First population pharmacokinetic analysis showing increased quinolone metabolite formation and clearance in patients with cystic fibrosis compared to healthy volunteers

Comparable Bioavailability and Disposition of Pefloxacin in Patients with Cystic Fibrosis and Healthy Volunteers Assessed via Population Pharmacokinetics

“…Intestinal exsorption and reabsorption : We explored a potential exsorption of pefloxacin from the central compartment into intestine which has been previously reported for fleroxacin and other quinolones using charcoal studies [11,13,14,33]. For some quinolones, the amount of parent drug recovered in feces [33,34] is much larger than the fraction of dose recovered in bile [13,14].…”

“…Quinolone antibiotics present an attractive oral treatment option for patients with CF. Several studies compared the PK of quinolones between patients with CF and healthy volunteers for ciprofloxacin [4,5,6,7,8,9], fleroxacin [10,11] and levofloxacin [12]. These quinolones are relatively hydrophilic with distribution coefficients (log D) of −1.24 for ciprofloxacin, −0.76 for fleroxacin and −0.50 for levofloxacin; and they are primarily renally eliminated [13,14,15,16].…”

“…These quinolones are relatively hydrophilic with distribution coefficients (log D) of −1.24 for ciprofloxacin, −0.76 for fleroxacin and −0.50 for levofloxacin; and they are primarily renally eliminated [13,14,15,16]. Most of these studies found comparable total and renal clearances and similar or slightly smaller nonrenal clearances in patients with CF compared to those in healthy volunteers [4,6,9,10,11,12]. One study with a small sample size reported a larger renal clearance of ciprofloxacin [5].…”

“…One study with a small sample size reported a larger renal clearance of ciprofloxacin [5]. Moreover, the renal clearances of two fleroxacin metabolites (i.e., N -oxide fleroxacin and N -demethylfleroxacin) were 53% and 70% larger based on a population PK analysis which accounted for body size and composition [11]. The mechanism for the higher renal clearance of these fleroxacin metabolites is not known.…”

“…Two studies [7,8] on ciprofloxacin compared the PK in pediatric patients with and without CF via population PK modeling; one of these studies [7] described body size by an allometric model based on total body weight (WT). In adult patients with CF, all but one study on quinolones [11] employed non-compartmental PK analysis to compare the PK in patients with CF to that in healthy volunteers [2,3]. Population PK modeling offers the advantage that it can simultaneously describe the population mean PK parameters and their between subject variability (BSV) for the parent drug and metabolites.…”