Pharmacokinetics and Tolerability of Intravenous Cefotetan Disodium for Injection in Healthy Chinese Volunteers: A Randomized, Open-Label, Single- and Multiple-Dose Study

摘要

Background: Cefotetan disodium for injection is a semisynthetic cephamycin antibiotic that exerts its bactericidal effects by inhibition of cell-wall synthesis. Despite being widely used in the treatment of various infections, little information is available on the pharmacokinetic properties of cefotetan disodium in Chinese subjects.Objectives: This study evaluated the pharmacokinetics of single and multiple intravenous doses of a generic formulation of cefotetan disodium in healthy Chinese volunteers. The effect of sex on the pharmacokinetics of cefotetan disodium was evaluated as a secondary objective.Methods: In this 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-hour intravenous infusion. Those allocated to the 1.0-g dose continued into the multiple-dose phase, in which they received 1.0 g BID for 7 consecutive days. During the single-dose phase, blood samples were collected at regular intervals from 0 to 15 hours after drug administration and were analyzed using a validated HPLC method. During the multiple-dose phase, blood samples were obtained before drug administration on days 5, 6, and 7 to determine the C_(min)at steady state; on day 7, blood samples were also collected from 0 to 15 hours after drug administration. Tolerability was assessed based on physical examinations, vital signs, laboratory tests (hematology, biochemistry, hepatic and renal function, and urinalysis), and subject interviews.Results: Three groups, each consisting of 5 men and 5 women, were enrolled in the single-dose phase. The mean (SD) age of subjects was 23.2 (2.2) years (range,19-30 years). Their mean weight was 57.0 (6.3) kg (range, 46.4-72.0 kg), and their mean height was 1.66 (0.08) m (range, 1.48-1.81 m). After intravenous administration of single doses of 0.5, 1.0, and 2.0 g, the cefotetan disodium C_(max)was 35.01 (6.98), 76.67 (10.52), and 154.33 (27.17) mg/L, respectively; the AUC_(0-15h) was 145.35 (18.36), 307.45 (33.07), and 746.09 (103.07) mg h/L; the AUC_(0-8) was 171.51 (20.61), 347.25 (44.20), and 843.84 (131.13) mg ? h/L; the t_(1/2) was 5.80 (1.29),4.91 (1.15), and 5.04 (1.26) hours; the CL was 2.96 (0.41),2.92 (0.39), and 2.42 (0.39) L/h; and the V_d was 24.55(5.19), 20.37 (3.66), and 17.30 (3.52) L. After administration of multiple doses, the cefotetan disodium C_(max.ss) was 80.53 (10.04) mg/L; the C_(max.ss)was 11.00 (4.04) mg/L; the AUC_SS was 347.92 (50.04) mg ? h/L; the steady-state plasma concentration was 28.99 (4.17) mg/L; the t_(1/2)was 6.24 (2.52) hours; the CL was 2.32 (0.64) L/h; and the V_d was 19.19 (4.58) L. No significant differences in pharmacokinetic parameters were noted by sex in the multiple-dose phase. Cefotetan disodium appeared to be well tolerated.Conclusions: In these healthy Chinese subjects, the cefotetan disodium AUC and C_(max) increased in a dose-proportional manner, whereas the t_(1/2) was independent of dose. The pharmacokinetic properties of cefotetan disodium were linear at doses of 0.5 to 2.0 g. After multiple doses, the pharmacokinetic parameters of cefotetan disodium were consistent with those after single doses. At the doses studied, cefotetan disodium appeared to be well tolerated in these healthy volunteers.