Evaluation of the pharmacodynamic and pharmacokinetic interaction between pagoclone and ethanol

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109936/1/cptclpt2003353.pd

Clinafloxacin Pharmacokinetics in Subjects with Various Degrees of Renal Function

As the primary route for elimination of clinafloxacin is renal clearance (CL(R)) of unchanged drug, studies were conducted to determine the pharmacokinetic profile of clinafloxacin following administration to young and elderly subjects, subjects with various degrees of renal function, and subjects requiring dialysis. These were open-label studies in which subjects received single oral clinafloxacin doses. Sixteen young subjects (18 to 35 years old) and 16 elderly subjects (>65 years old) were enrolled in a study comparing pharmacokinetic profiles of clinafloxacin in young and elderly subjects. Twenty subjects having various degrees of renal function were enrolled into one of three groups based on degree of renal function as measured by creatinine clearance (CL(CR)). Twelve subjects with severe renal impairment requiring dialysis enrolled in a third study. Clinafloxacin was generally well tolerated by all subjects. Clinafloxacin pharmacokinetic profiles in elderly subjects were dependent only on age-related decreases in renal function. Clinafloxacin maximum concentrations in plasma, areas under the concentration-time curves, and terminal elimination half-life values increased with decreasing CL(CR) values. Total apparent body clearance of clinafloxacin from the plasma after oral administration (CL(oral)) and CL(R) were dependent on CL(CR) according to the following relationships: CL(oral) = 2.3 · CL(CR) + 77 and CL(R) = 1.74 · CL(CR). Hemodialysis had no significant effect on clinafloxacin clearance. Based on the relationship between CL(CR) and clinafloxacin CL(oral) and CL(R) values, the clinafloxacin dose should be halved in patients having a CL(CR) of <40 ml/min. Further dose adjustment is not warranted in patients requiring hemodialysis

Drug Interactions with Clinafloxacin

Many fluoroquinolone antibiotics are inhibitors of cytochrome P450 enzyme systems and may produce potentially important drug interactions when administered with other drugs. Studies were conducted to determine the effect of clinafloxacin on the pharmacokinetics of theophylline, caffeine, warfarin, and phenytoin, as well as the effect of phenytoin on the pharmacokinetics of clinafloxacin. Concomitant administration of 200 or 400 mg of clinafloxacin reduces mean theophylline clearance by approximately 50 and 70%, respectively, and reduces mean caffeine clearance by 84%. (R)-Warfarin concentrations in plasma during clinafloxacin administration are 32% higher and (S)-warfarin concentrations do not change during clinafloxacin treatment. An observed late pharmacodynamic effect was most likely due to gut flora changes. Phenytoin has no effect on clinafloxacin pharmacokinetics, while phenytoin clearance is 15% lower during clinafloxacin administration

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