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: Cmax was 69.49±12.10 µg·mL-1, 132.03±22.56 µg·mL-1 and 237.75±42.12 µg·mL-1, respectively; AUClast 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; t1/2 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; Vd 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: Cmax,ss was 147.58±22.71 µg·mL-1; Cmin,ss was 12.92±3.70 µg·mL-1; Cavg was 45.10±7.78 µg·mL-1; AUCτ,ss was 541.15±93.36 µg·mL-1·h; AUC∞ was 612.06±114.23 µg·mL-1·h; t1/2 was 4.30±0.63 h; CL was 1.90±0.35L·h-1; Vd 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 Cmax 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 t1/2 was independent of dose. Except for Vd, there was no difference in other pharmacokinetic parameters between multiple and single administration.

Determination of residual solvents in cefotetan disodium by headspace gas chromatography / 中国药学杂志

OBJECTIVE: To establish a method for determining nine residual solvents in cefotetan disodium by headspace gas chromatography. METHODS: The residual solvents including methanol, acetone, acetonitrile, dichloromethane, butanone, ethyl ace-late, tetrahydrofuran in cefotetan disodium were quantitatively determined on a DB-624 column (30 m×0.32 mm, 1.8 μm). Water was solvent media. The residual solvents of anisole and isocaprylic acid in cefotetan disodium were quantitatively determined on a HP-FFAP column (25 m×0.32 mm, 0.5 μm). The 20% dimethylsulfoxide (DMSO) was used as the solvent. RESULTS: Nine residual solvents were completely separated. Good linearity of the solvents were obtained within the determination ranges. There between 0.9988 and 0.9997. The average recoveries of three levels were in the range of 95.71%-103.55%. The RSDs were 0.39%-2.28%. CONCLUSION: The established two methods are accurate and sensitive, and can be used for the determination of residual solvents in cefotetan disodium.

Pharmacokinetic study of cefotetan disodium for injection in Chinese healthy volunteers / 中国药学杂志

OBJECTIVE: To study the pharmacokinetics of cefotetan disodium for injection in Chinese healthy volunteers. METHODS: Thirty healthy volunteers were randomly divided into 3 groups with 5 males and 5 females in each group. The volunteers in each group were administered a single dose of cefotetan disodium of 0.5, 1.0, or 2.0 g, respectively. Those who got dose of 1.0 g were administered twice daily for 7 d. The concentrations of cefotetan disodium in plasma were determined by HPLC while the pharmacokinetic parameters were calculated by DAS software. RESULTS: The main pharmacokinetic parameters of cefotetan disodium after single-dose intravenous administration were as follows: ρmax(68.03 ± 15.95), (110.77 ± 17.67), (225.34 ± 19.63) mg · L-1; AUC0-15(242.88 ± 56.60), (415.22 ± 54.24), (856.18 ± 82.72) mg · h · L-1; t1/2(3.67 ± 0.48), (3.69 ± 0.40), (3.53 ± 0.26) h, respectively. The main pharmacokinetic parameters of cefotetan disodium after multiple-dose administration were as follows: ρmax(123.60 ± 15.74) mg · L-1; AUC0-15 (444.38 ± 62.78) mg · h · L-1; AUCSS(426.87 ± 59.36) mg · h · L-1; t1/2(3.29 ± 0.36) h; ρav(35.57 ± 4.95) mg · L-1, respectively. CONCLUSION: Cefotetan disodium for injection displays linear pharmacokinetics in the dose range of 0.5 to 2.0 g after single intravenous dosing. There is no significant accumulation after repeated dosing. There is no significant difference in the pharmacokinetic parameters between female and male subjects. Copyright 2012 by the Chinese Pharmaceutical Association.