexually transmitted disease including syphilis and gonorrhea, Legionnaires' disease, Lyme disease, Rocky Mountain spotted fever, Q fever, typhus, bubonic plague, gas gangrene, hospital acquired infections, leptospirosis, whooping cough, anthrax and infections caused by the
  • Chronic pneumonias mainly include those of Nocardia, Actinomyces and Blastomyces dermatitidis, as well as the granulomatous pneumonias (Mycobacterium tuberculosis and atypical mycobacteria, Histoplasma capsulatum and Coccidioides immitis).
  • methods for treating neoplasms using tetracycline compounds of the invention are also included (van der Bozert et al., Cancer Res., 48: 6686-6690 (1988)).
  • the infection can be caused by a bacterium (e.g. an anaerobic or aerobic bacterium).
  • a bacterium e.g. an anaerobic or aerobic bacterium.
  • the infection is caused by a Gram-positive bacterium.
  • the infection is caused by a Gram-positive bacterium selected from class Bacilli, including, but not limited to, Staphylococcus spp., Streptococcus spp., Enterococcus spp., Bacillus spp., Listeria spp.; phylum Actinobacteria, including, but not limited to, Propionibacterium spp., Corynebacterium spp., Nocardia spp., Actinobacteria spp. , and class Clostridia, including, but not limited to, Clostridium spp.
  • the infection is caused by a Gram-negative bacterium.
  • the infection is caused by a phylum Proteobacteria ⁇ e.g., Betaproteobacteria and Gammaproteobacteria), including Escherichia coli, Salmonella, Shigella, other Enterobacteriaceae, Pseudomonas, Moraxella, Helicobacter, Stenotrophomonas, Bdellovibrio, acetic acid bacteria, Legionella or alpha-proteobacteria such as Wolbachia.
  • the infection is caused by a Gram-negative bacterium selected from cyanobacteria, spirochaetes, green sulfur or green non-sulfur bacteria.
  • the infection is caused by a Gram-negative bacteria selected from Enterobacteriaceae (e.g., E. coli, Klebsiella pneumoniae including those containing extended-spectrum ⁇ -lactamases and/or carbapenemases), Bacteroidetes (e.g., Bacteroides fragilis), Vibrionaceae (Vibrio cholerae), Pasteur ellaceae (e.g.,
  • the infection is caused by Gram-negative bacterium selected from the group consisting of Enterobacteriaceae (e.g., E.
  • the infection is caused by an organism selected from the group consisting of K. pneumoniae, Salmonella, E. hirae, A. baumannii, M. catarrhalis, H. influenzae, P. aeruginosa, E. faecium, E. coli, S. aureus, and E. faecalis.
  • the infection is caused by an organism that grows intracellularly as part of its infection process.
  • the infection is caused by an organism selected from the group consisting of order Rickettsiales; phylum Chlamydiae; order
  • Mycoplasma spp. e.g. Mycoplasma pneumoniae
  • Mycobacterium spp. e.g. Mycobacterium tuberculosis
  • phylum Spirochaetales e.g. Borrelia spp. and Treponema spp.
  • the infection is caused by a Category A, B, or C Biodefense organisms as described at http://www.bt.cdc.gov/agent/agentlist- category.asp, the entire teachings of which are incorporated herein by reference.
  • Category A organisms include, but are not limited to, Bacillus anthracis (anthrax), Yersinia pestis (plague), Clostridium botulinum (botulism) or Francisella tularensis (tularemia).
  • the infection is a Bacillus anthracis infection.
  • Bacillus anthracis infection includes any state, diseases, or disorders caused or which result from exposure or alleged exposure to Bacillus anthracis or another member of the Bacillus cereus group of bacteria.
  • Additional infections that can be treated using compounds of the invention or a pharmaceutically acceptable salt thereof include, but are not limited to, anthrax, botulism, bubonic plague, and tularemia.
  • the infection is caused by a Category B Biodefense organism as described at http://www.bt.cdc.gov/agent/agentlist-category.asp, the entire teachings of which are incorporated herein by reference.
