EP2866819A1 - Instructions de dosage pour des lipopeptides se liant aux endotoxines - Google Patents

Instructions de dosage pour des lipopeptides se liant aux endotoxines

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Publication number
EP2866819A1
EP2866819A1 EP13732900.9A EP13732900A EP2866819A1 EP 2866819 A1 EP2866819 A1 EP 2866819A1 EP 13732900 A EP13732900 A EP 13732900A EP 2866819 A1 EP2866819 A1 EP 2866819A1
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EP
European Patent Office
Prior art keywords
lipopeptide
endotoxin
parenteral administration
polymyxin
preparation
Prior art date
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Application number
EP13732900.9A
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German (de)
English (en)
Inventor
Dieter Falkenhagen
Stephan Harm
Jens Hartmann
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Zentrum fur Biomedizinische Technologie Der Donau- Universitat Krems
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Zentrum fur Biomedizinische Technologie Der Donau- Universitat Krems
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Priority to EP13732900.9A priority Critical patent/EP2866819A1/fr
Publication of EP2866819A1 publication Critical patent/EP2866819A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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

Definitions

  • the invention relates to an endotoxin-binding lipopeptide selected from the group consisting of polymyxins, polymyxin derivatives, polymyxin analogues, their prodrugs and their pharmaceutically acceptable salts for the prophylaxis or treatment of diseases and conditions caused by endotoxemia.
  • the invention further relates to a preparation for parenteral administration comprising at least one such endotoxin-binding lipopeptide as the active ingredient and at least one pharmaceutically acceptable carrier and / or adjuvant for the prophylaxis or treatment of diseases and conditions caused by endotoxemia.
  • Endotoxins are lipopolysaccharides (LPS) in the cell wall of Gram-negative bacteria and are released by cell lysis and cell division. In fact, lipopolysaccharides are the most abundant lipid component of the outer cell membrane of Gram-negative bacteria. Endotoxins are pyrogenic substances and the affected individual reacts with a strong inflammatory reaction and fever when endotoxins enter the body, for example in the course of a microbial intoxication, and as key mediators cause an uncontrolled activation of the mononuclear-phagocytic system. An accumulation of endotoxins in the bloodstream as a result of endotoxemia leads to an uncontrolled activation of the immune cells and an imbalance of the coagulation system.
  • LPS lipopolysaccharides
  • sepsis which is characterized among other things by high fever, low blood pressure and, in severe cases, by multi-organ failure. Sepsis is a very serious condition; the lethality of individuals with severe sepsis or septic shock is about 30-60%, depending on the severity of the disease.
  • Endotoxemia due to Gram-negative bacterial infection is one of the most common causes of Systemic Inflammatory Response Syndrome (SIRS), sepsis, severe sepsis or septic shock, and the resulting serious complications
  • SIRS Systemic Inflammatory Response Syndrome
  • Patients with impaired immune responses, such as liver patients or patients undergoing chemotherapy are susceptible to bacterial infections, presenting symptoms of endotoxin poisoning, and acute liver failure or acute decompensation in chronic liver failure can also result in endotoxemia, which causes biochemically very similar to sepsis.
  • acute decompensation may occur in patients with chronic liver failure.
  • endotoxins derived from normal gut flora can overcome the intestinal barrier and stimulate the release of inflammatory mediators in the body, causing a sepsis-like condition.
  • a lipopolysaccharide molecule forms the region of the molecule which faces the bacterial cell; Lipid A anchors the molecule in the outer membrane of the Gram-negative bacterium.
  • the LPS molecule also has a central, highly conserved core region bound to the lipid A.
  • the third and outermost region is formed by an O-specific polysaccharide (O-antigen), the structure of which can vary widely within the various Gram-negative bacteria.
  • O-antigen O-specific polysaccharide
  • the toxic effect is due to the lipid A, which is released only during cell lysis.
