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Pharmacokinetics and Tolerability of Single and Multiple Intravenous Doses of Cefotetan Disodium in Healthy Chinese Volunteers.
Drug Des Devel Ther. 2020; 14:613-620.DD

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: 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.

Authors+Show Affiliations

Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China. Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China. Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China. Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China. Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China. Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China. Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China. Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China. College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.

Pub Type(s)

Case Reports

Language

eng

PubMed ID

32103903

Citation

Liu, Jian, et al. "Pharmacokinetics and Tolerability of Single and Multiple Intravenous Doses of Cefotetan Disodium in Healthy Chinese Volunteers." Drug Design, Development and Therapy, vol. 14, 2020, pp. 613-620.
Liu J, Zhai Y, Wu L, et al. Pharmacokinetics and Tolerability of Single and Multiple Intravenous Doses of Cefotetan Disodium in Healthy Chinese Volunteers. Drug Des Devel Ther. 2020;14:613-620.
Liu, J., Zhai, Y., Wu, L., Wu, G., Zheng, Y., Hu, X., & Shentu, J. (2020). Pharmacokinetics and Tolerability of Single and Multiple Intravenous Doses of Cefotetan Disodium in Healthy Chinese Volunteers. Drug Design, Development and Therapy, 14, 613-620. https://doi.org/10.2147/DDDT.S234619
Liu J, et al. Pharmacokinetics and Tolerability of Single and Multiple Intravenous Doses of Cefotetan Disodium in Healthy Chinese Volunteers. Drug Des Devel Ther. 2020;14:613-620. PubMed PMID: 32103903.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics and Tolerability of Single and Multiple Intravenous Doses of Cefotetan Disodium in Healthy Chinese Volunteers. AU - Liu,Jian, AU - Zhai,You, AU - Wu,Lihua, AU - Wu,Guolan, AU - Zheng,Yunliang, AU - Hu,Xingjiang, AU - Shentu,Jianzhong, Y1 - 2020/02/13/ PY - 2019/10/16/received PY - 2020/01/29/accepted PY - 2020/2/28/entrez PY - 2020/2/28/pubmed PY - 2020/2/28/medline KW - cefotetan disodium KW - healthy volunteers KW - multiple-dose KW - pharmacokinetics KW - plasma KW - single-dose SP - 613 EP - 620 JF - Drug design, development and therapy JO - Drug Des Devel Ther VL - 14 N2 - 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. SN - 1177-8881 UR - https://www.unboundmedicine.com/medline/citation/32103903/Pharmacokinetics_and_Tolerability_of_Single_and_Multiple_Intravenous_Doses_of_Cefotetan_Disodium_in_Healthy_Chinese_Volunteers L2 - https://dx.doi.org/10.2147/DDDT.S234619 DB - PRIME DP - Unbound Medicine ER -
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