Probability of Target Attainment of Tobramycin Treatment in Acute and Chronic Pseudomonas aeruginosa Lung Infection Based on Preclinical Population Pharmacokinetic Modeling

被引:5
作者
Dias, Bruna Bernar [1 ]
Carreno, Fernando [2 ]
Helfer, Victoria Etges [1 ]
Bernardi Garzella, Priscila Martini [1 ]
Fonseca de Lima, Daiane Maria [1 ]
Barreto, Fabiano [3 ]
de Araujo, Bibiana Verlindo [1 ]
Dalla Costa, Teresa [1 ]
机构
[1] Fed Univ Rio Grande do Sul UFRGS, Pharmaceut Sci Grad Program, BR-90610000 Porto Alegre, RS, Brazil
[2] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA
[3] Fed Lab Anim & Plant Hlth & Inspect LFDA RS, BR-90610000 Porto Alegre, RS, Brazil
关键词
tobramycin; popPK model; Pseudomonas aeruginosa infection model; biofilm; microdialysis; PTA; PULMONARY DISPOSITION; CYSTIC-FIBROSIS; PENETRATION;
D O I
10.3390/pharmaceutics14061237
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Biofilms and infectious process may alter free antimicrobial concentrations at the site of infection. Tobramycin (TOB), an aminoglycoside used to treat lung infections caused by Pseudomonas aeruginosa, binds to alginate present in biofilm extracellular matrix increasing its minimum inhibitory concentration (MIC). This work aimed to investigate the impact of biofilm-forming P. aeruginosa infection on TOB lung and epithelial lining fluid (ELF) penetration, using microdialysis, and to develop a population pharmacokinetic (popPK) model to evaluate the probability of therapeutic target attainment of current dosing regimens employed in fibrocystic and non-fibrocystic patients. The popPK model developed has three compartments including the lung. The ELF concentrations were described by a penetration factor derived from the lung compartment. Infection was a covariate in lung volume (V3) and only chronic infection was a covariate in central volume (V1) and total clearance (CL). Simulations of the recommended treatments for acute and chronic infection achieved >90% probability of target attainment (PTA) in the lung with 4.5 mg/kg q24h and 11 mg/kg q24h, respectively, for the most prevalent P. aeruginosa MIC (0.5 mg/mL). The popPK model was successfully applied to evaluate the PTA of current TOB dosing regimens used in the clinic, indicating the need to investigate alternative posology.
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页数:13
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