  • Category B organisms include, but are not limited to, Brucella spp, Clostridium perfringens, Salmonella spp., Escherichia coli 0157:H7, Shigella spp., Burkholderia mallei, Burkholderia pseudomallei, Chlamydia psittaci, Coxiella burnetii,
  • Staphylococcal enterotoxin B Rickettsia prowazekii, Vibrio cholerae
  • Additional infections that can be treated using compounds of the invention or a pharmaceutically acceptable salt thereof include, but are not limited to,
  • Category C pathogens include, but are not limited to, emerging pathogens that could be engineered for mass dissemination in the future because of availability; ease of production and dissemination; and potential for high morbidity and mortality rates and major health impact (e.g., multidrug-resistant Mycobacterium
  • the infection can be caused by one or more than one organism described above.
  • infections include, but are not limited to, intra-abdominal infections (often a mixture of a gram-negative species like E. coli and an anaerobe like B. fragilis), diabetic foot (various combinations of Streptococcus, Serratia, Staphylococcus and Enterococcus spp., anaerobes (S.E. Dowd, et al., PloS One 2008;3:e3326, the entire teachings of which are incorporated herein by reference) and respiratory disease (especially in patients that have chronic infections like cystic fibrosis - e.g., S. aureus plus P.
  • aeruginosa or H. influenzae atypical pathogens
  • wounds and abscesses variant gram-negative and gram- positive bacteria, notably MSSA/MRSA, coagulase-negative staphylococci, enterococci, Acinetobacter, P. aeruginosa, E. coli, B. fragilis
  • bloodstream infections (13% were polymicrobial (H. Wisplinghoff, et al., Clin. Infect. Dis. 2004; 39:311-317, the entire teachings of which are incorporated herein by reference)).
  • the infection is caused by an organism resistant to one or more antibiotics.
  • the infection is caused by an organism resistant to tetracycline or any member of first and second generation of tetracycline antibiotics (e.g., doxycycline or minocycline). In another embodiment, the infection is caused by an organism resistant to methicillin.
  • the infection is caused by an organism resistant to vancomycin.
  • the infection is caused by an organism resistant to a quinolone or fluoroquinolone.
  • the infection is caused by an organism resistant to tigecycline or any other tetracycline derivative. In a particular embodiment, the infection is caused by an organism resistant or nonsusceptible to tigecycline.
  • the infection is caused by an organism resistant to a ⁇ -lactam or cephalosporin antibiotic or an organism resistant to penems or carbapenems.
  • the infection is caused by an organism resistant to an antimicrobial peptide or a biosimilar therapeutic treatment.
  • Antimicrobial peptides also called host defense peptides
  • antimicrobial peptides are an evolutionarily conserved component of the innate immune response and are found among all classes of life.
  • antimicrobial peptide refers to any naturally occurring molecule or any combination thereof.
  • the infection is caused by an organism resistant to macrolides, lincosamides, streptogramin antibiotics, oxazolidinones, tetracycline and/or pleuromutilins.
  • the infection is caused by an organism resistant or nonsusceptible to PTK0796 (7-dimethylamino, 9-(2,2-dimethyl-propyl)- aminomethylcycline) .
  • the infection is caused by a multidrug-resistant pathogen (having intermediate or full resistance to any two or more antibiotics).
  • the term "subject” means a mammal in need of treatment or prevention, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • the subject is a human in need of the specified treatment.
  • the "same subject” can be administered Tygacil and Compound A at different times after a sufficient wash-out period between administrations.
  • the term "treating" or 'treatment” refers to obtaining desired pharmacological and/or physiological effect.
  • the effect can include achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder; delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.
  • preventing or “prevention” refers to reducing the likelihood of the onset or development of disease, disorder or syndrome.
  • “Therapeutically effective amount” means that amount of Compound A that elicits the desired biological response, for example, treatment of a bacterial infection in a subject.
