Steady-state pharmacokinetics of delavirdine in HIV-positive patients: Effect on erythromycin breath test
Steady-state pharmacokinetics of delavirdine in HIV-positive patients: Effect on erythromycin breath test
复制标题
DOI：
10.1016/s0009-9236(97)90133-8
复制
发表时间：
1997-05-01
影响因子：
6.7
通讯作者：
Stetson, PL
中科院分区：
文献类型：
--
作者：
Cheng, CL;Smith, DE;Stetson, PL
目的：在人类免疫缺陷病毒阳性患者中，在递增口服剂量和以相同剂量水平重复口服给药后，评价地拉韦啶和去异丙基地拉韦啶的稳态动力学。患者（n = 8名男性）在14天内连续给予递增口服剂量的地拉韦啶甲磺酸盐，用于阶段1（每8小时200 mg）、2（每8小时300 mg）和3（每8小时400 mg）。对照患者（n = 4名男性）在所有三个阶段每8小时给予300 mg口服剂量的药物。结果：地拉韦啶剂量递增组，口服清除率、最大稳态血药浓度/最小稳态血药浓度比值、对数线性终末速率常数呈非线性下降，半衰期随剂量增加而增加;去异丙基-地拉韦啶形成清除率与消除清除率的比率也降低。在对照组中，地拉韦啶和去异丙基地拉韦啶的动力学没有变化。地拉韦啶在递增剂量组和对照组的血浆蛋白结合率呈线性;平均而言，未结合分数分别约为2.3%和2.0%。在短期和长期暴露于所有剂量的甲磺酸地拉韦啶后，肝脏CYP 3A活性显著降低。地拉韦啶可以最大限度地抑制70%至75%的给药前ERMBT值，与IC 50约0.9 μ mol/L。结论：地拉韦啶是一种有效的和可逆的肝CYP 3A的抑制剂，它也是这种CYP 450亚型的底物。地拉韦啶与其他CYP 3A底物联合给药时可能会出现药物间相互作用。
Objective: The steady-state kinetics of delavirdine and desisopropyldelavirdine were evaluated in human immunodeficiency virus-positive patients after escalating oral doses and after repeated oral administrations at the same dose level.Study design: Patients (n = 8 males) were given escalating oral doses of delavirdine mesylate, in a sequential fashion, over 14 days for phases 1 (200 mg every 8 hours), 2 (300 mg every 8 hours), and 3 (400 mg every 8 hours). Control patients (n = 4 males) were given 300 mg oral doses of drug every 8 hours for all three phases. Hepatic CYP3A activity was evaluated with the erythromycin breath test (ERMBT).Results: In the escalating-dose group, delavirdine displayed nonlinear kinetics as indicated by the decreasing oral clearance, maximum steady-state plasma concentration/minimum steady-state plasma concentration ratio, and log-linear terminal rate constant, as well as by the increasing half-life at higher doses; the ratio of desisopropyl-delavirdine formation clearance to elimination clearance was also reduced. In the control group, the kinetics of delavirdine and desisopropyl-delavirdine were unchanged. Plasma protein binding was linear for delavirdine in the escalating-dose and control groups; on average, the fraction unbound was about 2.3% and 2.0%, respectively. Hepatic CYP3A activity was markedly reduced after short- and long-term exposure to all doses of delavirdine mesylate. Delavirdine could maximally inhibit 70% to 75% of predose ERMBT values, with an IC50 of about 0.9 mu mol/L.Conclusion: Delavirdine is a potent and reversible inhibitor of hepatic CYP3A; it is also a substrate for this CYP450 isoform. It is likely that delavirdine will exhibit drug-drug interactions when coadministered with other CYP3A substrates.