Pharmacokinetics and Tolerability of Single and Multiple Intravenous Doses of Cefotetan Disodium in Healthy Chinese Volunteers

摘要

Background: Cefotetan is highly stable to penicillinase and cephalosporin produced by gram-negative bacteria, and it has strong antimicrobial activity against most gram-negative bacteria, some anaerobic bacteria and streptococcus. The objective of this study was to evaluate the pharmacokinetic profile and tolerability of single and multiple intravenous doses of cefotetan disodium in healthy Chinese volunteers. Methods: In this single-center, open-label, dose-escalating study, subjects were randomized to receive a single dose of cefotetan disodium 0.5, 1.0, or 2.0 g administered as a 1 h intravenous infusion. After completion of the single-dose phase, subjects continued into the multiple-dose phase, in which they received 1.0 g cefotetan disodium BID for 7 consecutive days. Plasma samples were assayed by a validated high-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated and analyzed statistically. Tolerability was assessed based on physical examinations, vital signs, laboratory tests, and subject interviews. Results: After intravenous administration of single doses of 0.5, 1.0, and 2.0 g cefotetan disodium, the pharmacokinetics of cefotetan were as follows: Csubmax/sub was 69.49± 12.10 μg·mLsup? 1/sup, 132.03± 22.56 μg·mLsup? 1/sup and 237.75± 42.12 μg·mLsup? 1/sup, respectively; AUCsublast/sub was 278.29± 51.13 μg·mLsup? 1/sup·h, 543.25± 92.44 μg·mLsup? 1/sup·h and 1003.8± 172.39 μg·mLsup? 1/sup·h, respectively; AUCsub∞/sub was 284.42± 50.76 μg·mLsup? 1/sup·h, 551.38± 95.83 μg·mLsup? 1/sup·h and 1020.18± 181.19 μg·mLsup? 1/sup·h, respectively; tsub1/2/sub was 4.21± 0.83 h, 4.39± 0.53 h and 4.27± 0.74 h, respectively; CL was 1.81± 0.33 L·hsup? 1/sup, 1.86± 0.32 L·hsup? 1/sup and 2.02± 0.38 L·hsup? 1/sup, respectively; Vsubd/sub was 10.80± 1.89L, 11.78± 2.20L and 12.25± 1.99L, respectively. In the multiple-dose study, the pharmacokinetics of cefotetan were as follows: Csubmax,ss/sub was 147.58± 22.71 μg·mLsup? 1/sup; Csubmin,ss/sub was 12.92± 3.70 μg·mLsup? 1/sup; Csubavg/sub was 45.10± 7.78 μg·mLsup? 1/sup; AUCsubτ,ss/sub was 541.15± 93.36 μg·mLsup? 1/sup·h; AUCsub∞/sub was 612.06± 114.23 μg·mLsup? 1/sup·h; tsub1/2/sub was 4.30± 0.63 h; CL was 1.90± 0.35L·hsup? 1/sup; Vsubd/sub was 8.91± 1.57L; DF was 300.92± 33.28%; Accumulation Index was 1.17± 0.05. No serious adverse events were reported. Adverse events were generally mild. Conclusion: Cefotetan disodium showed favorable tolerability in this study. The Csubmax/sub and AUCs of cefotetan disodium demonstrated dose-dependent pharmacokinetic characteristics after single dose over a dose range (0.5– 2.0 g) in healthy subjects, whereas the tsub1/2/sub was independent of dose. Except for Vsubd/sub, there was no difference in other pharmacokinetic parameters between multiple and single administration.