Sharma A, Slugg P H, Hammett J L, Jusko W J
Department of Pharmaceutics, State University of New York, School of Pharmacy, State University of New York at Buffalo, Buffalo, NY 14260, USA.
J Clin Pharmacol. 1998 Dec;38(12):1116-21.
A double-blind, placebo-controlled, parallel-group, ascending, multiple-dose study was completed in 45 healthy male volunteers to assess the maximum tolerated dose, pharmacokinetics, and pharmacodynamics of BMS-187745, a squalene synthase inhibitor, administered as multiple oral doses of its prodrug BMS-188494. Participants received a daily oral dose of 10 mg for 2 weeks, or a daily oral dose of 25, 50, 100, or 200 mg for 4 weeks. The absorption rate constant (ka) and bioavailability (F) values were estimated by fitting the plasma BMS-187745 concentration-time data to a biexponential function with a first-order ka. Values for F were similar for all five dose levels, and thus were independent of dose. The ka values also were similar for all dose groups except the 50-mg group, for which ka values were somewhat higher. The change in urinary excretion rate of farnesyl pyrophosphate metabolite (dioic acid) was determined to be a pharmacodynamic measure. There was no significant change in dioic acid excretion at doses of less than 100 mg given for 4 weeks. An indirect pharmacodynamic response model with threshold concentration (CT) and based on inhibition of squalene synthase was proposed to describe the effect versus time data. The pharmacodynamic data from all dose levels were fitted simultaneously to the proposed model and the fitted parameters estimated as CT = 3.9 micrograms/mL, kout = 0.47 hr-1, IC50 = 4.1 micrograms/mL, and Imax = 1.0. The proposed indirect response model requiring a threshold concentration provides a useful means of quantitating responses for a new type of therapeutic agent.
一项双盲、安慰剂对照、平行组、递增、多剂量研究在45名健康男性志愿者中完成，以评估角鲨烯合酶抑制剂BMS-187745（以其前药BMS-188494的多个口服剂量给药）的最大耐受剂量、药代动力学和药效学。参与者接受每日口服剂量10mg，持续2周，或每日口服剂量25、50、100或200mg，持续4周。通过将血浆BMS-187745浓度-时间数据拟合到具有一级吸收速率常数（ka）的双指数函数来估计吸收速率常数（ka）和生物利用度（F）值。所有五个剂量水平的F值相似，因此与剂量无关。除50mg组外，所有剂量组的ka值也相似，50mg组的ka值略高。法尼基焦磷酸代谢物（二酸）的尿排泄率变化被确定为一种药效学指标。给予4周剂量小于100mg时，二酸排泄无显著变化。提出了一种基于角鲨烯合酶抑制作用的具有阈值浓度（CT）的间接药效学反应模型来描述效应与时间的数据。将所有剂量水平的药效学数据同时拟合到所提出的模型中，并估计拟合参数为CT = 3.9微克/毫升，kout = 0.47小时-1，IC50 = 4.1微克/毫升，Imax = 1.0。所提出的需要阈值浓度的间接反应模型为定量新型治疗剂的反应提供了一种有用的方法。
