Bioavailability and Intracellular Pharmacokinetics of Azithromycin in Adult Patients with Cystic Fibrosis

Abstract

Background: Chronic pulmonary infections with Pseudomonas aeruginosa are the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). Macrolides are thought to act primarily as antibacterial agents, however, there are reports suggesting that they have other nonbacterial activities, in particular anti-inflammatory activities. Azithromycin (AZM), an azalide macrolide has shown to impair the formation of alginate biofilm from mucoid P. aeruginosa. Clinical trials with AZM in CF have demonstrated significant improvements in pulmonary function and decreased hospitalizations. Our hypothesis is that the oral absorption of AZM, a lipid-soluble compound, is significantly reduced in CF due to pancreatic insufficiency. The specific aims of this study are to compare the rate and extent of absorption of AZM in CF patients and controls, and in addition, determine the intracellular pharmacokinetics between the two groups. Method: This is a prospective, randomized, controlled crossover study divided into 2 phases. In phase 1, all subjects (13 healthy volunteers and 12 cystic fibrosis patients) received a single oral or intravenous dose of azithromycin, followed by cross-over to the other form the following week. All subjects received a standard diet on study days. CF patients were allowed to take their pancreatic enzymes. Blood samples were obtained at specified time points over 96 hours following each dosage form. Phase 2 involved 11 healthy volunteers and 12 cystic fibrosis patients. Four days after the 2nd dose of phase 1, subjects of either arm continued to take 3 more oral doses with the same dose, a three times a week (TIW) regimen. Blood samples were obtained on day 1, 3, 5, 14 and 21 from the day of the first dose of the TIW regimen to determine the concentration of azithromycin in peripheral blood mononuclear cells (PBMCs). Serum concentrations were assayed using liquid chromatography-mass spectrometry. Pharmacokinetic analysis was performed using noncompartmental methods and a 3- and 4-compartment model using ADAPT II. Differences between groups were determined using a Mann-Whitney test. Result: The CF subjects differed significantly from controls based on weight and BMI. Ninety two percent of CF patients were pancreatic insufficient. The rate (Ka) and extent of absorption (Bioavailability) of AZM did not differ in patients with CF and controls. Distribution to the peripheral compartment was greater in healthy volunteers which may be attributed to greater adipose when compared with cystic fibrosis patients. Azithromycin demonstrates significant penetration into PBMCs in both groups, but no differences between the two groups were noted. Conclusion: No alteration in dosage of azithromycin is necessary in patients with CF taking pancreatic enzymes. The prolonged intracellular half-life of azithromycin supports the current every other day (QOD) dosing strategy.