Department of Pharmacology, School of Pharmaceutical Sciences, China Medical University, Shenyang, People's Republic of China.
Clin Ther. 2010 Mar;32(3):597-606. doi: 10.1016/j.clinthera.2010.03.017.
BACKGROUND: Ampicillin/probenecid is an antimicrobial formulation indicated for the treatment of respiratory, urinary tract, and gastrointestinal infections. Ampicillin sodium is the active antimicrobial ingredient that can act on the phase of bacterial breeding and inhibit the biosynthesis of bacterial mucopeptide in the cell wall. Probenecid acts synergistically by competitively inhibiting an organic anion transporter in renal tubules, increasing the plasma concentrations, and thus extending the plasma elimination t(1/2). OBJECTIVE: The aim of this study was to assess and compare the pharmacokinetic (PK) properties, bioavailability, and bioequivalence of a newly developed dispersible tablet formulation (test) of ampicillin/ probenecid with those of an established branded capsule formulation (reference) in healthy Chinese male volunteers. METHODS: A randomized-sequence, single-dose, open-label, 2-period crossover study was conducted in fasted healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 6 dispersible tablets (test) or branded capsules (reference) (1500 mg total; 250 mg each containing ampicillin 194.5 mg and probenecid 55.5 mg), followed by a 7-day washout period and administration of the alternate formulation. Plasma samples were collected over a 24-hour period following administration and analyzed for ampicillin and probenecid content by HPLC. PK parameters such as C(max), AUC(0-t), and AUC(0-infinity) were also determined. The formulations were considered bioequivalent if the geometric mean ratios of the log-transformed C(max) and AUC values were within the equivalence range (80%-125%) predetermined by the State Food and Drug Administration (SFDA) of the People's Republic of China. Tolerability was based on the observation of adverse events (AEs), monitoring of vital signs (blood pressure, heart rate, temperature, electrocardiography) and laboratory tests (hematology, blood biochemistry, hepatic function, urinalysis), and subject's interview on AEs. RESULTS: The study was performed in 20 healthy Chinese male volunteers (mean [SD] age, 21.4 [2.2] years; weight, 64.1 [5.5] kg; height, 173.7 [5.3] cm; and body mass index, 21.2 [1.6] kg/m(2)). The mean (SD) C(max), T(max), AUC(0-24), and AUC(0-infinity) after administration of the test and reference formulations, respectively, were as follows: ampicillin, C(max), 13.45 (3.43) versus 15.04 (5.68) microg/mL, T(max), 1.58 (0.49) versus 1.78 (0.55) hours, AUC(0-24), 50.78 (13.39) versus 57.44 (17.27) micro/mL/h, and AUC(0-infinity), 51.95 (13.45) versus 58.74 (17.19) microg/mL/h; probenecid, C(max), 15.56 (2.94) versus 16.01 (2.88) microg/mL, T(max), 2.85 (0.78) versus 3.30 (1.51) hours, AUC(0-24), 129.23 (27.59) versus 127.29 (26.89) microg/mL/h, and AUC(0-infinity) 133.85 (28.80) versus 131.21 (28.25) microg/mL/h. On ANOVA, neither period nor sequence effects were observed for any of the PK properties. The 90% CIs of ampicillin for the log-transformed ratios of C(max), AUC(0-24), and AUC(0-infinity)) were 86.5% to 108.0%, 96.7% to 107.8%, and 83.3% to 100.7%, respectively, and the corresponding values for probenecid were 90.2% to 108.3%, 96.8% to 107.8%, and 97.2% to 108.5%. No AEs were observed or reported up to 1 week after study end. CONCLUSIONS: In this small study in healthy Chinese male volunteers, a single 1500-mg dose of the dispersible tablet formulation (test) of ampicillin/probenecid met the SFDA's regulatory criteria for bioequivalence to the reference capsule formulation based on the rate and extent of absorption. Both formulations were well tolerated.
背景：氨苄西林/丙磺舒是一种抗菌制剂，用于治疗呼吸道、泌尿道和胃肠道感染。氨苄西林钠是一种具有抗菌活性的成分，可作用于细菌繁殖阶段，抑制细菌细胞壁中粘肽的生物合成。丙磺舒通过竞争性抑制肾小管中的有机阴离子转运体起协同作用，增加血浆浓度，从而延长血浆消除半衰期（t1/2）。
目的：本研究旨在评估和比较新开发的氨苄西林/丙磺舒分散片（试验）与已上市胶囊制剂（参比）在健康中国男性志愿者中的药代动力学（PK）特性、生物利用度和生物等效性。
方法：这是一项在健康中国男性志愿者中进行的随机、序列、单剂量、开放标签、2 期交叉研究。符合条件的参与者以 1:1 的比例随机分配，分别服用 6 片分散片（试验）或胶囊（参比）（总剂量为 1500mg；每片含氨苄西林 194.5mg 和丙磺舒 55.5mg），随后进行 7 天的洗脱期，再服用另一种制剂。给药后 24 小时内采集血浆样本，采用 HPLC 法测定氨苄西林和丙磺舒的含量。还确定了 Cmax、AUC（0-t）和 AUC（0-infinity）等 PK 参数。如果通过中国国家食品药品监督管理局（SFDA）规定的等效范围（80%-125%）预测，两种制剂的对数转化的 Cmax 和 AUC 值的几何均数比值在等效范围内，则认为两种制剂生物等效。基于不良事件（AE）的观察、生命体征（血压、心率、体温、心电图）和实验室检查（血常规、血液生化、肝功能、尿液分析）的监测，以及对 AE 的受试者访谈来评估耐受性。
结果：这项研究在中国 20 名健康男性志愿者中进行（平均[SD]年龄，21.4[2.2]岁；体重，64.1[5.5]kg；身高，173.7[5.3]cm；体重指数，21.2[1.6]kg/m2）。试验和参比制剂的 Cmax、Tmax、AUC（0-24）和 AUC（0-infinity）的平均值（SD）分别为：氨苄西林，Cmax，13.45（3.43）vs 15.04（5.68）μg/mL，Tmax，1.58（0.49）vs 1.78（0.55）小时，AUC（0-24），50.78（13.39）vs 57.44（17.27）μg/mL/h，AUC（0-infinity），51.95（13.45）vs 58.74（17.19）μg/mL/h；丙磺舒，Cmax，15.56（2.94）vs 16.01（2.88）μg/mL，Tmax，2.85（0.78）vs 3.30（1.51）小时，AUC（0-24），129.23（27.59）vs 127.29（26.89）μg/mL/h，AUC（0-infinity），133.85（28.80）vs 131.21（28.25）μg/mL/h。方差分析显示，任何 PK 特性均无周期或序列效应。氨苄西林对数转化比值的 90%置信区间（CIs）分别为 86.5%至 108.0%、96.7%至 107.8%和 83.3%至 100.7%，丙磺舒的相应值分别为 90.2%至 108.3%、96.8%至 107.8%和 97.2%至 108.5%。研究结束后 1 周内未观察到或报告任何不良事件。
结论：在这项在中国健康男性志愿者中进行的小型研究中，单次 1500mg 剂量的氨苄西林/丙磺舒分散片（试验）基于吸收的速率和程度，符合中国国家食品药品监督管理局的生物等效性监管标准。两种制剂均具有良好的耐受性。
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