SAFETY, TOLERATION, AND PHARMACOKINETICS OF INTRAVENOUS AZITHROMYCIN

To date, the clinical pharmacology of large intravenous doses of azith romycin has not been described. In the present study, single 2-h intra venous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and tw o received placebo) of healthy male subjects, Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [g ood] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous in fusion, Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cra mping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithr omycin was well tolerated, Because of the standardized 1-mg/ml infusat es, all subjects in the 4-g dosing group complained of an urgent need to urinate, There were no consistent trends in endogenous motilin leve ls throughout the study, The maximum concentration of azithromycin in serum (10 mu g/ml after a 4-g dose) and the area under the concentrati on-time curve (82 mu g . h/ml after a 4-g dose) were dose related, The mean pharmacokinetic parameters were an elimination half-life of 69 h , total systemic clearance of 10 ml/min/kg, and a volume of distributi on at steady state of 33.3 liters/kg, The pharmacokinetic results sugg est that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug, Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable co ncentrations may persist in serum for 10 days or more.