WO2020002740A1 - Dalbavancine à utiliser dans le traitement d'infections bactériennes des voies respiratoires chez des enfants et des patients pédiatriques - Google Patents

Dalbavancine à utiliser dans le traitement d'infections bactériennes des voies respiratoires chez des enfants et des patients pédiatriques Download PDF

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Publication number
WO2020002740A1
WO2020002740A1 PCT/ES2019/070453 ES2019070453W WO2020002740A1 WO 2020002740 A1 WO2020002740 A1 WO 2020002740A1 ES 2019070453 W ES2019070453 W ES 2019070453W WO 2020002740 A1 WO2020002740 A1 WO 2020002740A1
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Prior art keywords
compound
dalbavancin
treatment
individual
composition according
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Spanish (es)
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Félix GÓMEZ DE RUEDA
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Servicio Andaluz de Salud
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Servicio Andaluz de Salud
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention is within the medicine, and refers to the use of a lipoglycopeptide antibiotic, dalbavancin, for the treatment of respiratory tract diseases, preferably pneumonia, in children under 18 years.
  • Dalbavancin is a recently marketed semi-synthetic lipoglicopeptide (LGP) antibiotic, active against gram-positive bacteria and with a novel pharmacokinetic profile (PK) that provides a plasma half-life of about 9 days, being able to reach 18 days in cases of kidney failure severe (WRI).
  • This pharmacokinetic property is mainly due to a lipophilic chain, which on the one hand favors the formation of homodimers and insertion into the C55 lipid, and on the other a time-dependent activity when the maximum concentration (Cmax) is four times higher than the minimum concentration inhibitory (MIC).
  • Cmax maximum concentration
  • MIC minimum concentration inhibitory
  • Dalbavancin has demonstrated potent in vitro activity against gram-positive germs such as Staphylococcus aureus meticillin-resistant (SAMR), Streptococcus pneumoniae penicillin-resistant, Streptococcus pyogenes, Streptococcus agalactiae and the Streptococcus anginosus group,
  • SAMR Staphylococcus aureus meticillin-resistant
  • Streptococcus pneumoniae penicillin-resistant Streptococcus pyogenes
  • Streptococcus agalactiae Streptococcus anginosus group
  • Dalbavancin has been authorized for the treatment of acute bacterial infection of the skin and related skin structures (ABSSSI) in adults. It is presented as a lyophilized powder for administration in solution for intravenous infusion (for 30 minutes) containing 500 mg of active substance. The recommended dosage is 1000 mg at the start of treatment, followed by 500 mg one week later.
  • Fig. 1 Record of body temperatures (T) in degrees Celsius.
  • Fig. 4 Evolution of serum levels of C-Reactive Protein (CRP) in mg / l units.
  • CRP C-Reactive Protein
  • Fig. 6 Plasma triglyceride levels (TG) in units (mg / dl).
  • Fig. 7 Plasma levels of ferritin (FRT) in ng / ml.
  • the author of the present invention has shown that the administration of Dalbavancin to individuals under 18, preferably under 16, and even under 12, is safe at certain doses. In addition, they have shown that it is useful in the treatment of diseases of the respiratory system. It has been proven that they exert their effect and are not inactivated by the pulmonary surfactant, which postulates it as an alternative antibiotic to daptomycin (DPT) in respiratory infections and to linezolid (LNZ) in potential cases of hematological toxicity.
  • DPT daptomycin
  • LNZ linezolid
  • a first aspect of the present invention relates to a compound of general formula (I) (also referred to as the compound of the invention):
  • -R is equal to - CH (CH 3 ) 2 , - CH 2 CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , - CH 2 CH 2 CH 2 CH 3 , - CH 2 CH 2 CH (CH 3 ) 2 , - CH 2 CH 2 CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , (CH 3 ) 2 , CH 2 CH 3, Or nothing.
  • R1 is equal to H or CH 3 or any of its salts, preferably any pharmaceutically acceptable salt, esters, tautomers, polymorphs, pharmaceutically acceptable hydrates, or an isomer, prodrugs, derivatives, solvates or the like, or any combination thereof, for the prevention, relief and / or treatment of a bacterial infection of the respiratory system in an individual.
  • the bacterial disease of the respiratory system is pneumonia.
  • Pneumonia or pneumonia is a disease of the respiratory system that involves the inflammation of the alveolar spaces of the lungs.
  • Pneumonia can affect a complete pulmonary lobe (lobular pneumonia), a lobe segment, alveoli close to the bronchi (bronchopneumonia) or interstitial tissue (interstitial pneumonia).
  • lobular pneumonia lobular pneumonia
  • bronchopneumonia bronchopneumonia
  • interstitial tissue interstitial pneumonia
  • Pneumonia causes the tissue that forms the lungs to look red, swollen and painful.
  • Many patients with pneumonia are treated by GPs and do not enter hospitals.
  • Community-acquired pneumonia (CAP) or out-of-hospital pneumonia is that acquired outside hospitals, while nosocomial pneumonia (NN) is acquired during hospital stay, after 48 hours or two weeks have elapsed. of receiving the discharge.
  • CAP Community-acquired pneumonia
  • N nosocomial pneumonia
  • pneumonia is extrahospital.
  • the individual is under 18, more preferably the individual under 16, more preferably in an individual under 12 years.