  • Polymyxins are antibiotic substances originally derived from the bacterium Bacillus polymyxa and have been used for a long time to treat infections with Gram-negative bacteria in humans and animals. Polymyxins interfere with the cell wall structure by increasing the permeability of the cell membrane, which causes cell lysis. Polymyxins bind not only phospholipids but also lipopolysaccharides (endotoxins) with high affinity. The antibacterial mechanism of polymyxins is described, for example, in a publication by Tony Velkov et al. (Velkov et al., 2010 Journal of Medicinal Chemistry: 53 (5): 1898-1916).
  • polymyxin B and polymyxin E have gained certain therapeutic importance as antibiotics. To date, these two polymyxins are the only therapeutically approved representatives of their class of substances. Polymyxin B and colistin are FDA approved for parenteral infusion in the US. Polymyxin B and Colistin have been used for decades for oral or topical therapies. For parenteral, systemic treatment of diseases and conditions due to infection with Gram-negative bacteria, however, they come only as a last resort as an antibiotic for therapeutic use due to their neuro-and nephrotoxic side effects.
  • Colistin seems to be less nephrotoxic than polymyxin B, by However, the required higher dosage is at least partially compensated, so that can be expected in the clinical routine about the same extent with nephrotoxic reactions.
  • sufficient data on the nephrotoxicity of the two antibiotics are not available from today's perspective. New York-based infectiologists describe renal failure in 14% of 60 patients treated with polymyxin B. Doctors in Greece describe marked nephrotoxicity in the majority of patients with renal insufficiency already at baseline. In contrast, no significant changes were found in patients with normal kidney function.
  • polymyxin B in the form of the sulfate salt of Polymxin Bl and B2 for parenteral administration is currently available from Bedford Laboratories ("Polymyxin B for Injection 500,000 Units", manufacturer: Bedford Laboratories) According to the manufacturer's information, parenteral administration is intravenous, intramuscular or in the case of meningitis intrathecal, wherein the maximum daily dose reported is typically 2.5 mg / kg body weight per day divided into two to three infusions
  • the serum concentration of polymyxin after administration is in the range of 1 to 6 ⁇ g / ml In severe cases, it may also be higher in the range of 6 to 50 g / ml Colistin is administered predominantly in the form of colistin-methanesulfonate with a serum concentration in the range of approximately 1 to 3 ⁇ g / ml.
  • Polymyxin E) is used in the same way as Polymyxin B, usually in higher doses.
  • Polymyxin B Resistance to polymyxin B is rather unusual but may develop if the antibiotic fails to reach the cytoplasmic membrane due to changes in the outer membrane.
  • Polymyxins are effective against many Gram-negative pathogens, such as E. coli, Enterobacter, Klebsiella spp. and also against P. aeruginosa. Proteus arias and S. marcescens, which are normally resistant; the sensitivity of ß. fragilis is variable.
  • the minimum inhibitory concentrations for E. coli are in the range of 0.04 - 3.7 mg / 1 and for P. aeruginosa between 1.2 and 33.3 mg / 1 (Garidel and Brandenburg, 2009, Anti-Infective Agents in Medicinal Chemistry, 8: 367-385).
  • adsorption materials As a commonly used alternative to the administration of polymyxins in the form of a medicament, extracorporeal blood and / or blood plasma purification methods (therapeutic apheresis) have been established using suitable adsorption materials.
  • Apheresis methods and adsorber materials for eliminating toxic and / or harmful substances from blood and blood plasma are well known in the art.
  • Known adsorber materials comprise porous or fibrous carrier materials, on the surfaces of which polymyxin B is immobilized, for example, covalently or by means of hydrophobic interaction. To date, no neurotoxic and nephrotoxic side effects have been reported with such adsorbent materials, which are widely used in the treatment of septic conditions.
  • Adsorbent materials functionalized with polymyxin B are known, for example, from EP 0 110 409 A1, WO 2010/083545 and WO 2011/160149.
  • apheresis methods using suitable adsorbers have the disadvantage that they can not be applied across the board on account of the high technical complexity, the limited availability of the therapy sites and the significantly higher manufacturing and therapy costs compared to the medicamentous treatment and therefore only those for intensive care Supply necessary needs can be met.
