116 Pharmacokinetic variability of ciprofloxacin in cystic fibrosis – is CYP3A4 involved?

Objectives Ciprofloxacin (CIP), is frequently used, when treating cystic fibrose (CF) patients with intermittent P. aeruginosa lung colonization. However, approximately 20% of the patients progress to chronic infection despite early intervention. The aim of this study was to investigate the pharmacokinetics of CIP, to evaluate if CYP3A4-related metabolism is involved and to find the optimal dose needed to eradicate intermittently colonizing bacteria in the lungs of CF patients. Methods An open-label, prospective pharmacokinetic study was preformed. Twenty-one CF-patients were each given 500 mg CIP orally. During the following 12 hr, 8 blood samples were collected. The optimal dose and interval was then calculated by Monte Carlo simulation. CYP3A4-activity was mesured using the Erythromycin Breath Test (ERMBT). Results An 14-fold variation in AUC for CIP (median 473.5 mg/mL·min, range 138–1880), and a 30-fold variation in Cmax for CIP (median 2 mg/mL, range 0.25–7.6) were found. For CYP3A4-activity the variation was 8-fold. No correlation was found between the CYP3A4-activity and CIP-concentrations. The probability of eradicating intermittent P. aeruginosa colonization in the lungs of CF patients was found to be 17% (1 dose/day), 40% (2 doses/day) and 57% (3 doses/day), respectively when 500 mg CIP was given. It was 63% (1 dose/day), 89% (2 doses/day) and 94% (3 doses/day), respectively when 750 mg CIP was given. Conclusion The study showed a large pharmacokinetic difference of CIP in CF patiens, not explained by CYP3A4 variation. To prevent treatment faliure in intermittently colonized patients CIP should be given at 750 mg three times daily to adult CF patients.