Αρχειοθήκη ιστολογίου

Δευτέρα 25 Ιουνίου 2018

Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia [PublishAheadOfPrint]

Background: Azithromycin is extensively used in children acquired with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin was used off-label in children partly due to lacking of pharmacokinetic data. Our objective was to evaluate the population pharmacokinetics (PPK) and optimize dose strategy in order to improve treatment in this distinctive population.

Methods: This was a prospective, multi-center, open-labeled pharmacokinetic study. Blood samples were collected from hospitalized pediatric patients and concentrations were determined by LC-MS/MS. PPK analysis was conducted using NONMEM software.

Results: The pharmacokinetic data from 95 pediatric patients (age range 2.1 – 11.7 years) were available for analysis. The PPK was best fitted by two-compartment model with linear elimination. Covariate analysis verified body weight and alanine aminotransferase (ALT) had significant effect on azithromycin pharmacokinetics, yielding a 24% decrease of clearance in patients with ALT>40. Monte Carlo simulation showed that for children with normal liver function, a loading dose strategy (a loading dose of 15mg/kg followed by maintenance doses of 10 mg/kg) would achieve the ratio of the area under free drug plasma concentration-time curve over 24 hours (fAUC) to MIC90 (fAUC/MIC) target of 3 h in 53.2% hypothetical patients, using normative MIC susceptibility breakpoint of 2 mg/L. For children with ALT>40, the proposed dose needed to decrease by 15% to achieve comparable exposure. The corresponding risk of overdose for the recommended dosing regimen was less than 5.8%.

Conclusion: The PPK of azithromycin was evaluated in CAP children and an optimal dosing regimen was constructed based on developmental pharmacokinetic-pharmacodynamic modeling and simulation.



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