  • EP 2 332 965 describes synthetic peptides derived from naturally occurring polymyxins and octapeptins having antibacterial properties for use as an antibiotic to treat individuals with a bacterial infection, and to methods for producing these peptides.
  • WO 2010/075416 discloses polymyxin, in particular polymyxin B-derived chemical compounds with antibacterial properties as antibiotic against a variety of Gram-negative bacteria.
  • the compounds described therein have a reduced toxicity compared to polymyxin B.
  • drug-administered endotoxin binding lipopeptides such as polymyxins, polymyxin analogs or polymyxin prodrugs and their pharmaceutically acceptable salts such that prophylaxis or treatment of diseases and conditions caused by endotoxemia.
  • the new dosage regimen is expected to bring significant improvements in toxic side effects while maintaining high efficacy and to be a much less expensive treatment option for patients with endotoxemia than the ad
  • a new dosage regimen which is characterized by i) parenteral administration of a bolus of the lipopeptide to reach a lipopeptide serum concentration of 0.01 ⁇ g / ml to 0.8 ⁇ g / ml and
  • polymyxins or polymyxin derivatives and polymyxin analogues in the conventional sense as antibiotics, ie to eliminate gram-negative bacteria, but in significantly lower concentrations (4- to 100-fold lower) for inactivating the endotoxins in patients with endotoxemia.
  • Inactivation of the endotoxins means that their biological activity, in particular on the release of inflammatory mediators such as cytokines, is inhibited or blocked.
  • the proinflammatory phase e.g. in sepsis or in SIRS caused by gram-negative endotoxins, is suppressed or reduced.
  • the novel dosing regimen allows parenteral administration of polymyxins and their analogues, derivatives and prodrugs while circumventing nephro- and neurotoxic side-effects.
  • the serum lipopeptide concentration in the dosage regimen according to the invention is thus at a factor of 4 to 100 below the concentration achieved when the approved antibiotic polymyxin B preparations are administered parenterally.
  • the dosing instructions according to the invention are based on the stated surprising fact that in the investigation of various polymyxin-functionalized adsorbent materials, endotoxin binding by polymxin occurs exclusively via a very small amount of desorbed and transferred into the blood or blood plasma polymyxin molecules.
  • These surprising and unpredictable results are based on the fact that after targeted washing of the adsorber materials in which desorbable polymyxin molecules were removed from the adsorber surface, no endotoxin adsorption could be detected by the polymyxin molecules still immobilized on the adsorber material surface. It has been found that even with covalent binding of polymyxin to the adsorber surface, a certain amount of polymyxin molecules is bound by nonspecific forces.
  • polymyxin molecules can desorb from the adsorber surface during therapeutic application and in the released state render harmless endotoxins present in the blood or blood plasma of the patient.
  • endotoxinadsorption by adsorbent materials based on porous or fibrous support materials, on the surfaces of polymyxin B for example, covalently or immobilized by hydrophobic interaction, exclusively on a very small material desorbed from the carrier and released into the blood or blood plasma
  • Amount of free polymyxin molecules is due.
  • the binding between polymyxin and endotoxins apparently occurs only when both the hydrophobic and the positively charged amino groups of polymyxin B are accessible to the endotoxins.
  • novel dosage initiation described in this disclosure is based on these surprising results and defines significantly lower serum concentrations of endotoxin-binding lipopeptides such as polymyxin compared to those established in the standard polymyxin B and colistin therapies that have been practiced for many decades.
  • polymyxin and “polymyxins” as used herein refer to known, naturally occurring chemical compounds which are originally derived from the bacterium Bacillus polymyxa (polymyxin B) and Bacillus colistinus (polymyxin E).
  • the polymyxins can either be isolated from bacteria or made synthetically.
  • the bacterium-derived polymyxin B is composed of 6 derivatives called polymyxin Bl, polymyxin B2, polymyxin B3, polymyxin B4, polymyxin B5 and polymyxin B6.