  • a therapeutically effective amount is an amount which in comparison to the recommended dosing regimen of tigecycline results in a higher AUC than tigecycline without undesirable side effects.
  • the effective amount of Compound A is from about 1- 1.5 mg/kg subject body weight once a day.
  • the effective amount of a compound of the invention is from about 0.625-1 mg/kg subject body weight twice a day.
  • population of human subjects means the entire population tested and for which there is AUCo-t au (ss) data.
  • the entire population must be healthy human subjects and must comprise at least six members.
  • the entire population must be human subjects who are being treated for a bacterial infection and must comprise at least six members.
  • Twice a day refers to two administrations per every 24 hour period.
  • a suitable interval between the two administrations includes any time period which maintains a therapeutically effective plasma level of Compound A. Such an interval can be, for example, about 12 hours.
  • Compound A was prepared for administration as follows: 52.5 mg of Compound A (free base equivalent) in the form of a lyophilized powder (59.4 mg of salt form and 420 mg mannitol) is reconstituted with a volume of 10 mL of sterile water for injection. The reconstituted sterile liquid is further diluted for infusion in D5W (and/or normal saline).
  • the activity of Compound A and tigecycline were compared with respect to in vivo efficacy in animal models, drug exposure and tolerability in Phase 1 clinical trials and PK/PD relationships.
  • An improved tolerability profile was seen for Compound A with respect to the incidence and severity of gastrointestinal tolerability. Such an improvement can allow once daily dosing of Compound A and higher AUCs than tigecycline.
  • the SAD study investigated single doses of 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, and 3.0 mg/kg, administered by intravenous infusion over 30 minutes.
  • DGs Dose escalations were performed sequentially. 56 healthy adult volunteers 18-50 years old were recruited. Each of the 7 Dose Groups (DGs) consisted of 8 subjects (6 randomized to receive Compound A and 2 matching placebo). All subjects provided plasma and urine samples for an assessment of the pharmacokinetics.
  • Plasma PK was dose-proportional and linear with respect to AUC, C max , and 0-8 hour urine concentrations. All estimated T1 ⁇ 2 were between 12-24 hours, with DG 3 mg/kg having the largest estimated T1 ⁇ 2 while DG 0.10 mg/kg had the smallest. Table 1
  • PK, safety and tolerability data indicate Compound A may be of utility at dose regimens up to and including 2 mg/kg/day and are consistent with the potential utility of once-daily doses in the treatment of important bacterial infections.
  • AUC data for compound A is from population PK analyses
  • Compound A demonstrated a lower incidence and severity of nausea and emesis as compared to tigecycline, despite reaching higher levels of exposure.
  • Methodology 32 healthy adult volunteers, 6 randomized to receive Compound A and 2 matching placebo per dose group, received 30 minute (30') infusions of 0.50 mg/kg q24h and 1.50 mg/kg q24h or 60 minute (60') infusions of 1.5 mg/kg q24h and 1.0 mg/kg ql2h.
  • the invention provides a method of achieving an arithmetic mean AUCo-tau(ss) of greater than 7,050 ng Compound A-h/mL over 24 hrs in a population of human subjects by administering intravenously to each member of the population the same dose of Compound A, wherein the dose is selected from 1.5 mg/kg body weight once a day in a 30 minute infusion; 1.5 mg/kg body weight once a day in a 60 minute infusion; and 1.0 mg/kg body weight twice a day, each administration in a 60 minute infusion; and wherein the dose is administered over at least 7 consecutive days.
  • the method achieves an arithmetic mean AUCo-tau(ss) of greater than 8,500 ng Compound A-h/mL over 24 hrs in the population.
  • the invention provides a method of achieving an arithmetic mean AUCo-t au (ss) of greater than 10,000 ng Compound A-h/mL over 24 hrs in a population of human subjects by administering intravenously to each member of the population Compound A at a dose 1.0 mg/kg body weight twice a day, each administration in a 60 minute infusion; and wherein the dose is administered over at least 7 consecutive days.
