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You Zhai,1,2 Lihua Wu,1,2 Yunliang Zheng,1,2 Minglan Wu,1,2 Yujie Huang,1,2 Qian Huang,1,2 Jianzhong Shentu,1– 3 Qingwei Zhao,1,2 Jian Liu1,2 1Research 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; 2Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3College of Medicine, Zhejiang University, Hangzhou, People’s Republic of ChinaCorrespondence: Jian LiuResearch Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People’s Republic of ChinaTel +86 571 87236537Fax +86 571 87214223Email lindaliu87@zju.edu.cnPurpose: This study compares the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of amitriptyline hydrochloride tablets, and assesses the bioequivalence of the two products in healthy Chinese volunteers to obtain sufficient evidence for the marketing approval of the generic drug.Materials and Methods: A randomized, open-label, two-period crossover study (clinicaltrials.gov, NCT03646526) was conducted under both fasting and fed conditions in healthy Chinese volunteers (24 subjects/condition). Eligible subjects randomly received a single 25 mg dose of either the test or the reference formulation, followed by a 3-week washout period. Blood samples were collected until 144 h following administration. The pharmacokinetic parameters were acquired based on the concentration-time profiles, including the areas under the plasma concentration-time curve (AUC0-t, AUC0-∞), the peak plasma concentration (Cmax), the time to achieve Cmax (Tmax), and the elimination half-life (t1/2). The geometric mean ratios (GMRs) and the corresponding 90% confidence intervals (CIs) of amitriptyline were acquired for bioequivalence analysis, and values of these parameters for nortriptyline were used for comparison of therapeutic outcomes. Safety assessments included laboratory tests, physical examination, vital signs, and incidence of adverse events (AEs).Results: The values of t1/2 and Tmax for amitriptyline were not significantly different between the test and reference products under both fasting and fed conditions (P > 0.05). The GMRs of Cmax, AUC0–t, and AUC0-∞ between the two products, and corresponding 90% CIs, were all within the range of 80% to 125% under both fasting and fed conditions. The test and reference products were well tolerated and did not elicit serious adverse events.Conclusion: This study demonstrated that the generic and reference products were well tolerated by the subjects and bioequivalent, according to the rate and extent of the drug absorption.Keywords: bioequivalence, pharmacokinetics, amitriptyline hydrochloride, nortriptyline

Jian Liu,1,2 You Zhai,1,2 Lihua Wu,1,2 Guolan Wu,1,2 Yunliang Zheng,1,2 Xingjiang Hu,1,2 Jianzhong Shentu1– 3 1Research 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; 2Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3College of Medicine, Zhejiang University, Hangzhou, People’s Republic of ChinaCorrespondence: Jianzhong ShentuResearch Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People’s Republic of ChinaTel +86 571 87236560Fax +86 571 87214223Email stjz@zju.edu.cnBackground: 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.Keywords: cefotetan disodium, pharmacokinetics, healthy volunteers, plasma, single-dose, multiple-dose