  • the polymyxin approved by the FDA for parenteral infusion is composed only of polymyxin Bl to B4.
  • polymyxin B and polymyxin E are clinically relevant.
  • polymyxin derivative refers to a polymyxin-derived compound obtainable by modification of naturally occurring polymyxins, for example, by chemical modification of the dab side chains, the cyclic peptide ring or the fatty acid chain of the polymyxin molecular structure
  • a detailed review of Polymy - xin-based antibiotics, analogs and derivatives are described in the publication by Velkov et al., (Velkov et al., 2010, Journal of Medicinal Chemistry, 53 (5): 1898-1916)
  • a representative example of a polymyxin derivative is polymyxin nonapeptide, a polymyxin B derivative lacking the hydrophobic moiety and an amino acid.
  • polymyxin analog refers to a chemical lipopeptide compound structurally similar or similar to a polymyxin (polymyxin-like lipopeptide) and having the same endotoxin binding activity as polymyxins or polymyxins has comparable endotoxin binding activity.
  • polymyxin analogue can be found in the disclosure WO 2008/006125 Al.
  • prodrug refers to a precursor compound of the endotoxin-binding lipopeptide as defined wherein the precursor compound is converted to the active endotoxin-binding lipopeptide in vivo
  • the prodrugs are colistin methanesulfonate and polymyxin B methanesulfonate sodium call.
  • endotoxinemia is used herein for all conditions in which clinically relevant amounts of endotoxins are present in the blood of the patient which subsequently result in the induction of cytokines, preferably in conditions such as sepsis and SIRS.
  • the dosing instructions are suitable both for the treatment and the prophylaxis of diseases and conditions caused by endotoxemia.
  • prophylactic administration of the endotoxin-binding lipopeptide when endotoxemia is present but no clinical symptoms are present
  • Prophylactic therapy may be particularly indicated in those patients who are expected to develop endotoxemia due to their disease
  • the endotoxin-binding lipopeptides are administered according to the dosage regimen of the present invention.
  • the invention can therefore be used advantageously as an additional therapeutic or prophylactic measure in the context of a conventional treatment of bacterial infectious diseases by means of antibiotics to intercept the induced by antibiotics endotoxin secretion, which subsequently leads to the induction of cytokines.
  • parenteral administration refers to routes of administration other than enteral and topical administration, and more particularly relates to an infusion, the infusion preferably including, but not limited to, intravenous, subcutaneous, Parenteral administration has the advantage that the lipopeptide serum concentration to be achieved can be rapidly adjusted and maintained both during inital bolus administration and while maintaining serum concentration for a predeterminable period of time Form of intravenous infusion or by infusion into the blood carried in extracorporeal blood circulation as described in detail below.
  • the invention can be used for both the human and the veterinary medical field.
  • patient as used herein thus refers to humans and animals. Because of the increased incidence of multiresistant infections, tente strains and the associated need for new forms of therapy, the invention is particularly for the human medical area of high relevance.
  • polymyxins Since naturally occurring polymyxins, originally derived from the bacterium Bacillus polymyxa, are among the best-studied peptide antibiotics and have been used for decades in the treatment of diseases and conditions due to endotoxemia, it is preferred that the endotoxin-binding lipoprotein be used.
  • tid is a polymyxin. More preferably, the lipopeptide is selected from the group consisting of the only so far approved for clinical use polymyxins polymyxin B and colistin (polymyxin E). However, most preferred is polymyxin B, as it has been found to be most effective for human medical use. Polymyxin B is preferably used in the form of polymyxin B sulfate.
  • a further subject of the invention is further a preparation for parenteral administration comprising at least one endotoxin-binding lipopeptide as defined in this disclosure as the active ingredient and optionally at least one pharmaceutically acceptable carrier and / or adjuvant.
  • the preparation may comprise only one type of endotoxin-binding lipopeptide or a mixture of two or more endotoxin-binding lipopeptides, for example a mixture of polymyxin Bl, B2, B3 and B4.