  • the Individual is under 11 years, optionally under 10 years, 9 years, 8 years, 7 years, 6 years, 5 years, 4 years, 3 years, 2 years , or less than 1 year
  • Davalblcina is indicated for infections of the skin and soft tissues.
  • Davalbicin is effective in the treatment of bacterial infections of the respiratory tract in individuals under 18 years of age. Therefore, in another preferred embodiment of this aspect of the invention, the bacterial infection is a respiratory infection.
  • the compounds of the present invention represented by formula (I) may include isomers, depending on the presence of multiple bonds, including optical isomers or enantiomers, depending on the presence of chiral centers.
  • the individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention, that is, the term isomer also refers to any mixture of Isomers, such as diastereomers, racemic, etc., even their optically isomers. assets or mixtures in different proportions thereof.
  • the individual enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.
  • prodrugs of the compounds of formula (I) include any derivative of a compound of formula (I) - for example and not limited to: esters (including esters of carboxylic acids, amino acid esters, phosphate esters, esters of sulphonate of metal salts, etc.), carbamates, amides, etc. - which when administered to an individual can be transformed directly or indirectly into said compound of formula (I) in said individual.
  • said derivative is a compound that increases the bioavailability of the compound of formula (I) when administered to an individual or that enhances the release of the compound of formula (I) in a biological compartment.
  • the nature of said derivative is not critical as long as it can be administered to an individual and provides the compound of formula (I) in a biological compartment of an individual.
  • the preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.
  • derivative includes both pharmaceutically acceptable compounds, that is, derivatives of the compound of formula (I) that can be used in the manufacture of a medicament or food compositions, as pharmaceutically unacceptable derivatives, and that these may be useful in the preparation of pharmaceutically acceptable derivatives.
  • the compounds of the invention may be in crystalline form as free compounds or as solvates.
  • solvate includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula (I) that can be used in the manufacture of a medicament, as pharmaceutically acceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts.
  • the nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable.
  • the solvate is a hydrate.
  • Solvates can be obtained by conventional solvation methods known to those skilled in the art.
  • the compounds of formula (I), their salts, prodrugs or solvates will preferably be found in a pharmaceutically acceptable or substantially pure form, that is, having a pharmaceutically acceptable level of purity excluding pharmaceutical additives. normal such as diluents and carriers, and not including material considered toxic at normal dosage levels.
  • the purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, and still more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I), or of its salts, solvates or prodrugs.
  • a second aspect of the invention relates to a composition, hereinafter composition of the invention, comprising at least one compound of the invention, or any of its salts, preferably any pharmaceutically acceptable salt, esters, tautomers, polymorphs, hydrates. pharmaceutically acceptable, or an isomer, prodrugs, derivatives, solvates or the like, or any combination thereof, the prevention, relief and / or treatment of a bacterial infection of the respiratory system in an individual.
  • the bacterial disease of the respiratory system is pneumonia.
  • the pneumonia is extrahospital.
  • the individual is under 18, more preferably the individual under 16, more preferably in an individual under 12 years.
  • the individual is younger than 11 years old, optionally younger than 10 years old, 9 years old, 8 years old, 7 years old, 6 years old, 5 years old, 4 years old, 3 years old, 2 years old , or less than 1 year.
  • the bacterial infection is a respiratory infection.
  • the composition of the invention comprises one or more, preferably two or more, in some cases three or more, in some cases four or more, in some cases five or more closely related counterparts, designated "A 0 , ' TV ', "B 0 ", “Bi”, “C 0 “, “Ci”, “C 2 ", “D 0 “ and “Di”, as described below, or monomers, multimers (ie dimer or higher order multimer), tautomers, asters, solvates or pharmaceutically acceptable salts thereof
  • “dimer” or “multimer” refers to a homodimer or homomultimer, that is, a compound dimer or multimer of monomers of the same homologue of dalbavancin, or a heterodimer or heteromultimer, that is, a dimer or multimer composed of monomers of at least two different dalbavancin homologs. The factors differ in the fatty acid side chain structures of the acidic moiety N -acy
  • the composition of the invention is Dalbavancin.
  • Dalbavancin is a semi-synthetic cyclic lipoglycopeptide antibiotic consisting of a mixture of five closely related counterparts that can be grouped into two structural families, designated dalbavancin A and dalbavancin B.
  • the dalbavancin A family consists of two subtypes: dalbavancin A 0 and Ai.
  • Dalbavancin B is composed of three subtypes: B 0 , B ⁇ and B 2.
  • the pharmacological substance of Dalbavancin is a hydrochloride salt, although the compounds of the present invention are not limited and include all possible equivalent salts.
