Kevin R. Sweeney

Bioavailability and pharmacokinetics of ofloxacin in healthy volunteers.

The pharmacokinetics and bioavailability of ofloxacin in 20 healthy male volunteers were studied in an open-label, randomized, two-way crossover study. Ofloxacin (400 mg) was administered either as a 1-h infusion or as an oral tablet. The mean peak concentration after intravenous infusion was 4.30 +/- 0.69 microgram/ml, and that after oral administration was 3.14 +/- 0.53 microgram/ml, occurring 1.74 +/- 0.57 h after dosing. The bioavailability (F) of the oral dosage form of ofloxacin was virtually identical to that of the intravenous form (F = 105% +/- 7%). This complete bioavailability of ofloxacin is supportive of the use of the oral dosage form for the treatment of infections in hospitalized patients either as a replacement for intravenous ofloxacin therapy or in streamlining therapy from the intravenous to the oral route.

Toxic interaction between acetazolamide and salicylate: Case reports and a pharmacokinetic explanation

Two elderly patients, who were chronically receiving aspirin, developed lethargy, incontinence, and confusion after dosing with acetazolamide. Unbound plasma acetazolamide concentrations were elevated and plasma protein binding was reduced, suggesting an interaction with aspirin. In vitro studies demonstrated a concentration‐dependent effect of salicylate on acetazolamide binding to serum proteins. At a therapeutic serum acetazolamide level of 8.0 µg/ml, the unbound percentage of acetazolamide in serum was 3.3% and increased to 11.0% and 30.0%, with serum salicylate levels of 200 and 386 µg/ml, respectively. Furthermore, the apparent association constant of acetazolamide for binding to serum proteins was decreased by 58% and 86% of its control value at these respective salicylate concentrations. The maximal binding capacity of serum for acetazolamide was not affected by salicylate. Pharmacokinetic studies in four volunteers showed that the plasma protein binding and renal clearance of acetazolamide were significantly reduced during chronic salicylate dosing. Salicylate appears to competitively inhibit the plasma protein binding of acetazolamide and simultaneously to inhibit acetazolamide renal tubular secretion. Caution is advised when acetazolamide and salicylate are used concurrently.

Relative bioavailability in healthy volunteers of ciprofloxacin administered through a nasogastric tube with and without enteral feeding.

The bioavailability of ciprofloxacin after its administration through a nasogastric (NG) feeding tube was studied in six healthy volunteers. Each subject received, on separate occasions, an intact 750-mg ciprofloxacin tablet, a crushed tablet as a suspension through an NG tube, and a crushed tablet as a suspension through an NG tube while receiving enteral feeding. No statistically significant differences were observed in the area under the curve, maximum concentration in serum, and time to peak concentration among these three modes of administration. These findings suggest that ciprofloxacin is well absorbed after administration via an NG tube (compared with an orally administered intact tablet) even in the presence of enteral feeding.

Teicoplanin pharmacokinetics in healthy volunteers after administration of intravenous loading and maintenance doses.

Teicoplanin is an investigational glycopeptide antibiotic that is structurally and microbiologically similar to vancomycin. Since teicoplanin possesses a very long elimination half-life, the manufacturer suggests that the drug be administered every 12 h for the first day of therapy and once daily thereafter. We studied the multiple-dose (6 mg/kg per dose) pharmacokinetics of teicoplanin in volunteers following intravenous administration every 12 h for 5 days and then every 24 h for 9 days in an attempt to identify the optimal duration of the every-12-h loading-dose regimen. Multiple serum samples were obtained throughout the study, including intensive sampling after the first and last doses; urine was collected during the entire study. A three-exponential equation was fitted to the serum concentration data. The mean terminal-phase half-life was 157 +/- 93 h. Concentrations of teicoplanin in serum similar to those observed after the administration of the last dose (day 14) were observed following the fourth or fifth dose given every 12 h. Therefore, it is suggested that for clinical dosing regimens for teicoplanin, dosing every 12 h for approximately 48 h should be used, followed by once-daily dosing thereafter.

Absorption of ciprofloxacin administered through a nasogastric or a nasoduodenal tube in volunteers and patients receiving enteral nutrition

The absorption of ciprofloxacin was higher when administered through a nasoduodenal tube than through a nasogastric tube, indicating that even though acidic gastric pH is needed for rapid disintegration, dissolved ciprofloxacin might not be stable in the gastric environment. If the length of exposure or the different gastric environment in each individual affects the overall absorption of ciprofloxacin, this could explain the reported variability in ciprofloxacin absorption and suggests the need for the development of an enteric-coated tablet. Further studies are needed to fully characterize the absorption of ciprofloxacin in patients with different illnesses, gastric transit times, gastrointestinal environments and of different ages.