  • the method achieves an arithmetic mean AUCo-tau(ss) of greater than 12,500 ng Compound A-h/mL over 24 hrs in the population.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Compound A and a pharmaceutically acceptable carrier, wherein the composition is formulated for intravenous administration to a human, wherein when administered to a population of human subjects over 7 consecutive days, wherein each member of the population is administered the same dosage selected from 1.5 mg Compound A /kg body weight once a day in a 30 minute infusion; 1.5 mg Compound A /kg body weight once a day in a 60 minute infusion; and 1.0 mg Compound A /kg body weight twice a day, each administration in a 60 minute infusion; produces an arithmetic mean AUCo-tau(ss) of greater than 7,050 ng Compound A- h/mL over 24 hrs.
  • the composition is formulated for intravenous administration to a human, wherein when administered to a population of human subjects over 7 consecutive days, wherein each member of the population is administered the same dosage selected from 1.5 mg Compound A /kg body weight once a day in a 30 minute infusion; 1.5
  • composition produces an arithmetic mean AUCo -ta u(ss) of greater than 8,500 ng Compound A-h mL over 24 hrs.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Compound A and a pharmaceutically acceptable carrier, wherein the composition is formulated for intravenous administration to a human, wherein when administered to a population of human subjects over 7 consecutive days, wherein each member of the population is administered 1.0 mg Compound A /kg body weight twice a day, each administration in a 60 minute infusion; produces an arithmetic mean AUCo-tau(ss) of greater than 10,000 ng Compound A-h/mL over 24 hrs.
  • the pharmaceutical composition produces an arithmetic mean AUCo-t au (ss) of greater than 12,500 ng Compound A-h/mL over 24 hrs in the population.
  • ACUo-t aU (ss) over 24 hours can be determined by compartmental or non-compartmental analyses. As long as one of those analyses yields results within the parameters set forth above, the method or composition is deemed to be a part of the present invention.
  • Table 4 Summary Statistics and Pharmacokinetic Parameter Values for Compound A MAD Study Using Population PK Modeling
  • Compound A urine concentrations in excess of the MIC90 of key pathogens that cause cUTIs (e.g., E. coli, K. pneumoniae, E. faecalis, E. faecium, MRS A, MSSA; see Tables 14-16 for MIC data).
  • Compound A has an excellent spectrum for empiric treatment of cUTIs caused by either gram-negative or gram-positive bacteria, with MIC 5 0/MIC90 values of 0.25/0.5 and 0.5/1 ⁇ g/ml against 176 Escherichia coli and 219 Klebsiella pneumoniae isolates, respectively, and MIC90S of 0.12 ⁇ g ml vs.
  • PK, safety and tolerability data indicate Compound A has significant exposure at dose regimens up to and including 2 mg/kg/day and are consistent with the potential utility of once-daily doses for the treatment of serious bacterial infections, including those caused by multidrug-resistant gram-negative pathogens.
  • the urine concentrations of Compound A are >2 ⁇ g/ml throughout 10 days of therapy, thereby providing sufficient levels to treat infections caused by key urinary tract patho gens .
  • FIG. 1 is a graphical representation of the results of Nausea/Vomiting and the AUCs for Compound A at the indicated dose and tigecycline at the indicated dose. The comparison of AUC and incidence of nausea/vomiting show that
  • Compound A can be dosed to achieve higher doses and systemic exposure levels before generating a similar rate of gastrointestinal adverse events associated with tigecycline.
  • N Nausea
  • V Vomiting
  • Plasma protein binding was also determined over a concentration range of 0.1-2.5 ⁇ g/mL using human plasma collected with heparin and equilibrium (Teflon microdialysis chambers) of test compound in phosphate-buffered saline against phosphate-buffered saline at 37° C for 22 hours.
  • CD-I female mice were rendered neutropenic by pretreatment with cyclophosphamide and then challenged with different bacterial strains in the thigh.
  • Treatment was IV with a single dose of Compound A.
  • Treatment was IV 1.5 hours post-challenge, with bacterial burden reduction recorded 24 hours post-challenge.
