Pharmacokinetics of clinafloxacin after single and multiple doses.

Clinafloxacin (CI-960) is a potent broad-spectrum, fluoroquinolone antibiotic that has been studied for parenteral and oral administration in patients with serious infections. The objectives of these studies were to examine the pharmacokinetics and safety of clinafloxacin following administration of single and twice-daily intravenous (i.v.) and oral doses to volunteers. Plasma and urine samples were assayed by validated liquid chromatographic methods, and pharmacokinetic parameter values were determined by noncompartmental methods. Safety was evaluated by clinical observation and laboratory tests. Absorption was rapid after oral administration, with maximum concentrations in plasma (C(max)) generally occurring within 2 h. Concentrations in plasma declined biexponentially, with an average terminal half-life of 4 to 6 h after single doses and 5 to 7 h after multiple doses. Increases in C(max) and area under the concentration-time curves (AUC) were generally proportional to the dose. The volume of distribution was much greater than total body water. Approximately 40 to 75% of the clinafloxacin doses were excreted unchanged into urine. Absolute bioavailability of orally administered clinafloxacin was approximately 90% and did not change with increasing dose. Therefore, switching patients from i.v. to oral dosing should achieve similar concentrations in plasma. The tolerability of clinafloxacin was acceptable. No serious adverse events occurred. C(max) values and minimum plasma clinafloxacin concentrations during multiple dosing exceeded MICs for a wide range of organisms.

Clinafloxacin versus piperacillin-tazobactam in treatment of patients with severe skin and soft tissue infections.

Patients (n = 409) with severe skin and soft tissue infections (SSTIs) were randomized to receive clinafloxacin or piperacillin-tazobactam (plus optional vancomycin for methicillin-resistant cocci), administered intravenously, with the option to switch to oral medication. Most patients had cellulitis, wound infections, or diabetic foot infections. Staphylococcus aureus, Enterococcus faecalis, and Pseudomonas aeruginosa were the most common baseline pathogens. Fewer baseline pathogens were resistant to clinafloxacin (1.8%) than to piperacillin-tazobactam (6.2%) (P = 0.001). The clinafloxacin and piperacillin-tazobactam groups did not differ significantly in clinical cure rates (68.8 and 65.2%, respectively) or microbiologic eradication rates (61.5 and 57.2%). Clinafloxacin yielded higher eradication rates for all three of the most common pathogenic species, although no differences were statistically significant. Within the power of this study, the overall frequency of adverse events was similar (P = 0.577) in the two treatment groups. Drug-associated adverse events (P = 0.050) and treatment discontinuations (P = 0.052) were marginally more frequent in the clinafloxacin group, primarily due to phototoxicity in outpatients receiving clinafloxacin. Although most cases of phototoxicity were mild to moderate, four cases were reported as severe. In summary, clinafloxacin monotherapy was equivalent in effectiveness to therapy with piperacillin-tazobactam plus optional vancomycin in the treatment of hospitalized patients with severe SSTIs.

A validated liquid chromatographic method for the antiallergy agent CI-922 in dog and rat plasma.

A sensitive, specific and rapid liquid chromatographic procedure to selectively monitor CI-922 in dog and rat plasma was developed and validated. Plasma samples were acidified and extracted with ethyl ether. The organic layer was evaporated to dryness, reconstituted with mobile phase, and the analytes were separated and quantified on an octadecylsilane stationary phase (lambda = 340 nm). The procedure was linear from 0.05 to 3.0 mug ml(-1) with a detection limit of 0.02 mug ml(-1). The accuracy of the method had relative errors of 7.6, 4.2 and 5.4% for dog plasma controls containing 0.5, 1.50 and 2.5 mug CI-922 ml(-1), respectively. The corresponding precision was 5.0, 4.0 and 4.8% (RSD). Similarly, relative standard deviations less than 4.6% and relative errors of less than 1.4% were obtained for rat plasma controls. The method is suitable for pharmacology, toxicology and pharmacokinetic studies of CI-922.

Bioavailability of calcium valproate in normal men compared with the free acid and sodium salt.

Calcium valproate has been formulated into tablets containing the equivalent of 250 mg valproic acid (VPA). The bioequivalence of this preparation (Valontin, Parke-Davis) has been studied in 12 normal adult males in parallel with other products containing the free acid (Depakene capsules, Abbott) and the sodium salt (Depakene syrup, Abbott). Each subject received a single 500-mg oral dose of each product at 2-week intervals in a randomized three-way crossover study. Assays were carried out for VPA in blood and urine specimens which were collected over extended time periods. Peak plasma levels were attained on the average within 30 min with the syrup, 1.13 h with the capsules, and 1.38 h with the tablets. There were no significant differences in the peak plasma levels attained with the three products, or in the plasma half-lives of VPA and areas under the time-concentration curves. The plasma level curves appeared to be biexponential, with terminal half-lives that averaged 16.6 h. One subject showed a remarkably long half-life (28-38 h) after each of the three doses, indicating the possibility of genetic differences between individuals in the disposition of VPA. The urinary excretion of VPA in most subjects ran parallel to the plasma levels and could not be detected 96 h after dosing; however, the subject with the long plasma half-life continued to excrete VPA in his urine for at least 2 additional days. The mean recovery of VPA in 6-day urine represented 12-14% of the dose and ranged from 5.5 to 27.9% in different individuals. There were no significant differences between the three formulations in the pattern of urinary excretion.