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Influence of multiple courses of therapy on aminoglycoside clearance in adult patients with cystic fibrosis.

OBJECTIVES
To investigate factors affecting aminoglycoside clearance in adult patients with cystic fibrosis who received multiple courses of antibiotic therapy over a period of up to 15 years.


METHODS
Aminoglycoside concentration-time data and relevant clinical characteristics were collated from clinical pharmacokinetic databases established in Glasgow, Scotland and The Hague, The Netherlands. Data from Glasgow (1993-2009) were used for population model development; data from The Hague (2002-11) were used for model validation. NONMEM was used to determine structural and covariate models, with a particular focus on between-occasion variability and changes in aminoglycoside handling over multiple courses of therapy.


RESULTS
The Glasgow dataset comprised 1075 courses of aminoglycoside therapy (96% tobramycin and 4% gentamicin) in 166 patients and included 2238 concentration measurements. The data were best described by a two-compartment model with creatinine clearance and height influencing aminoglycoside clearance, and height influencing volume of distribution. Between-subject and between-occasion variabilities in clearance were low, at 18% and 11%, respectively; between-subject variability was 12% for volume of distribution. Internal and external model validations were satisfactory. Multiple courses of therapy (ranging from 2 to 28 courses per patient) were not associated with any systematic changes in aminoglycoside clearance.


CONCLUSIONS
Height was a better descriptor of aminoglycoside pharmacokinetics than weight in adult patients with cystic fibrosis. No changes in clearance were observed over time, even in patients who had received multiple courses of therapy over several years.