Robin L. Davis

Pharmacokinetics of ciprofloxacin in cystic fibrosis.

We studied the pharmacokinetics of ciprofloxacin in 12 adult males with and 12 adult males without cystic fibrosis (CF). In a randomized crossover sequence, the subjects received 200 mg intravenously or 750 mg orally. With intravenous dosing, subjects also received 651 mg of iothalamate, a marker of glomerular filtration, and 700 mg of antipyrine, an indicator of hepatic oxidative drug metabolism. Pharmacokinetic parameters were determined by model independent methods. In the CF subjects, the ciprofloxacin concentration in serum during the first hour after intravenous administration was higher, and the oral absorption rate was slower. Other parameters did not differ between the groups. Mean concentrations in serum 5 min postinfusion were 3.08 and 2.14 micrograms/ml, and mean peak concentrations after oral dosing were 3.24 and 3.34 micrograms/ml in subjects with and without CF, respectively. Mean values for elimination half-life in all subjects were 4.8 and 5.0 h after intravenous and oral administration, respectively. The mean renal clearances in all subjects after intravenous and oral administration were 19.4 and 14.5 liters/h and accounted for 64 and 47% of the total clearance, respectively. These values were significantly greater than renal iothalamate clearance, indicating that tubular secretion contributed to the renal clearance of ciprofloxacin. A total of 69 and 35.4% of the administered ciprofloxacin was recovered from the urine within 48 h after intravenous and oral administration, respectively. The mean bioavailability was 71.2% and did not differ between the groups. We conclude that similar dosing regimens can be used to treat patients with CF and their normal counterparts.

Pharmacokinetics of three oral formulations of ciprofloxacin.

We compared the absorption of three formulations of ciprofloxacin after oral administration in 18 normal adult male volunteers. Each subject received 500 mg of ciprofloxacin as two 250-mg tablets, one 500-mg tablet, or a solution in a randomized crossover sequence. Pharmacokinetic parameters were determined by model independent methods. Because a solution is considered to be the ideal oral dosage form, the results determined for the tablets were compared to those for the solution. Mean values for the maximum concentration of drug in serum, the time to maximum concentration of drug in serum, and the elimination half-life were 3.23 micrograms/ml, 1.00 h, and 5.04 h, respectively, for the solution. The mean renal clearance of ciprofloxacin was 372 ml/min and accounted for at least 50% of the total clearance. We recovered 44.4, 48.6, and 55.8% of the administered ciprofloxacin from the urine as unchanged drug within 24 h after dosing with the 250-mg tablets, 500-mg tablets, or solution, respectively. The 500-mg tablets were found to be bioequivalent to the solution with regard to all pharmacokinetic parameters. The 250-mg tablet was not bioequivalent to either of the other formulations; the relative bioavailability values were 78.7 and 74.1%, respectively, for the 500-mg tablet and the solution. The clinical significance of this difference in bioavailability is yet to be determined.

Effect of the Addition of Ciprofloxacin on Theophylline Pharmacokinetics in Subjects Inhibited by Cimetidine

OBJECTIVE: Although the effect of individual enzyme inhibitors on hepatic microsomal enzyme activity has been studied extensively, little data exist on the effects of combinations of inhibiting agents. The purpose of this study was to investigate the effect of the addition of a second hepatic oxidative enzyme inhibitor on the inhibition of metabolism in subjects already maximally inhibited by cimetidine. Ciprofloxacin was used as the second inhibitor. DESIGN: In a randomized crossover sequence, subjects received theophylline 5 mg/kg on day 6 of therapy with cimetidine 2400 mg/d, ciprofloxacin 1 g/d, both drugs, or while drug-free. SETTING: National Institutes of Health-funded General Clinical Research Center. PARTICIPANTS: Eight normal volunteers (6 men, 2 women; mean age 25.2 y). OUTCOME MEASURES: Theophylline pharmacokinetic parameters after each treatment were determined by model independent pharmacokinetic analysis. Statistical analysis of the data for differences between treatments was assessed by ANOVA for repeated measures. RESEARCH: When administered alone, ciprofloxacin and cimetidine caused a significant increase in theophylline elimination half-life and a decrease in clearance. Theophylline elimination half-life was significantly longer during combined therapy compared with either drug alone. Theophylline clearance was lower during combined treatment, although this relationship did not reach statistical significance. CONCLUSIONS: The addition of a second enzyme inhibitor in subjects receiving maximally inhibiting doses of cimetidine can produce a further decrease in the hepatic metabolism of drugs that are metabolized by the cytochrome P-450 microsomal enzyme system. As cimetidine and ciprofloxacin are frequently used together for a variety of common clinical indications, clinicians should be aware of this drug interaction and should consider that a similar effect may occur when other enzyme inhibitors are used concomitantly.