Effect of sucralfate on pharmacokinetics of fleroxacin in healthy volunteers.

The effect of sucralfate on the pharmacokinetics of fleroxacin was assessed in 20 healthy male volunteers. The study was of a two-way crossover design in which subjects were randomized to one of the following two regimens at the time of entry: (i) a single 400-mg dose of fleroxacin alone or (ii) a 400-mg dose of fleroxacin given once and 1 g of sucralfate given every 6 h starting 24 h before fleroxacin treatment and continuing for 48 h after fleroxacin treatment. Blood samples were collected immediately before fleroxacin administration and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 h postdosing. Fleroxacin concentrations in plasma and urine were determined by high-performance liquid chromatography. While concurrent of fleroxacin and sucralfate resulted in a decrease in the area under the plasma concentration-time curve, a decrease in the maximum concentration, and an increase in the time to the maximum concentration (P < 0.05), these changes were modest compared with the interaction of other quinolones with sucralfate. The relative bioavailability of fleroxacin given with sucralfate, calculated from the area under the concentration-time curve, was 76% compared with that of fleroxacin alone. This is significantly better than the bioavailabilities of other quinolones (1.8 to 12.3%) when they are administered with sucralfate.

The Relative Bioavailability of Temafloxacin Administered through a Nasogastric Tube With and Without Enteral Feeding

SummaryThe relative bioavailability of a single oral dose of temafloxacin given with and without enterai feeding was determined in 18 healthy male volunteers in a randomised crossover study. Subjects were administered 600mg of temafloxacin orally as an intact tablet, or a crushed tablet suspended in water administered through a nasogastric tube with or without an enterai feeding solution [Osmolite® (Ross) 100 ml/h started 2h before administration of temafloxacin and continued for 4h postdose]. Plasma samples were analysed by a high performance liquid Chromatographic technique. Mean peak plasma concentrations (Cmax) for the oral tablet, crushed tablet, and crushed tablet with enterai feeding solution were 3.95 ± 1.02, 4.85 ± 0.69, and 4.69 ± 0.61 mg/L/70kg, respectively, and mean calculated area under the concentration-time curve from time 0 to 48h (AUC(0–48h)) values were 48.1 ± 11.0,54.5 ± 6.52, and 49.7 ± 5.89 mg/L · h/70kg, respectively. In terms of AUC(0–48h) and Cmax, the relative bioavailability of temafloxacin after nasogastric delivery of crushed temafloxacin given with and without an enterai feeding solution was equivalent to the reference oral regimen.

Penetration of fleroxacin and ciprofloxacin into skin blister fluid: a comparative study.

The penetration of multiple-dose concentrations of oral fleroxacin (400 mg every 24 h) and ciprofloxacin (500 mg every 12 h) into skin blister fluid in 12 healthy volunteers was determined in a randomized crossover study. Serum, blister fluid, and paper disk samples were analyzed by large-plate microbiologic assay. The mean areas under the concentration-time curve (AUC) for serum were 88.6 and 18.2 micrograms.h/ml/70 kg for fleroxacin and ciprofloxacin, respectively. The mean AUC for blister fluid and paper disks were 71.2 and 15.0 micrograms.h/ml/70 kg and 77.8 and 15.4 micrograms.h/ml/70 kg for fleroxacin and ciprofloxacin, respectively. Calculated penetration into interstitial fluid ranged from 74 to 92% for fleroxacin and 56 to 96% for ciprofloxacin; penetration was calculated by using the ratio of maximum drug concentration or AUC in blister fluid and paper disks to maximum drug concentration or AUC in serum. There was no significant difference between fleroxacin and ciprofloxacin in the percent penetration into skin blister fluid.

Comparison of the pharmacokinetic and pharmacodynamic activity of piperacillin and mezlocillin

Study Objective. To compare serum bactericidal activity over time and pharmacokinetics resulting from single doses of piperacillin (PIP) and a single dose of mezlocillin (MEZ).

Lomefloxacin concentrations in bone after a single oral dose

We studied the penetration characteristics of lomefloxacin in bone in 30 patients with osteoarthritis undergoing total hip replacement. Patients were given a single oral 400 mg dose at various times from 1 to 12 hours prior to removal of bone samples. The peak plasma and bone (subchondral bone from femoral head) concentrations reached approximately 4.0 micrograms/mL at 2 hours post-dose and 3.0 micrograms/mL at 3 hours post-dose, respectively. At 12 hours post-dose both plasma and bone concentrations were still greater than 1.0 microgram/mL. Two hours after dosing the average bone-to-plasma ratio was greater than 0.6. These data indicate that a single 400 mg oral dose of lomefloxacin attains bone concentrations that are above its usual minimum inhibitory concentrations for susceptible organisms.