Pharmacokinetic and pharmacodynamic evaluation of the lantibiotic MU1140

Presented are the pharmacokinetics (PK), exposure–response relationship, and the PK/pharmacodynamic (PD) index predictive of maximum therapeutic efficacy for the lantibiotic MU1140. MU1140, at a dose of 12.5 or 25 mg/kg, was administered intravenously, to characterize its PK parameters in rat. The r...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2010-05, Vol.99 (5), p.2521-2528
Main Authors: Ghobrial, Oliver, Derendorf, Hartmut, Hillman, Jeffrey D.
Format: Article
Language:English
Subjects:
ADME
Animals
antiinfectives
Bacteriocins - blood
Bacteriocins - pharmacokinetics
Bacteriocins - pharmacology
Biological and medical sciences
Computer Simulation
Dose-Response Relationship, Drug
General pharmacology
Half-Life
Injections, Intravenous
Male
Medical sciences
Microbial Sensitivity Tests
Models, Biological
Nonlinear Dynamics
Pharmaceutical technology. Pharmaceutical industry
pharmacokinetic/pharmacodynamic models
pharmacokinetics
Pharmacology. Drug treatments
preclinical pharmacokinetic
Rats
Rats, Sprague-Dawley
Staphylococcus aureus - drug effects
Time Factors
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Summary:Presented are the pharmacokinetics (PK), exposure–response relationship, and the PK/pharmacodynamic (PD) index predictive of maximum therapeutic efficacy for the lantibiotic MU1140. MU1140, at a dose of 12.5 or 25 mg/kg, was administered intravenously, to characterize its PK parameters in rat. The recently developed in vitro PD model of MU1140 activity was enhanced by incorporation of the PK of MU1140 in rat. The linked PK/PD model was used in a simulation study to determine the PK/PD index predictive of in vivo efficacy. MU1140 total plasma concentration–time profiles declined biexponentially with elimination terminal half‐life of 1.6 ± 0.1 h. Rapid injection of MU1140 was associated with a hypersensitivity reaction that can be blocked by premedication with diphenhydramine. The simulation study revealed that Staphylococcus aureus concentrations correlated with T > MIC making it the PK/PD index best predictive of efficacy. Collectively, these findings suggest that the best route of administration of MU1140 is slow infusion which will increase the time its concentration remains above the MIC, thus maximizing the therapeutic effect and minimizing the observed toxicity. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2521–2528, 2010
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.22015