Vancomycin Pharmacokinetics in Spinal Cord Injured Patients: A Comparison with Age-matched, Able-bodied Controls

To compare the pharmacokinetics of vancomycin in chronic spinal cord injured patients and hospitalized, age-matched, able-bodied controls, we evaluated 14 spinal cord injured patients and 14 controls. Pharmacokinetic parameters of total body clearance (CL), distribution volume (V), elimination rate constant (k) and elimination half-life (t1/2) were calculated from two steady-state vancomycin serum concentrations by the method of Sawchuk and Zaske. Demographic data such as age, ideal body weight (IBW), total body weight (TBW) and serum creatinine at start of therapy (SCr), pharmacokinetic parameters and predicted dosages to achieve specific peak (30 mcg/ml) and through concentrations (5-10 mcg/ml) were calculated for both groups. Statistical comparisons were made using a two sample, Students t-test. Demographic data between groups differed only in mean serum creatinine (p = 0.04). There were no statistically significant differences in mean pharmacokinetic parameters of CL and V or mean predicted dosages. Mean elimination rate constant was significantly smaller and mean elimination half-life was significantly longer in spinal cord injured patients (p = 0.02 and p = 0.04, respectively). The longer dosing interval predicted in spinal cord injured patients trended toward statistical significance (p = 0.10). We conclude that with chronic spinal cord injury, 1) the elimination half-life of vancomycin is increased and these patients may require longer dosing intervals and 2) distribution volume and predicted vancomycin doses are unaltered compared with controls.

Prospective randomized study comparing the efficacy and safety of ciprofloxacin with cefaclor in the treatment of patients with purulent bronchitis

We compared safety and efficacy of ciprofloxacin and cefaclor in the treatment of patients with purulent bronchitis. Fifty-five patients were randomized prospectively to receive ciprofloxacin with a dose of 500 mg orally twice daily or cefaclor 250 mg over 8 hr for 5 days or longer. Patient groups did not differ with respect to age, duration of illness, severity of infection, or number of other concomitant disease states. A significantly larger number of patients in the ciprofloxacin group had poor health status (39.3% vs 7.4% for the ciprofloxacin and cefaclor groups, respectively, p = 0.02). The response to therapy did not differ between groups. Infection was completely resolved in 71.4% vs 66.7% and markedly improved in 7.1% and 11.1% for the ciprofloxacin and cefaclor groups, respectively. The response to therapy and adverse reaction rate did not differ between groups. Seven patients treated with ciprofloxacin and five patients treated with cefaclor developed adverse reactions. We conclude that ciprofloxacin is a useful agent for the treatment of purulent bronchitis.

Effect of orally administered activated charcoal on vancomycin clearance.

Vancomycin is a narrow-spectrum antibiotic that has concentration-dependent efficacy and toxicity. Recent literature indicates that orally administered activated charcoal can enhance the clearance of intravenously administered drugs. To evaluate the effects of activated charcoal on vancomycin clearance, six healthy male volunteers received vancomycin (1 g) intravenously with and without activated charcoal coadministration. In a randomized crossover sequence, subjects were given 50 g of activated charcoal immediately before the vancomycin infusion was begun and 15 g at 2, 4, 6, and 8 h afterwards, or an equal volume of water. Multiple doses of charcoal did not have a statistically significant effect on any pharmacokinetic parameter for vancomycin. Mean control values +/- standard deviation for vancomycin clearance, elimination half-life, and 24-h urinary recovery were 6.4 +/- 1.0 liters/h, 6.6 +/- 1.5 h, and 856 +/- 116 mg, respectively. Mean values for the same parameters were 6.4 +/- 1.0 liters/h, 6.0 +/- 0.9 h, and 897 +/- 130 mg when activated charcoal was given. We conclude that multiple doses of orally administered activated charcoal do not enhance vancomycin clearance in subjects with normal renal function when serum concentrations are within the therapeutic range. The results of this investigation cannot be extrapolated to patients with toxic vancomycin concentrations or renal dysfunction. The use of activated charcoal in these populations warrants further study.