Absolute bioavailability and intracellular pharmacokinetics of azithromycin in patients with cystic fibrosis

Abstract

Chronic pulmonary infections with Pseudomonas aeruginosa are the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). The macrolide antibiotics exhibit immunomodulatory and antivirulence activity. Clinical trials with azithromycin in CF have demonstrated significant improvements in pulmonary function and decreased hospitalizations. The purpose of this study was to compare the pharmacokinetics (PK) of azithromycin in patients with CF and controls. The study was conducted as an open-label, parallel, two-period crossover study involving 12 healthy volunteers and 12 patients with CF. Period 1 examined the serum PK following a single oral and intravenous dose, while period 2 examined the intracellular PK following multiple-dose oral administration. CF subjects differed significantly from controls based on weight (53.1 versus 71.0 kg; P < 0.01) and body mass index (19.7 versus 23.2; P < 0.01), respectively. Ninety-two percent of CF patients were pancreatic insufficient and were receiving pancreatic enzymes. The rate (time to reach maximum serum drug concentration, 3.0 versus 3.0 h; P = 0.78) and extent of absorption (absolute bioavailability, 34.2 versus 42.8%; P = 0.37) were similar in patients with CF and controls, respectively. Distribution to the tissues (rate of drug transfer from the central to the peripheral compartment, 1.22 versus 0.759 h(-1); P = 0.03) and elimination (rate of elimination from the central compartment, 0.693 versus 0.492 h(-1); P < 0.01) were more rapid in the healthy volunteers than in the CF subjects, respectively. Mononuclear cell concentrations (15.2 +/- 6.0 mg/liter) far exceeded the maximum serum drug concentration ( approximately 50-fold), demonstrating significant intracellular accumulation. These results indicate no alteration in dosage of azithromycin is necessary in patients with CF taking pancreatic enzymes.

FIG. 1.

Four-compartment PK model. Numbers indicate the central compartment (no. 1), peripheral compartment (no. 2), cellular compartment (no. 3), and absorptive compartment (no. 4). b, oral bolus; F, bioavailability; τ, oral lag time; V_c, volume of central compartment; V_p, volume of peripheral compartment; V_cell, volume of cellular compartment; K_cp and K_pc, intercompartmental rate constants between central and peripheral compartments; K_cl and K_lc, intercompartmental rate constant between central and cellular compartments; r(t) = intravenous infusion rate; K₁₀, elimination rate from central compartment; K_a, absorption rate constant.

FIG. 2.

Median azithromycin serum concentrations versus time following a single oral (a) and a single intravenous (b) dose of 500 mg. Squares, healthy volunteer subjects; circles, cystic fibrosis subjects. Each value represents the median ± standard error (n = 24).

FIG. 3.

Representative plot with fitted serum (r² = 0.933) and intracellular (r² = 0.900) azithromycin concentrations.