  • Dalbavancin often includes "MAG", a non-homologous variant described below that lacks the acllglucuronamlna moiety. individually, the homologues of dalbavancin and MAG are sometimes referred to herein as components of dalbavancin. eleven
  • Dalbavancin is prepared by chemical modification of the natural glycopeptide complex A-40,926 as described in Malabarba and Donad ⁇ o (1999) Drugs of the Future 24 (8): 839-846.
  • the predominant component of dalbavancin is Factor B 0 , which represents> 75% of the entire complex.
  • each of the components present in a composition of the invention is dictated by a variety of factors, including, for example, the fermentation conditions employed in the preparation of the natural glycopeptide complex A-40926, which is the precursor of dalbavancin (see, for example, US Patent No. 5,843,679), the conditions used to recover A-40926 from the fermentation broth, the chemical reactions used to selectively esterify the carboxyl group of the sugar moiety of A- 40926, the conditions employed to amide the peptidyl carboxyl group, the conditions employed to saponify the ester of the carboxyl group from the function of N-acylaminoglucuronic acid, the conditions employed to recover dalbavancin from the synthetic mixture, and the like.
  • dalbavancin compositions comprise at least about 80, and more preferably at least 85%, 90%, 95%, or about 98% by weight of compound B 0 .
  • dalbavancin comprises the following amounts of B0:
  • the composition further comprises a pharmaceutically acceptable carrier or excipient.
  • the composition is a pharmaceutical composition.
  • the composition only comprises as active ingredient one or more of the compounds of the invention, although it may comprise other pharmaceutically acceptable excipients and carriers.
  • compositions are the adjuvants and vehicles known to those skilled in the art and commonly used in the elaboration of therapeutic compositions.
  • the term "therapeutically effective amount” refers to the amount of the agent or compound capable of developing the therapeutic action determined by its pharmacological properties, calculated to produce the desired effect and, in general, will be determined, among other causes, due to the characteristics of the compounds, including the age, condition of the patient, the severity of the alteration or disorder, and the route and frequency of administration.
  • the compounds described in the present invention, their salts, prodrugs and / or solvates as well as the pharmaceutical compositions containing them can be used together with other drugs, or additional active ingredients, to provide a combination therapy.
  • Said additional drugs may be part of the same pharmaceutical composition or, alternatively, they may be provided in the form of a separate composition for simultaneous or non-simultaneous administration to the pharmaceutical composition comprising a compound of formula (I), or a salt, prodrug or solvate thereof.
  • the pharmaceutical composition further comprises another active ingredient.
  • active substance means any component that potentially provides a pharmacological activity or other different effect on the diagnosis, cure, mitigation, treatment, or prevention of a disease, or that affects the structure or function of the body of man or other animals.
  • the term includes those components that promote a chemical change in the preparation of the drug and are present therein in a modified form intended to provide the specific activity or effect.
  • pharmaceutical form hereinafter pharmaceutical form of the invention, comprising the compound of the invention or the composition of the invention.
  • pharmaceutical form means the mixture of one or more active ingredients with or without additives that have physical characteristics for proper dosage, preservation, administration and bioavailability.
  • compositions for oral administration can be prepared by conventional methods of Galenic Pharmacy, as mixing and dispersion.
  • the tablets can be coated following methods known in the pharmaceutical industry.
  • compositions and pharmaceutical forms can be adapted for parenteral administration, such as sterile solutions, suspensions, or lyophilized products of the Invention, using the appropriate dose.
  • Suitable excipients such as pH buffering agents or surfactants, can be used.
  • the aforementioned formulations can be prepared using conventional methods, such as those described in the Pharmacopoeias of different countries and in other reference texts.
  • medication refers to any substance used for prevention, diagnosis, relief, treatment or cure of diseases in man and animals.
  • the administration of the compounds, compositions or pharmaceutical forms of the present invention can be performed by any suitable method, such as intravenous infusion and oral, topical or parenteral routes. Oral administration is preferred for the convenience of patients and for the chronic nature of the diseases to be treated.
  • the amount administered of a compound of the present invention will depend on the relative efficacy of the compound chosen, the severity of the disease to be treated and the weight of the patient. However, the compounds of this invention will be administered one or more times a day, for example 1, 2, 3 or 4 times daily, with a total dose between 0.1 and 1000 mg / kg / day. It is important to keep in mind that it may be necessary to introduce variations in the dose, depending on the age and condition of the patient, as well as modifications in the route of administration.
  • the compounds and compositions of the present invention can be used together with other medicaments in combination therapies.
