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

Abstract

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.

Keywords:

• cefotetan disodium
• pharmacokinetics
• healthy volunteers
• plasma
• single-dose
• multiple-dose

Acknowledgment

This study was funded by Zhejiang Jianfeng Pharmaceutical Co., Ltd. (Jinhua, China, the manufacturer of Cefotetan disodium) and the National Natural Science Foundation of China (No. 81702862).

Data Sharing Statement

Individual deidentified participant data is not going to be shared. And all available data have been showed in the article. No other study-related document will be made available.

Disclosure

All authors report no conflicts of interest in this work.