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Methods for administration of antibiotics

A method of administration and technology of antibiotics, which can be used in antibacterial drugs, anti-infective drugs, pharmaceutical formulations, etc., and can solve problems such as low toxicity and unpredictability

Inactive Publication Date: 2002-05-08
CUBIST PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the likelihood that infrequent administration of aminoglycosides produces low toxicity to patients does not predict the same likelihood that daptomycin does

Method used

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  • Methods for administration of antibiotics
  • Methods for administration of antibiotics
  • Methods for administration of antibiotics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Study A:C max Effects on CPK and skeletal muscle toxicity

[0037] In order to study C max Effects on Skeletal Muscle Toxicity, Dogs (4 male dogs / group) administered intravenously with saline q8h, daptomycin 25mg / kg q24h, daptomycin 75mg / kg q24h and daptomycin 25mg / kg q8h20 sky. Skeletal muscle toxicity was determined by increases in dog CPK levels above the normal range and by microscopic changes in bone tissue.

[0038] Steady-state plasma concentrations of daptomycin at day 18 of dosing were determined by HPLC. C at 25 mg / kg q8h compared to 25 mg / kg q24h max The levels are essentially the same (1.23 times higher). C at 75 mg / kg q24h max Levels were 2.8-fold at 25 mg / kg q8h. See attached figure 1 The upper panel of (Study A). AUC at 25 mg / kg q8h was essentially the same (0.37-fold higher) compared to 75 mg / kg q24h (see Table 2 and appendix figure 2 above picture).

[0039] There was a dose-proportional increase in peak CPK activity when the dose ...

Embodiment 2

[0049] Example 2 Study B: Effect of Plasma Concentration Thresholds on Skeletal Muscle Toxicity

[0050] To study the effect of threshold plasma concentrations on skeletal muscle toxicity, dogs (4 male dogs / group) were administered intravenous saline q8h, daptomycin 5 mg / kg q24h (approximate NOEL q24h) and daptomycin 5 mg / kg q8h Program 20 days.

[0051] Steady-state plasma concentrations of daptomycin at day 18 of dosing were determined by HPLC as described in Example 1. The q8h interval represents the 3 half-lives in the dog (t 1 / 2 = 2.5 hours) and respond to steady state C max has the lowest impact. 5mg / kg q24h and 5mg / kg q8h of C max It is the same for both dosing regimens. See attached figure 1 The lower panel of (Study B). However, the AUC at 5 mg / kg q8h was about 3 times (2.6 times) that at 5 mg / kg q24h (see Table 4 and appendix figure 2 the figure below).

[0052]Serum CPK levels were determined as disclosed in Example 1. CPK levels at 5 mg / kg q24h were unch...

Embodiment 3

[0061] To study the C of quinupristin / dalfopristin max For skeletal muscle toxicity, dogs (4 male dogs / group) were given intravenous saline q8h, quinupristin / dalfopristin 25mg / kgq24h, quinupristin / dalfopristin 75mg / kg q24h, and quinupristin The dosing regimen of nupristin / dalfopristin 25mg / kg q8h for 20 days.

[0062] Steady-state plasma concentrations of quinupristin / dalfopristin at day 18 of dosing were determined by HPLC. The C of 25 mg / kg q8h, 25 mg / kg q24h and 75 mg / kg q24h was determined as described in Example 1 max levels and AUC. Similarly, CPK levels and the incidence of muscle-related histopathological findings were determined as described in Example 1 at 25 mg / kg q8h, 25 mg / kg q24h and 75 mg / kg q24h. For skeletal muscle, 6 sites were examined for each of 4 dogs, for a total of 24 sites. If no microscopic myopathy or effects on CPK levels are observed at any dose regimen, the dose may be increased. For example, C at 50 mg / kg q8h, 50 mg / kg q24h and 150 mg / kg q24...

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Abstract

The invention provides methods for administering a therapeutically effective amount of daptomycin while minimizing skeletal muscle toxicity. The methods provide daptomycin administration at a dosing interval of 24 hours or greater. This long dosing interval minimizes skeletal muscle toxicity and allows for higher peak concentrations of daptomycin, which is related to daptomycin's efficacy. The invention also provides methods of administering lipopeptide antibiotics other than daptomycin while minimizing skeletal muscle toxicity by administering a therapeutically effective amount of the lipopeptide antibiotic at a dosage interval that does not result in muscle toxicity. The invention also provides methods of administering quinupristin / dalfopristin while minimizing skeletal muscle toxicity by administering a therapeutically effective amount of quinupristin / dalfopristin at a dosage interval that does not result in muscle toxicity.

Description

[0001] Technical Field of the Invention [0002] The present invention relates to improved methods for the administration of lipopeptide antibiotics, such as daptomycin (or translated as daptomycin), which are effective against Gram-positive bacteria, including antibiotic-resistant strains. Bactericidal activity. The present invention also provides improved methods of administering quinopristin / dalfopristin, which also has potent bactericidal activity against Gram-positive bacteria, including antibiotic-resistant strains. Background of the invention [0003] The rapid increase in the incidence of Gram-positive infections, including those caused by resistant bacteria, has brought renewed attention to the development of new classes of antibiotics. One such antibiotic is the lipopeptide antibiotic including daptomycin. Daptomycin has potent bactericidal activity in vitro against clinically relevant Gram-positive bacteria that cause severe and life-threatening disease. These ba...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00A61K31/424A61K31/7036A61K38/08A61K38/12A61P31/04
CPCA61K38/12A61K38/08A61K38/10A61P31/00A61P31/04A61K2300/00A61K38/00
Inventor F·B·小奥莱森F·P·塔利
Owner CUBIST PHARMA INC
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