  • a "pharmaceutically acceptable carrier and / or adjuvant” may be any substance known for the preparation of parenteral dosage forms such as injections, infusion solutions, etc. Formulations suitable for the invention for injection and infusion solutions are given in Example 5 below.
  • the preparation for parenteral administration is in the form of an injection preparation or an infusion preparation.
  • the endotoxin-binding lipopeptide is preferably present in the form of a lyophilized powder for producing a sterile aqueous injection preparation or infusion preparation, wherein the powder can be dissolved, for example, in sterile water, 5% dextrose solution, a Ringer's solution or a physiological sodium chloride solution.
  • the lipopeptide is in the preparation in dissolved form in step i) for the parenteral administration of a bolus, preferably in a concentration of 5 mg / 1 to 200 mg / l, and in step ii) for maintaining serum concentration preferably at a concentration of 0.04 mg / 1 to 13 mg / 1, more preferably from 0.1 mg / 1 to 7 mg / 1, most preferably 0.5 mg / 1 to 4 mg / 1 before.
  • the serum lipopeptide concentration is in a range of 0.1 ⁇ g / ml to 0.6 ⁇ g / ml, preferably 0.1 ⁇ g / ml to 0.4 ⁇ g / ml, most preferably between 0.1 ⁇ g / ml to 0.25 ⁇ g / ml, since at these serum concentrations an efficient therapy without neuro-and nephrotoxic side effects is feasible even in serious disease processes such as sepsis, severe sepsis or septic shock.
  • bolus is thus understood as a single parenteral administration of the endotoxin-binding lipopeptide in the form of a preparation, preferably in the form of an injection or infusion preparation, wherein the formulation for bolus administration preferably has a higher concentration of lipopeptide than that preparation used in step ii) for the subsequent maintenance of lipopeptide serum concentration.
  • the bolus delivery in step i) is preferably over a period of at least 10 minutes, more preferably at least 60 minutes, most preferably at least 120 minutes, preferably by parenteral injection or infusion, ideally not during a dialysis treatment.
  • the bolus administration (step i)) is preferably by injection, for example, administering a once-off bolus of 10 to 250 ml of the prepared solution for injection at the start of treatment.
  • the bolus administration may also be by infusion.
  • this serum concentration of lipopeptides which is adjusted very rapidly by means of bolus administration, is maintained for a predeterminable time, wherein the maintenance of the serum concentration is preferably carried out by infusion, which preferably takes place continuously.
  • the infusion rate is dependent on the serum half-life for the lipopeptide in the patient.
  • the serum half-life for polymyxin B in patients with normal renal function is typically 13 hours, that is for Colistin depending on the literature at 6 to 7.4 hours.
  • the clearance of the particular filter used and / or the clearance of an adsorber system for the administered lipopeptide must be taken into consideration, as described in detail below.
  • the period of maintaining the lipopeptide serum concentration is the total duration of therapy, that is, as long as there is endotoxemia. This period can last from a few hours to 2 weeks, or even longer, during which time the unwanted induction of cytokines is reduced or suppressed.
  • the maintenance of the lipopeptide serum concentration by intravenous administration takes place in step ii).
  • the endotoxin-binding lipopeptide is administered intravenously via a venous access, preferably by means of a metering pump.
  • step ii) the maintenance of the lipopeptide serum concentration by infusion into the blood of a patient guided in an extracorporeal blood circulation of an extracorporeal perfusion system takes place at a position downstream of a dialyzer (dialysis filter) assigned to the extracorporeal blood circulation.
  • a dialyzer dialysis filter assigned to the extracorporeal blood circulation.
  • the infusion of the lipopeptide takes place via a supply line into the blood which circulates in the extracorporeal blood circulation, at a point downstream of the dialyzer, ie immediately before the blood is returned to the patient.
  • bolus delivery downstream of the dialyzer may also be injected into the extracorporeal bloodstream.
  • the bolus dose should preferably be taken before dialysis treatment, continuous infusion simultaneously with dialysis and at a position preferably downstream of the dialyzer.
