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Bioavailability and intracellular pharmacokinetics of azithromycin in patients with cystic fibrosis
Author(s) -
Bi L.,
Huynh K. M.,
Louie S.,
Hoem N.,
Kriengkauykiat J.,
Gill M.,
Beringer P.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.040
Subject(s) - cystic fibrosis , pharmacokinetics , medicine , bioavailability , azithromycin , crossover study , pharmacology , dosing , gastroenterology , antibiotics , chemistry , pathology , biochemistry , alternative medicine , placebo
Background Azithromycin (AZM) significantly improves pulmonary function in patients with cystic fibrosis (CF). Our hypothesis is that the absorption of AZM may be altered in CF due to pancreatic insufficiency. Additionally, MDR1 and CFTR are coordinatley regulated which may alter the intracellular disposition of P‐gp substrates. The objective is to compare the bioavailability and intracellular (IC) concentrations of AZM in patients with CF and healthy volunteers (HV). Methods A prospective, randomized, controlled crossover study involving 12 CF patients and 11 age‐matched HV. In period I, all subjects received either a single PO or IV dose of AZM followed by crossover with one week washout. In period II, all patients received AZM QOD×3d. Blood and PBMC samples were obtained at specified times, and were assayed using LC‐MS/MS. PK analysis was performed using a 3‐compartment model with ADAPT II. Differences between groups were determined using Mann‐Whitney test. Results The rate and extent of absorption did not differ between the two groups. Distribution to the peripheral compartment was greater in the HV which may be attributed to greater adipose when compared with the CF patients. AZM demonstrates significant penetration into PBMCs in both groups. No significant differences in IC PK between groups were noted. Conclusion No alteration in dosage of AZM is necessary in patients with CF taking pancreatic enzymes. The prolonged intracellular half‐life supports the current QOD dosing strategy. (see Table) Clinical Pharmacology & Therapeutics (2005) 77 , P38–P38; doi: 10.1016/j.clpt.2004.12.040PK results Median (SD)CF HV PKa (h‐1) 0.48 (0.88) 0.45 (0.27) 0.60 F (%) 34.8 (13.5) 40.1 (17.8) 0.34 Cserum 52h (ng/ml) 19.3 (10.3) 21.9 (9.7) 0.61 C PBMC 72h (mcg/ml) 9.7 (8.9) 13.3 (7.3) 0.55 T 1/2 PBMC (h) 77.0 (37.0) 92.0 (23.1) 0.85