GlaxoSmithKline, Research Triangle Park, NC, USA Shionogi & Co., Ltd, Osaka, Japan.
Br J Clin Pharmacol. 2011 Jul;72(1):103-8. doi: 10.1111/j.1365-2125.2011.03947.x.
S/GSK1349572 is an unboosted, once daily, next generation integrase inhibitor with potent activity, low pharmacokinetic (PK) variability and a novel resistance profile. As the primary route of metabolism is via glucuronidation, the effects of atazanavir (ATV, a UGT1A1 inhibitor) and atazanavir/ritonavir (ATV/RTV) on S/GSK1349572 PK were evaluated.
A randomized, open label, two period, crossover study was conducted in healthy adult subjects. Twenty-four subjects received S/GSK1349572 30 mg every 24 h for 5 days. Subjects then were administered S/GSK1349572 30 mg every 24 h in combination with either ATV/RTV 300/100 mg every 24 h (n= 12) or ATV 400 mg every 24 h (n= 12) for 14 days. Serial PK samples and safety assessments were obtained throughout the study.
The combination of S/GSK1349572 with ATV/RTV or ATV was generally well tolerated. All adverse events were mild or moderate, and no subject withdrew because of an adverse event. The AE of highest frequency was ocular icterus, observed only during combination of S/GSK1349572 and ATV or ATV/RTV. Co-administration with ATV/RTV resulted in increased plasma S/GSK1349572 area under the concentration-time curve during a dosing interval (AUC(0,τ)), observed maximal concentration (C(max) ), and concentration at the end of dosing interval at steady state (C(τ) ) by 62%, 34% and 121%, respectively. Co-administration with ATV resulted in increased plasma S/GSK1349572 AUC(0,τ), C(max) , and C(τ) by 91%, 50% and 180%, respectively.
Co-administration of ATV/RTV and ATV was generally well tolerated and produced a modest, non-clinically significant increase in S/GSK1349572 exposure. No dose adjustment for S/GSK1349572 is necessary when co-administered with ATV and ATV/RTV.
S/GSK1349572 是一种未增强的、每日一次的下一代整合酶抑制剂，具有强大的活性、低药代动力学（PK）变异性和新型耐药谱。由于主要代谢途径是通过葡萄糖醛酸化，因此评估了阿扎那韦（ATV，一种 UGT1A1 抑制剂）和阿扎那韦/利托那韦（ATV/RTV）对 S/GSK1349572 PK 的影响。
在健康成年受试者中进行了一项随机、开放标签、两期、交叉研究。24 名受试者接受 S/GSK1349572 30mg 每 24 小时一次，连续 5 天。然后，受试者接受 S/GSK1349572 30mg 每 24 小时一次，联合阿扎那韦/利托那韦 300/100mg 每 24 小时一次（n=12）或阿扎那韦 400mg 每 24 小时一次（n=12），连续 14 天。整个研究过程中均获得了连续的 PK 样本和安全性评估。
S/GSK1349572 与阿扎那韦/利托那韦或阿扎那韦联合使用通常耐受性良好。所有不良事件均为轻度或中度，无受试者因不良事件退出。AE 中最常见的是眼部黄疸，仅在 S/GSK1349572 与阿扎那韦或阿扎那韦/利托那韦联合使用时观察到。与阿扎那韦/利托那韦联合使用使 S/GSK1349572 的血浆 AUC（0，τ）、C（max）和 C（τ）在稳态时的终末浓度分别增加 62%、34%和 121%。与阿扎那韦联合使用使 S/GSK1349572 的 AUC（0，τ）、C（max）和 C（τ）分别增加 91%、50%和 180%。
阿扎那韦/利托那韦和阿扎那韦联合使用通常耐受性良好，使 S/GSK1349572 暴露适度增加，无临床意义。当与阿扎那韦和阿扎那韦/利托那韦联合使用时，无需调整 S/GSK1349572 的剂量。