  • Table 11 The results are shown in Table 11 along with MIC values.
  • Compound A was highly effective in septicemia models, demonstrating PD50S of ⁇ 1 mg/kg against S. aureus, including tetracycline- resistant strains, MRSA and S. pyogenes.
  • the PD 50 s against E. coli were 1.2-4.4 mg/kg.
  • the PD50 values for Compound A against S. aureus strains were comparable to those for tigecycline (MICs to strains used in the systemic models are shown in Table 11).
  • Compound A PD 50 values were comparable to tigecycline against Escherichia coli isolates for infections with an E. coli strain expressing an extended spectrum ⁇ -lactamase (ESBL), EC133, and one that does not, E. coli ATCC 25922.
  • ESBL extended spectrum ⁇ -lactamase
  • CLSI Commission International Standards Institute
  • CLSI Performance standards for antimicrobial susceptibility testing; nineteenth information supplement.
  • CLSI document M100- S19, CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA, 2009 Briefly, frozen bacterial strains were thawed and subcultured onto Mueller Hinton Broth (MHB) or other appropriate media (Streptococcus requires blood and Haemophilus requires hemin and NAD). Following incubation overnight, the strains were subcultured onto Mueller Hinton Agar and again incubated overnight. Colonies were observed for appropriate colony morphology and lack of contamination.
  • Isolated colonies were selected to prepare a starting inoculum equivalent to a 0.5 McFarland standard.
  • the starting inoculum was diluted 1 :125 (this is the working inoculum) using MHB for further use.
  • Test compounds were prepared by dilution in sterile water to a final concentration of 5.128 mg/mL.
  • Antibiotics stored frozen, thawed and used within 3 hours of thawing
  • compounds were further diluted to the desired working concentrations.
  • the assays were run as follows. Fifty of MHB was added to wells 2 - 12 of a 96-well plate. One hundred ⁇ , of appropriately diluted antibiotics was added to well 1. Fifty ⁇ , of antibiotics was removed from well 1 and added to well 2 and the contents of well 2 mixed by pipetting up and down five times. Fifty ⁇ ⁇ of the mixture in well 2 was removed and added to well 3 and mixed as above. Serial dilutions were continued in the same manner through well 12. Fifty iL was removed from well 12 so that all contained 50 ih. Fifty iL of the working inoculum was then added to all test wells. A growth control well was prepared by adding 50 i of working inoculum and 50 ⁇ , of MHB to an empty well. The plates were then incubated at 37 °C overnight, removed from the incubator and each well was read on a plate reading mirror. The lowest concentration (MIC) of test
  • MIC minimum inhibitory concentration
  • Haemophilus influenzae HI262 Tetracycline-resistant, ampicillin-resistant
  • MDR multidrug-resistant
  • MRS A rnethicillin-resistant S. aureus
  • MSSA methicillin- sensitive S. aureus
  • HA-MRSA hospital-associated MRS A
  • tet(K) major gram-positive tetracycline efflux mechanism
  • tet(M) major gram-positive tetracycline ribosome-protection mechanism
  • ESBL + extended spectrum ⁇ -lactamase Results
  • Organism 3 N d n n n
  • Organism 3 N d n n n
  • MSSA methicillin-susceptible S. aureus
  • MRSA methicillin-resistant S. aureus
  • MRSA PVL + MRSA isolates confirmed to contain Panton- Valentine leukocidin
  • MSSE methicillin-susceptible Staphylococcus epidermidis
  • MRSE methicillin-resistant S.
  • VSE vancomycin-susceptible E. faecalis and E. faecium
  • VRE vancomycin-resistant E.