  • the endotoxin-binding lipopeptide is not only degraded by the body, but is also removed via the dialyzer from the blood, it is useful in the dosage of the infused lipopeptide in the blood guided in the extracorporeal blood circulation, the lipopeptide clearance of the body and the Lipopeptide clearance of the dialyzer to be considered.
  • a depletion device for example in the form of an adsorber cartridge or a plasma circuit with adsorbent particles suspended therein, is also associated with the extracorporeal perfusion system, it is favorable if the lipopeptide clearance of a depletion device assigned to the extracorporeal perfusion system is additionally taken into account when metering the infused lipopeptide.
  • adsorbers of a polystyrene-divinylbenzene copolymer adsorb lipopeptides such as polymyxins in addition to physiologically relevant components such as cytokines, so that the consideration of the lipopeptide clearance of the adsorber is advantageous for the dosage of the infused lipopeptide.
  • the invention is advantageously used for the treatment of an infection with gram-negative bacteria, in particular for the prophylaxis or for the treatment of a systemic inflammatory reaction (SIRS), sepsis, severe sepsis or septic shock.
  • SIRS systemic inflammatory reaction
  • Representative examples of conditions that can be treated according to the present disclosure are those that occur as a result of infection with Gram-negative bacteria and that can subsequently result in SIRS, sepsis, severe sepsis with multiple organ failure, or septic shock.
  • Gram-negative bacteria include Escherichia spp, Haemophilus influenzae, Pseudomonas aeruginosa, Pasteurella, Enterobacter spp., Salmonella spp., Shigella spp.
  • the invention is particularly advantageous in gram-negative bacteria, for which an increased occurrence of multidrug-resistant strains has been observed, in which case Pseudomonas aeruginosa should be emphasized as a particularly relevant representative.
  • antibiotics are used in the case of an infection with Gram-negative bacteria and the cell lysis induced by the administration of antibiotics leads to increased endotoxin release.
  • the invention advantageously has the prophylaxis or treatment of an inflammatory response due to acute liver failure or acute decompensation in chronic liver failure, in particular a systemic inflammatory response (SIRS), sepsis, severe sepsis with multiple organ failure or septic shock.
  • SIRS systemic inflammatory response
  • sepsis sepsis
  • severe sepsis severe sepsis with multiple organ failure or septic shock.
  • RES reticuloendothelial system
  • Kupffer cells by endocytosis.
  • Patients with chronic liver failure may experience acute decompensation.
  • endotoxins of the normal intestinal flora can overcome the intestinal barrier and therefore pass unhindered through the liver leading to a systemic inflammatory response (SIRS), sepsis, severe sepsis with multiple organ failure, or septic shock.
  • SIRS systemic inflammatory response
  • the invention further relates to a method for the prophylaxis or treatment of diseases and conditions caused by endotoxemia by administering an endotoxin binding lipopeptide selected from the group consisting of polymyxins, polymyxin derivatives, polymyxin analogs, their prodrugs and their pharmaceutically acceptable Salting, by i) parenterally administering a bolus of the lipopeptide to reach a serum lipopeptide concentration of from 0.01 ⁇ g / ml to 0.8 ⁇ g / ml and ii) maintaining that lipopeptide serum concentration by parenteral administration of the lipopeptide for a preselected period of time.
  • an endotoxin binding lipopeptide selected from the group consisting of polymyxins, polymyxin derivatives, polymyxin analogs, their prodrugs and their pharmaceutically acceptable Salting
  • Example V Endotoxin (LPS) inactivation as a function of polymyxin concentration using endotoxins from E. coli and Pseudomonas aeruginosa.
  • the aim of this experiment is to determine the plasma polymyxin B (PMB) concentration-dependent endotoxin activation in the plasma (batch test I). In addition, it will be investigated to what extent this endotoxin inactivation results in an inhibition of cytokine release (batch test II).
