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

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: C(max) was 69.49±12.10 µg·mL(−1), 132.03±22.56 µg·mL(−1) and 237.75±42.12 µg·mL(−1), respectively; AUC(last) was 278.29±51.13 µg·mL(−1)·h, 543.25±92.44 µg·mL(−1)·h and 1003.8±172.39 µg·mL(−1)·h, respectively; AUC(∞) was 284.42±50.76 µg·mL(−1)·h, 551.38±95.83 µg·mL(−1)·h and 1020.18±181.19 µg·mL(−1)·h, respectively; t(1/2) 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·h(−1), 1.86±0.32 L·h(−1) and 2.02±0.38 L·h(−1), respectively; V(d) 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: C(max,ss) was 147.58±22.71 µg·mL(−1); C(min,ss) was 12.92±3.70 µg·mL(−1); C(avg) was 45.10±7.78 µg·mL(−1); AUC(τ,ss) was 541.15±93.36 µg·mL(−1)·h; AUC(∞) was 612.06±114.23 µg·mL(−1)·h; t(1/2) was 4.30±0.63 h; CL was 1.90±0.35L·h(−1); V(d) 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 C(max) 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 t(1/2) was independent of dose. Except for V(d), there was no difference in other pharmacokinetic parameters between multiple and single administration.