  • the other drugs may be part of the same composition or of a different composition, for administration at the same time or at different times.
  • a unit dose of the compound or composition of the invention is provided in the form of dry powder (e.g., lyophilized) and reconstituted in a pharmaceutically acceptable carrier, such as a sterile aqueous formulation, before administration to an individual.
  • a pharmaceutically acceptable carrier such as a sterile aqueous formulation
  • the pharmaceutically acceptable vehicle includes 5% dextrose in water.
  • a pharmaceutical composition of the invention can be administered to a mammal in need of treatment or prevention of a bacterial infection, such as a human being.
  • a pharmaceutical composition may include at least one antibiotic, such as an antibiotic that is effective (e.g., Bactericide) against a Gram-negative bacterium and / or an antibiotic that is effective against Gram-positive species against what Dalbavancin is not effective, such as VanA vancomycin-resistant bacterial strains.
  • an antibiotic that is effective (e.g., Bactericide) against a Gram-negative bacterium and / or an antibiotic that is effective against Gram-positive species against what Dalbavancin is not effective, such as VanA vancomycin-resistant bacterial strains.
  • One or more stabilizing substances are used to inhibit the degradation of one or more components of dalbavancin during storage as a dry powder formulation (for example, lyophilized) and / or as an aqueous formulation before administration to an individual. Over time, degradation may result in the undesirable formation of less active and / or inactive components that could potentially cause adverse effects in vivo.
  • Preferred stabilizers include non-ionic components such as sugars or sugar alcohols, for example, a mono-, di- or polysaccharide, or a derivative thereof, such as, for example, mannitol, lactose, sucrose, sorbitol, glycerol, cellulose , trehalose, maltose, or dextrose, or mixtures thereof.
  • the compound and / or composition of the invention can be administered as a single dose or as multiple doses.
  • a single dose may include at least about 0.1, 0.25, 0.5, 1, 1, 5, 2, 2.5 or 3 grams.
  • two doses of about five to about ten days are administered, such as a week apart.
  • the first dose can be from about 500 to about 5000 mg and the second dose can be from about 250 mg to about 2,500 mg.
  • the first dose includes about 1.5 to about 3 times, often at least about twice the amount contained in the second dose.
  • the first dose may be approximately 1000 mg and the second dose may be approximately 500 mg.
  • the plasma level in an individual before the administration of the second dose is generally at least about 4 mg, often at least about 10 mg, often at least about 20 mg, more often at least about 30 mg per liter of plasma.
  • the dose is an initial load adjusted by weight at 15 mg / kg and 1 maintenance dose of 7.5 mg / kg at 7-8 days, preferably at 8 days.
  • 3 maintenance doses 7.5 mg / kg are administered on days 6-9, 13-17 and 20-25, and much more preferably on days 7, 14 and 21, or on days 8, 16, 24.
  • the route of administration is parenteral, for example intravenous administration.
  • the administration is intravenous with the rate of administration controlled so that the administration occurs for at least about 30 minutes or more.
  • treatment refers to combating the effects caused as a result of a disease or pathological condition of interest in a subject (preferably mammal, and more preferably a human) that includes:
  • prevention consists in preventing the onset of the disease, that is, preventing the disease or pathological condition from occurring in a subject (preferably mammal, and more preferably a human), in particularly, when said subject has a predisposition for the pathological condition.
  • fever is considered when the axillary temperature is between 37 to 38 ° C, while fever is considered when the temperature measured in the armpit is> 38 ° C and the rectal temperature> 38, 5C.
  • the temperature records ranged from fever and fever values, reaching peak values of 40, 1 ° C and where the average body temperature values were 37.20 ° C (95% CI 36.62 to 37.75).
  • An echocardiogram-Doppler® was performed to rule out possible endocarditis, showing normal results except slight aortic regurgitation without interest (Fig 1).
  • the cytobiochemistry of the pleural fluid was compatible by the presence of bacteria, with 50% glucose levels (50 mg / dl). Although at the time of admission he registered a leukocytosis of 37,000 leukos / pL, in the leukocyte count (RL), a few days after admission, the analytical results still showed a leukocytosis in pleural fluid of 24,350 leukocytes / pL, Time of activated partial thromboplastline (TTPa): 24, 1 seconds (normal range: 25.0-37.0), D-dimer: 19.550 ng / ml (normal range: 0-500), CRP: 291, 6 mg / L (normal range: 0-5 mg / L) and procalcitonin (PCT): 2.30 ng / ml (normal range: 0-0.05 ng / ml). During the first 20 days, he had 2-3 febrile peaks daily.
  • TTPa Time of activated partial thromboplastline
  • PCT procalc
  • CVC central venous catheter
  • DPT daptomycin
  • RFP rlfampicin
  • MCR macrolides
  • CF fluoroquinolones
  • DBV Dalbavancina
  • the average value of leukocytes was 23,231, 17 leukocytes / pL (95% CI 19,504.63 to 26,957.70) and placing the median at 25,400 leukocytes / pL.
  • the mean values of CRP and PCT were respectively 195.28 mg / L (95% CI 140.82 to 249.73) and 8.33 ng / ml (2.23 to 14.43) (Fig. 3 - 5).