  • PMB plasma polymyxin B
  • LPS Pseudomonas aeruginosa (L-7018 Fa. Sigma Lot: 128K4115, -70 ° C, a 100 ⁇ 10-3 g / ml (1 mg / ml))
  • LPS E. coli (L-4130 Fa. Sigma Lot: 110M4086M, -70 ° C, a 100 ⁇ 10-3 g / ml (1 mg / ml))
  • the LPS is used in batch with a final concentration of 0.5 ng / ml.
  • the batches are carried out in 3 ml of pyrogen-free glass vials.
  • batch test I different PMB concentrations (from Sigma, P-1004) are added in a two-fold mixture and incubated for 60 min at 37 ° C. on the overhead shaker (see Table 2).
  • LAL Charles River's Limulus Amebocyte Lysate test
  • the plasma spiked with LPS and PMB is returned after the Bat test I to the cell concentrate obtained from the blood donor in a ratio of 1: 1 (see Table 2).
  • the samples from batch test I were used with a PMB concentration of 0 (without PMB), 250, 500 and 1000 ng / ml.
  • a sample without LPS and with 1000 ng / ml PMB was carried.
  • samples are taken, centrifuged off and 50 ⁇ plasma frozen at -80 ° C. for later cytokine quantification.
  • the experimental data for the cytokine batch are listed in Table 2.
  • the aim is a PMB serum concentration of 100 ng PMB / ml plasma -> a total of 4.2 mg PMB is required.
  • the target is a PMB serum concentration of 250 ng PMB / ml plasma -> a total of 10.5 mg PMB is required.
  • Example 3 Dosing instructions for polymyxin B (PMB) during extracorporeal blood purification (dialysis and adsorption treatment) to maintain an existing PMB serum concentration
  • the blood purification device comprises an extracorporeal blood circulation in which the blood of the patient is guided and a dialyzer (dialysis filter) arranged in the extracorporeal blood circulation.
  • a dialyzer dialysis filter
  • the blood purification device is assigned an adsorber system, for example in the form of an adsorption cartridge, the adsorber system being located on the blood side in the extracorporeal blood circulation (hemoperfusion) or in a plasma circulation connected to the extracorporeal blood circulation via a plasma filter (plasma or fractionated plasma adsorption ) can be connected.
  • the PMB dialysis clearance can be determined experimentally and depends on the plasma flow and the type of dialysis filter used. In the example given, this is 60 ml / min.
  • the PMB clearance of the adsorber depends on the adsorber material used as well as on the filtrate flow or, in the case of hemoperfusion, on the blood flow. In the example given, this is 45 ml / min.
  • the PMB patient clearance was determined in the example given from the half-life for PMB of 13.6 and is 36 ml / min.
  • the PMB total clearance (C total) is obtained by addition.
  • the resulting decrease in PMB is shown in FIG.

Abstract

L'invention concerne un lipopeptide se liant aux endotoxines choisi dans le groupe composé de polymyxines, de dérivés de polymyxines, d'analogues de polymyxines, de leurs promédicaments et de leurs sels pharmaceutiquement acceptables, ainsi qu'une préparation pour l'administration parentérale contenant un tel lipopeptide, pour la prophylaxie ou le traitement de maladies et de troubles provoqués par une endotoxinémie, par i) administration parentérale d'un bolus du lipopeptide pour atteindre une concentration sérique en lipopeptide de 0,01 µg/ml à 0,8 µg/ml, et ii) maintien de cette concentration sérique en lipopeptide par administration parentérale du lipopeptide sur une durée définie.
EP13732900.9A 2012-06-29 2013-06-27 Instructions de dosage pour des lipopeptides se liant aux endotoxines Withdrawn EP2866819A1 (fr)

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EP12174285.2A EP2679236A1 (fr) 2012-06-29 2012-06-29 Conduite de dosage pour lipopeptides se liant à l'endotoxine
PCT/EP2013/063496 WO2014001444A1 (fr) 2012-06-29 2013-06-27 Instructions de dosage pour des lipopeptides se liant aux endotoxines
EP13732900.9A EP2866819A1 (fr) 2012-06-29 2013-06-27 Instructions de dosage pour des lipopeptides se liant aux endotoxines

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