Shadle Craig R, Lee Yih, Majumdar Anup K, Petty Kevin J, Gargano Cynthia, Bradstreet Thomas E, Evans Judith K, Blum Robert A
Clinical Pharmacology, Merck Research Laboratories, BLB-33, 5 Sentry Parkway West, Blue Bell, PA 19422.
J Clin Pharmacol. 2004 Mar;44(3):215-23. doi: 10.1177/0091270003262950.
The NK(1) receptor antagonist aprepitant (EMEND(R)), developed for use in combination with a 5HT(3) receptor antagonist and a corticosteroid to prevent highly emetogenic chemotherapy-induced nausea and vomiting (CINV), has been shown to have a moderate inhibitory effect as well as a possible inductive effect on cytochrome P450 (CYP) 3A4. Aprepitant has been noted to produce modest decreases in plasma S(-)-warfarin concentrations, suggesting potential induction of CYP2C9. Because metabolism of some chemotherapeutic agents may involve CYP3A4, the potential inductive effect of the CINV dosing regimen of aprepitant on this metabolic pathway was evaluated using intravenous midazolam, a sensitive probe substrate of CYP3A4. The time course of induction of CYP2C9 by aprepitant was also evaluated using oral tolbutamide, a probe substrate of CYP2C9. In this double-blind, randomized, placebo-controlled, single-center study, 24 healthy subjects were randomized (12 subjects per group) to receive either an aprepitant 3-day regimen (aprepitant 125 mg p.o. on day 1 and aprepitant 80 mg p.o. on days 2 and 3) or matching placebo. All subjects also received probe drugs (midazolam 2 mg i.v. and tolbutamide 500 mg p.o.) once prior to aprepitant dosing (baseline) and again on days 4, 8, and 15. The ratio (aprepitant/placebo) of the geometric mean area under the plasma concentration curve (AUC) fold-change from baseline for midazolam was 1.25 on day 4 (p < 0.01), 0.81 on day 8 (p < 0.01), and 0.96 on day 15 (p = 0.646). The ratio (aprepitant/placebo) of the geometric mean AUC fold-change from baseline for tolbutamide was 0.77 on day 4 (p < 0.01), 0.72 on day 8 (p < 0.001), and 0.85 on day 15 (p = 0.05). Assessed using intravenous midazolam as a probe, aprepitant 125/80 mg p.o. administered over days 1 to 3 produced clinically insignificant weak inhibition (day 4) and induction (day 8) of CYP3A4 activity and no effect on CYP3A4 activity on day 15. Assessed using oral tolbutamide as a probe, the aprepitant regimen also produced modest induction of CYP2C9 activity on days 4 and 8, which resolved nearly to baseline by day 15. Thus, the aprepitant regimen for CINV results in modest, transient induction of CYPs 3A4 and 2C9 in the 2 weeks following administration.
NK(1)受体拮抗剂阿瑞匹坦（商品名：意美®），被开发用于与5HT(3)受体拮抗剂及皮质类固醇联合使用，以预防高致吐性化疗引起的恶心和呕吐（CINV），已显示出对细胞色素P450（CYP）3A4有中度抑制作用以及可能的诱导作用。已注意到阿瑞匹坦可使血浆S(-)-华法林浓度适度降低，提示可能诱导CYP2C9。由于某些化疗药物的代谢可能涉及CYP3A4，因此使用静脉注射咪达唑仑（一种CYP3A4的敏感探针底物）评估了阿瑞匹坦CINV给药方案对该代谢途径的潜在诱导作用。还使用口服甲苯磺丁脲（一种CYP2C9的探针底物）评估了阿瑞匹坦诱导CYP2C9的时间进程。在这项双盲、随机、安慰剂对照、单中心研究中，24名健康受试者被随机分组（每组12名受试者），分别接受阿瑞匹坦3天给药方案（第1天口服阿瑞匹坦125 mg，第2天和第3天口服阿瑞匹坦80 mg）或匹配的安慰剂。所有受试者在阿瑞匹坦给药前（基线）以及第4、8和15天各接受一次探针药物（静脉注射咪达唑仑2 mg和口服甲苯磺丁脲500 mg）。与基线相比，咪达唑仑血浆浓度曲线下几何平均面积（AUC）的变化倍数的阿瑞匹坦/安慰剂比值在第4天为1.25（p < 0.01），第8天为0.81（p < 0.01），第15天为0.96（p = 0.646）。甲苯磺丁脲与基线相比AUC变化倍数的阿瑞匹坦/安慰剂比值在第4天为0.77（p < 0.01），第8天为0.72（p < 0.001），第15天为0.85（p = 0.05）。以静脉注射咪达唑仑为探针评估，第1至3天口服125/80 mg阿瑞匹坦对CYP3A4活性产生了临床上无显著意义的轻度抑制（第4天）和诱导（第8天），且在第15天对CYP3A4活性无影响。以口服甲苯磺丁脲为探针评估，阿瑞匹坦给药方案在第4天和第8天也对CYP2C9活性产生了适度诱导，到第15天几乎恢复到基线水平。因此，用于CINV的阿瑞匹坦给药方案在给药后的2周内会导致CYP 3A4和2C9产生适度、短暂的诱导。