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Abstract

La présente invention concerne l'utilisation d'un antibiotique lipoglycopeptidique, la dalbavancine, pour le traitement de maladies des voies respiratoires, de préférence la pneumonie, chez des individus de moins de 18 ans.
PCT/ES2019/070453 2018-06-27 2019-06-27 Dalbavancine à utiliser dans le traitement d'infections bactériennes des voies respiratoires chez des enfants et des patients pédiatriques Ceased WO2020002740A1 (fr)

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ESP201830644 2018-06-27
ES201830644 2018-06-27

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WO2020002740A1 true WO2020002740A1 (fr) 2020-01-02

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PCT/ES2019/070453 Ceased WO2020002740A1 (fr) 2018-06-27 2019-06-27 Dalbavancine à utiliser dans le traitement d'infections bactériennes des voies respiratoires chez des enfants et des patients pédiatriques

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050277581A1 (en) * 2002-11-18 2005-12-15 Vicuron Pharmaceuticals Inc. Dalbavancin compositions for treatment of bacterial infections

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050277581A1 (en) * 2002-11-18 2005-12-15 Vicuron Pharmaceuticals Inc. Dalbavancin compositions for treatment of bacterial infections

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BARBER K ET AL.: "Dalbavancin use for the treatmentof methicillin- resistant Staphylococcus aureus pneumonia", JOURNAL OF PHARMACOLOGY AND PHARMACOTHERAPEUTICS, vol. 8, no. 2, 4 January 2017 (2017-01-04), ind., pages 77 - 79, ISSN: 0976-500X *
GAUGUET S ET AL.: "S. aureus pneumonia in the pediatric ICU: bench to bedside", SCCM COMMUNICATIONS. CRITICAL CONNECTIONS, April 2011 (2011-04-01), pages 12 - 14 *
GOMEZ DE RUEDA F ET AL.: "A case report of dalbavancin Off-Label use in a 4 years old pediatric patient", EUROPEAN JOURNAL OF CLINICAL PHARMACY, vol. 21, no. 2, 4 January 2019 (2019-01-04), esp., pages 112 - 115, ISSN: 2385-409X *
GONZALEZ D ET AL.: "Dalbavancin Pharmacokinetics and Safety in Children 3 Months to 11 Years of Age", PEDIATRIC INFECTIOUS DISEASE JOURNAL, vol. 36, no. 7, 1 July 2017 (2017-07-01), usa, pages 645 - 653, XP055670705, ISSN: 0891-3668, DOI: 10.1097/INF.0000000000001538 *

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