Parasrampuria Dolly A, de Boer Peter, Desai-Krieger Daksha, Chow Andrew T, Jones C Richard
Johnson & Johnson Pharmaceutical R&D, Raritan, New Jersey, USA.
J Clin Pharmacol. 2003 Apr;43(4):406-13. doi: 10.1177/0091270002250615.
The objective of this study was to investigate the pharmacokinetics and ex vivo pharmacodynamics of increasing doses of RWJ 67657, along with the effect of food at one dose level in a first-in-human (FIH) study. This was a placebo-controlled, double-blind, randomized trial in healthy male subjects. Subjects received increasing doses of RWJ 67657 or placebo as a single oral dose (0.25-30 mg/kg) under fasting conditions. The effect of food was investigated for the 10-mg/kg dose. Plasma concentrations of RWJ 67657 were measured over a period of 48 hours using a validated LC-MS/MS method. To evaluate the pharmacodynamics of RWJ 67657, inhibition of cytokine production was monitored from exvivo-stimulated polymorphonuclear blood cells (PBMCs). Pharmacokinetic/pharmacodynamic modeling was used to characterize the inhibitory activity of RWJ 67657. RWJ 67657 was rapidly absorbed (mean tmax = 0.6-2.5 h). The pharmacokinetics of RWJ 67657 appear to be nonlinear with respect to single-dose administration of the investigative formulation. Coadministration of food did not have a significant effect on half-life or time to peak concentration (tmax) but decreased the exposure. Mean Cmax values in the presence of food were almost 50% lower than during fasting (542 vs. 1283 ng/mL), and the AUC decreased from 2832 to 1904 ng.h/mL with food. RWJ 67657 inhibited TNF-alpha, IL-8, and IL-6 in a concentration-dependent manner with mean IC50 values of 0.18 microM, 0.04 microM, and 0.43 microM, respectively. At 20 mg/kg, the median inhibition was greater than 85%. There were no significant adverse effects associated with single doses of this drug. This study demonstrates that RWJ 67657 has acceptable safety and pharmacokinetics to warrant further investigation in a repeat-dose setting. In addition, the early determination of effect on biomarkers suggests potential efficacy in diseases mediated by proinflammatory and inflammatory cytokines.
本研究的目的是在一项首次人体试验（FIH）中，研究递增剂量的RWJ 67657的药代动力学和体外药效学，以及在一个剂量水平下食物的影响。这是一项在健康男性受试者中进行的安慰剂对照、双盲、随机试验。受试者在禁食条件下接受递增剂量的RWJ 67657或安慰剂作为单次口服剂量（0.25 - 30 mg/kg）。对10 mg/kg剂量研究了食物的影响。使用经过验证的液相色谱 - 串联质谱法（LC-MS/MS）在48小时内测定RWJ 67657的血浆浓度。为了评估RWJ 67657的药效学，监测了体外刺激的多形核血细胞（PBMCs）中细胞因子产生的抑制情况。采用药代动力学/药效学模型来表征RWJ 67657的抑制活性。RWJ 67657吸收迅速（平均tmax = 0.6 - 2.5小时）。就研究制剂的单剂量给药而言，RWJ 67657的药代动力学似乎是非线性的。食物的共同给药对半衰期或达峰时间（tmax）没有显著影响，但降低了暴露量。食物存在时的平均Cmax值比禁食时低近50%（542对1283 ng/mL），并且食物使AUC从2832降至1904 ng.h/mL。RWJ 67657以浓度依赖性方式抑制TNF-α、IL-8和IL-6，平均IC50值分别为0.18 microM、0.04 microM和0.43 microM。在20 mg/kg时，中位数抑制率大于85%。单剂量使用该药物未观察到显著的不良反应。本研究表明，RWJ 67657具有可接受的安全性和药代动力学，值得在重复给药情况下进一步研究。此外，对生物标志物影响的早期测定表明，其在由促炎和炎性细胞因子介导的疾病中具有潜在疗效。