  • Streptococcus pyogenes Streptococcus pyogenes
  • Organism N Compound A Tigecycline Carbapenem FQ 3 Gen Ceph Gentamicin Pip/ Tazo
  • Organism N Compound A Tigecycline Carbapenem FQ 3 Gen Ceph Gentamicin Pip/ Tazo
  • Carbapenem meropenem, ertapenem, or imipenem;
  • FQ Fluoroquinolone levofloxacin or ciprofloxacin;
  • 3rd Gen Ceph third generation cephalosporin (either cefotaxime or ceftazidime);
  • Pip/Tazo Piperacillin/tazobactam (only the piperacillin MIC in the presence of 4 of tazobactam is shown);
  • ES L + extended spectrum p-lactamase producing isolates
  • a ⁇ MIC 90 of Cmpd A ⁇ MIC 90 of tigecycline for: Escherichia coli, ESpL + E. coli, Klebsiella pneumoniae, ESpL + . pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Serratia marcescens, Enterobacter cloacae, Enterobacter aerogenes, Stenotrophomonas maltophilia, Acinetobacter baumannii, Acinetobacter hvqffii, Salmonella spp., Haemophilus influenzae, Moraxella catarrhalis, and Pseudomonas aeruginosa
  • Compound A was evaluated in murine lung infection models. After cyclophosphamide treatment that rendered the mice neutropenic, mice were intranasally challenged with either a MRSA isolate containing a tet(M) mechanism or with a multidrug-resistant S. pneumoniae tet(M) strain. Compound A or comparators were dosed 2 and 12 hours post-challenge by the indicated route (FIG. 2). Twenty-four hours post-initiation of treatment, mice were euthanized, lungs removed, and the bacterial burden was determined. Compound A reduced S.
  • MICs of Compound A (Cpd A) and doxycycline against S. pneumoniae SP160 tet(M) was ⁇ 0.016 and 8 ⁇ g/ml, respectively.
  • MICs of Compound A (Cpd A) and doxycycline against S. pneumoniae SP160 tet(M) was ⁇ 0.016 and 8 ⁇ g/ml, respectively.
  • Compound A is also effective in reducing the bacterial burden in kidneys from mice that have been infected with a tetracycline-resistant uropathogenic strain of E. coli or an ESpL-producing strain of K. pneumoniae (FIG. 3). Treatment with Compound A or comparators was IV at the dose indicated, 12 and 24 hours post- challenge. Compound A at 5 or 10 mg/kg BID, reduced the bacterial burden by 4 logs and was comparable to tigecycline at 10 mg/kg, BID and to levofloxacin at 2 mg/kg, BID in treatment of a tetracycline-resistant (tetR) E. coli strain. In treating the ES PL-producing isolate of K. pneumoniae 10-20 mg/kg of Compound A was found to be equivalent to the gold standard, meropenem at 30 mg/kg BID.
  • SP160 tet(M) was ⁇ 0.016 and 8 ⁇ g/ml, respectively.
  • MICs of Compound A (Cpd A) and meropenem against K. pneumoniae KP453 were 0.5 and 0.031 ⁇ g/ml, respectively.
  • a pretest to determine if Compound A's activity was impacted artificially by BCYE supplement or iron was done by testing ATCC isolates of Staphylococcus aureus and Escherichia coli on BYE, BYE without ferric pyrophosphate (modB YE) and cation-adjusted Mueller-Hinton agar (MH).
  • Legionella BCYE Growth supplement was used as the medium to test Legionella strains.
  • Escherichia coli ATCC25922 and Staphylococcus aureus ATCC29213 were tested in a pilot study comparing the activities of antibiotics in Mueller Hinton Broth (MH), standard BYE, and modified BYE ("Mod BYE";
  • pneumophila strains were 1/2, 4/8 and 0.25/0.5 ⁇ g/ML, respectively.
  • L. pneumophila serogroup 1 usually the most frequently recovered serogroup, the MIC50/90 of Compound A, tetracycline, and erythromycin was 0.5/2, 4/8, and 0.25/0.5 ⁇ g/mL.
  • Compound A had excellent activity against L. pneumophila, especially as its activity was artificially suppressed in BYE agar.

