Abstract
This thesis describes the pharmacokinetics of azithromycin in cystic fibrosis (CF) patients during maintenance therapy, azithromycin drug-drug interactions and the effects of long term use of azithromycin on pulmonary function and microbial resistance.
We studied pharmacokinetic parameters of 500 mg azithromycin per day during maintenance (chronic) therapy in
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adult CF patients. The t1/2 was > 7 d in blood and in isolated PMNs. On average, the concentration in PMNs was 2100 times the concentration in plasma 24 h after dosing azithromycin and 70% of azithromycin in blood was incorporated in or bound to PMNs. Elevated concentrations were found in sputum (12 to 53 mg/L).
The long t ½ indicated that a less frequent dosing scheme could be feasible. We studied pharmacokinetics and sputum penetration of azithromycin in CF patients after a change from daily dosing of azithromycin to a once weekly dosing scheme. The weekly dose was reduced with a factor 3.5 (500 mg daily vs 1000 mg weekly). This lead to a reduction of AZM exposure by a factor (±SD) of 2.5 (±0.8) in plasma, 2.8 (±0.9) in blood and 2.3 (±1.1) in PMNs and 3.0 (±1.5) in sputum concentration. We concluded that reduction in frequency was feasible and resulted in an approximately linear reduction of azithromycin exposure.
In an earlier study, inhibition of the DNA hydrolysing capacity of dornase alfa by azithromycin was reported(Ripoll 1996). We found that in-vitro azithromycin did not inhibit the DNA hydrolysing capacity of dornase alfa at clinically representative sputum concentrations. These data combined with the data found in clinical trials do, in our opinion, not restrict the concurrent use of dornase alfa and azithromycin.
We evaluated the long term effect of azithromycin on pulmonary function by comparing patients infected with P. aeruginosa (using azithromycin) to a non-pseudomonas infected cohort (not using azithromycin). We found an amelioration in pulmonary function in the first year after start of therapy. In the following years a decline in pulmonary function was found. The rate of decline of pulmonary function however, was comparable in both groups.
Comparing 1997 (the last year before introduction of azithromycin maintenance therapy) and 2007 we observed a decrease in incidence of staphylococcal infections and an marked increase, from 10% to 85%, in macrolide resistance of S. aureus. This finding has been documented before in cystic fibrosis patients in Rotterdam (Phaff 2006), and has to be taken into account when azithromicin maintenance therapy is started.
Based on the pharmacokinetic data found in our study and on a literature search of available clinical trials we propose a dosing scheme with 4 weight groups and a dose level between 20 and 33 mg/kg/week in pediatric and adult CF patients.
The comparable rate of decline in P. aeruginosa infected and uninfected patients is a valuable achievement of current CF treatment, including azithromycin maintenance therapy, but cannot be contributed to azithromycin alone, since, in the timeframe we analyzed, also other anti Pseudomonas therapies have been introduced
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