Prediction of bone penetration and efficacies of five fluoroquinolone antibiotics in the treatment of pseudomonal chronic osteomyelitis using a rat model

A systematic study of the fluoroquinolone antibiotics was conducted to investigate the factors that can be used to predict penetration of five fluoroquinolone antibiotics (ciprofloxacin, pefloxacin, fleroxacin, ofloxacin and lomefloxacin) into infected tibia bone of rats, and to correlate drug effectiveness with bone penetration.^ The hypothesis to be tested in this study is that penetration of fluoroquinolone antibiotics into bone is related to the volume of distribution of a drug, in vitro apparent partition coefficient, and total body clearance. The hypothesis was tested in a rat chronic osteomyelitis model.^ In-vitro apparent partition coefficient of these antibiotics was determined using an oil-in-water system, volume of distribution and total body clearance were obtained in the infected animals after a single IV bolus dose, and the penetration ratio of antibiotics into infected tibia bone was determined after a single IP dose. Efficacy of antibiotic treatment was determined after 28 days of treatment. The following order of antibiotic efficacy was observed: ciprofloxacin has the best efficacy, then lomefloxacin, ofloxacin, pefloxacin, and fleroxacin has the worst efficacy in the treatment of Pseudomonal chronic osteomyelitis. The results of the study suggested that the in vivo penetration ratio (PR) can be predicted using a combination of total body clearance (Cl\sb{\rm T}) and apparent partition coefficient as indicated by stepwise comparison analysis. A better bone penetration of fluoroquinolone antibiotics should result in better efficacy. In addition, a sigmoidal relationship is observed between efficacy and bone penetration. Finally, the efficacy of antibiotic treatment and area under the bone concentration-time curve can also be described by a sigmoidal relationship using the Hill equation.

Antiviral activity, pharmacokinetics and safety of vicriviroc, an oral CCR5 antagonist, during 14-day monotherapy in HIV-infected adults.

International audienceObjective: To determine antiviral activity, pharmacokinetic properties, and safety of vicriviroc, an orally available CCR5 antagonist, as monotherapy in HIV-infected patients. Design and methods: An ascending, multiple dose, placebo-controlled study randomized within treatment group. Forty-eight HIV-infected individuals were enrolled sequentially to dose groups of vicriviroc: 10, 25 and 50 mg twice a day, and were randomly assigned within group to receive vicriviroc or placebo (16 total patients/group) for 14 days. Results: Significant reductions from baseline HIV RNA after 14 days were achieved in all active treatment groups. Suppression of viral RNA persisted 2-3 days beyond the end of treatment. Reductions of 1.0 log10 HIV RNA or greater were achieved in 45, 77 and 82% of patients in the three groups, respectively. Eighteen, 46 and 45% of subjects achieved declines of 1.5 log10 or greater in HIV RNA in the three groups, respectively. Vicriviroc was rapidly absorbed with a half-life of 28-33 h, supporting once-daily dosing. Pharmacokinetic parameters were dose linear; steady state was achieved by day 12. Two subjects experienced a transient detectable X4-tropic virus. Vicriviroc was well tolerated in all dose groups. The frequency of adverse events was similar in the vicriviroc and placebo groups: 72 and 62%, respectively. The most frequently reported adverse events included headache, pharyngitis, nausea and abdominal pain, which were not dose related. Conclusion: Whereas all doses were well tolerated and produced significant declines in plasma HIV RNA, total oral daily doses of 50 or 100 mg vicriviroc monotherapy for 14 days appeared to provide the most potent antiviral effect in this study