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Abstract

L'invention concerne une méthode de traitement d'une infection bactérienne chez un sujet humain, la méthode comprenant l'administration par voie intraveineuse au sujet d'un composé représenté par la formule structurelle (I) suivante, ou de l'un de ses sels pharmaceutiquement acceptables (composé A). Le composé A peut être administré une fois par jour en une quantité comprise entre environ 1 mg/kg et 1,5 mg/kg du poids corporel du sujet ou deux fois par jour en une quantité par dose comprise entre environ 0,625 mg/kg et 1 mg/kg du poids corporel du sujet.
PCT/US2011/047624 2010-08-12 2011-08-12 Méthodes de traitement d'infections bactériennes Ceased WO2012021829A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015517524A (ja) * 2012-05-14 2015-06-22 パラテック ファーマシューティカルズ インコーポレイテッド （４Ｓ，４ａＳ，５ａＲ，１２ａＳ）−４−ジメチルアミノ−３，１０，１２，１２ａ−テトラヒドロキシ−７−［（メトキシ（メチル）アミノ）−メチル］−１，１１−ジオキソ−１，４，４ａ，５，５ａ，６，１１，１２ａ−オクタヒドロ−ナフタセン−２−カルボン酸アミドの使用方法
WO2017097891A1 (fr) 2015-12-10 2017-06-15 Sandoz Ag Éravacycline cristalline
WO2017125557A1 (fr) 2016-01-22 2017-07-27 Sandoz Ag Bis-chlorhydrate d'éravacycline cristalline
CN111971068A (zh) * 2018-04-20 2020-11-20 康柏辛股份有限公司 败血症和败血性休克的治疗

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010017470A1 (fr) * 2008-08-08 2010-02-11 Tetraphase Pharmaceuticals, Inc. Composés de tétracycline c7-fluorosubstituée

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010017470A1 (fr) * 2008-08-08 2010-02-11 Tetraphase Pharmaceuticals, Inc. Composés de tétracycline c7-fluorosubstituée

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015517524A (ja) * 2012-05-14 2015-06-22 パラテック ファーマシューティカルズ インコーポレイテッド （４Ｓ，４ａＳ，５ａＲ，１２ａＳ）−４−ジメチルアミノ−３，１０，１２，１２ａ−テトラヒドロキシ−７−［（メトキシ（メチル）アミノ）−メチル］−１，１１−ジオキソ−１，４，４ａ，５，５ａ，６，１１，１２ａ−オクタヒドロ−ナフタセン−２−カルボン酸アミドの使用方法
EP2849757A4 (fr) * 2012-05-14 2015-11-18 Paratek Pharm Innc Procédés d'utilisation du (4s,4as,5ar,12as)-4- diméthylamino-3,10,12,12a-tétrahydroxy-7-[(méthoxy(méthyl)amino)-méthyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphtacène-2-carboxamide
WO2017097891A1 (fr) 2015-12-10 2017-06-15 Sandoz Ag Éravacycline cristalline
WO2017125557A1 (fr) 2016-01-22 2017-07-27 Sandoz Ag Bis-chlorhydrate d'éravacycline cristalline
CN108495844A (zh) * 2016-01-22 2018-09-04 桑多斯股份公司 结晶埃拉环素二盐酸盐
EP3390358B1 (fr) 2016-01-22 2020-09-23 Sandoz AG Bis-hydrochlorure cristalin d'eravacycline
EP3778567A1 (fr) 2016-01-22 2021-02-17 Sandoz Ag Bis-hydrochlorure cristalin d'eravacycline
US10975029B2 (en) 2016-01-22 2021-04-13 Sandoz Ag Crystalline eravacycline bis-hydrochloride
AU2017208574B2 (en) * 2016-01-22 2022-09-22 Sandoz Ag Crystalline eravacycline bis-hydrochloride
CN108495844B (zh) * 2016-01-22 2022-12-02 桑多斯股份公司 结晶埃拉环素二盐酸盐
CN111971068A (zh) * 2018-04-20 2020-11-20 康柏辛股份有限公司 败血症和败血性休克的治疗

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