Unit of Clinical Pharmacology, Department of Clinical Sciences, Luigi Sacco University Hospital, Università di Milano, Milan, Italy.
Ther Drug Monit. 2010 Dec;32(6):782-6. doi: 10.1097/FTD.0b013e3181fa53b7.
Raltegravir (RAL) is primarily metabolized by uridine diphosphate-glucorunosyl transferase 1A1 (UGT1A1). Atazanavir (ATV), a strong inhibitor of UGT1A1, has been shown to increase plasma concentrations of RAL by approximately 50% in healthy volunteers. However, the extent of this interaction has not been studied in HIV-infected patients. A pharmacokinetic study was performed in 22 HIV-infected adults treated with 400 mg RAL plus 300 mg ATV 300 twice a day. Both drugs showed high pharmacokinetic variability (RAL AUC 0-12 7649 ± 4862 ngh/mL; ATV AUC 0-12 = 19237 ± 13136 ngh/mL). Notably, RAL trough concentrations were significantly higher compared with those measured in HIV subjects (n = 24) on RAL plus nucleoside reverse transcriptase inhibitors (506 ± 411 versus 177 ± 262 ng/mL, P < 0.01). A significant correlation was found between RAL and ATV area under the curve (AUC) (r = 0.611, P = 0.005). Notably, patients with ATV AUC 0-12 above the mean or with concentrations exceeding the half maximal inhibitory concentration for UGT1A1 had twofold higher RAL AUCs compared with patients with lower ATV exposure. Coadministration of ATV significantly increased plasma concentrations of RAL, especially in HIV-1-infected patients exposed to high concentrations of the protease inhibitor. This pharmacokinetic drug interaction could be handled by routine measurements of ATV trough concentrations and by the assessment of plasma RAL concentrations 2 to 3 hours after the morning drug intake.
拉替拉韦（RAL）主要通过尿苷二磷酸葡萄糖醛酸基转移酶 1A1（UGT1A1）代谢。阿扎那韦（ATV）是 UGT1A1 的强抑制剂，在健康志愿者中已显示可使 RAL 的血浆浓度增加约 50%。然而，尚未在 HIV 感染者中研究这种相互作用的程度。在接受每日两次 400mg RAL 和 300mg ATV 治疗的 22 例 HIV 感染成人中进行了一项药代动力学研究。两种药物均表现出较高的药代动力学变异性（RAL AUC0-12 为 7649 ± 4862ngh/mL；ATV AUC0-12 为 19237 ± 13136ngh/mL）。值得注意的是，RAL 谷浓度与 HIV 感染者（n=24）接受 RAL 和核苷逆转录酶抑制剂治疗时测量的浓度相比显著升高（506±411 与 177±262ng/mL，P＜0.01）。RAL 和 ATV 曲线下面积（AUC）之间存在显著相关性（r=0.611，P=0.005）。值得注意的是，ATV AUC0-12 高于平均值或浓度超过 UGT1A1 半最大抑制浓度的患者，其 RAL AUC 是 ATV 暴露量较低患者的两倍。阿扎那韦的共同给药显著增加了 RAL 的血浆浓度，尤其是在暴露于高浓度蛋白酶抑制剂的 HIV-1 感染者中。这种药代动力学药物相互作用可以通过常规测量 ATV 谷浓度和评估早上服药后 2 至 3 小时的血浆 RAL 浓度来处理。
