Weller Stephen, Borland Julie, Chen Shuguang, Johnson Mark, Savina Paul, Wynne Brian, Wajima Toshihiro, Peppercorn Amanda F, Piscitelli Stephen C
GlaxoSmithKline, Research Triangle Park, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC, 27709, USA.
Eur J Clin Pharmacol. 2014 Jan;70(1):29-35. doi: 10.1007/s00228-013-1590-9. Epub 2013 Oct 6.
Dolutegravir (DTG), an unboosted HIV integrase inhibitor (INI), is metabolized by UGT1A1 and to a minor extent by CYP3A. Renal elimination of unchanged DTG is very low (< 1 %). As renal impairment may affect pharmacokinetics (PK), even for drugs primarily metabolized or secreted in bile, this study investigated the effect of renal impairment on the PK of DTG.
This was an open-label, single-dose study of oral DTG 50 mg administered to subjects with severe renal impairment (creatinine clearance [CLcr] <30 mL/min; not on dialysis) and to healthy controls (CLcr >90 mL/min) matched for gender, age and body mass index (8 subjects per group). Serial PK samples were collected up to 72 h post-dose for determination of DTG and DTG-glucuronide (DTG-Gluc) concentrations in plasma. DTG unbound fraction in plasma was determined at 3 and 24 h. PK parameters were determined by non-compartmental methods and compared between groups by analysis of covariance.
DTG was well tolerated with a low incidence of Grade 1 adverse events. DTG PK parameters showed significant overlap between groups. DTG mean exposure was lower in subjects with severe renal impairment compared to healthy, matched subjects: AUC(0-∞) and Cmax were 40 % and 23 % lower, while mean DTG-Gluc was increased. Renal impairment did not affect DTG fraction unbound in plasma.
The modest reductions in mean PK exposures for DTG and increases for DTG-Gluc in the severe renal impairment group are not considered clinically significant. DTG does not require dose adjustment in patients with renal impairment.
多替拉韦（DTG）是一种无需增效的HIV整合酶抑制剂（INI），通过UGT1A1代谢，少量经CYP3A代谢。原形DTG经肾脏排泄极少（<1%）。由于肾功能损害可能影响药代动力学（PK），即使对于主要经胆汁代谢或分泌的药物也是如此，因此本研究调查了肾功能损害对DTG药代动力学的影响。
这是一项开放标签、单剂量研究，对重度肾功能损害（肌酐清除率[CLcr]<30 mL/min；未接受透析）的受试者以及性别、年龄和体重指数匹配的健康对照者（CLcr>90 mL/min）口服50 mg DTG（每组8名受试者）。给药后长达72小时采集系列PK样本，以测定血浆中DTG和DTG - 葡萄糖醛酸苷（DTG - Gluc）的浓度。在3小时和24小时测定血浆中DTG的游离分数。通过非房室方法确定PK参数，并通过协方差分析在组间进行比较。
DTG耐受性良好，1级不良事件发生率较低。DTG的PK参数在组间有显著重叠。与健康匹配受试者相比，重度肾功能损害受试者的DTG平均暴露量较低：AUC(0 - ∞)和Cmax分别低40%和23%，而DTG - Gluc平均值升高。肾功能损害未影响血浆中DTG的游离分数。
重度肾功能损害组中DTG平均PK暴露量的适度降低以及DTG - Gluc的升高在临床上不被认为具有显著意义。肾功能损害患者使用DTG无需调整剂量。
