Infectious Diseases MDC, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Br J Clin Pharmacol. 2012 Aug;74(2):336-45. doi: 10.1111/j.1365-2125.2012.04194.x.
To evaluate potential drug interactions with antiretroviral therapies or supportive therapies for use in conjunction with the once daily, next generation non-nucleoside reverse transcriptase inhibitor GSK2248761 in patients with HIV-1 infection.
A series of phase I drug interaction studies was conducted.
GSK2248761 was shown to be a weak CYP3A4 and CYP2D6 inhibitor in a clinical study with a probe cocktail. Mean plasma concentration-time profiles for atazanavir, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), darunavir (DRV, administered with ritonavir [RTV]), and drospirenone/ethinylestradiol were similar following co-administration of GSK2248761. Plasma raltegravir AUC(0,τ) and C(max) increased by 18% with no change in Cτ when raltegravir was co-administered with GSK2248761. Lopinavir (LPV) plasma AUC(0,τ), C(max) and Cτ decreased by 23%, 14% and 40%, respectively, following administration of lopinavir/ritonavir with GSK2248761. Atorvastatin, rosuvastatin and simvastatin AUC(0,∞) and C(max) increased following co-administration with GSK2248761, with the largest changes observed for simvastatin (3.7-fold and 4.3-fold). Changes in maximum and extent of GSK2248761 exposure were marginal after co-administration with atazanavir, TDF/FTC and raltegravir compared with GSK2248761 administered alone. Co-administration of GSK2248761 with DRV/RTV and LPV/RTV increased plasma GSK2248761 exposures by 1.25- to ≤2-fold compared with GSK2248761 administered alone, and increases in GSK2248761 exposure were higher following single dose co-administration of DRV/RTV or LPV/RTV compared with multiple doses. There were few drug-related AEs, and no treatment-related trends in blood chemistry, haematology, urinalysis, vital signs or ECG findings.
These studies indicate that GSK2248761 was safe and well tolerated in healthy adults treated in these studies at the doses and duration of therapy evaluated.
评估与抗逆转录病毒疗法或支持性疗法联合使用每日一次的下一代非核苷类逆转录酶抑制剂 GSK2248761 时与 HIV-1 感染相关的潜在药物相互作用。
进行了一系列的 I 期药物相互作用研究。
在使用探针混合物的临床研究中，GSK2248761 显示为一种弱 CYP3A4 和 CYP2D6 抑制剂。当与 GSK2248761 联合使用时，阿扎那韦、替诺福韦二吡呋酯/恩曲他滨（TDF/FTC）、达芦那韦（与利托那韦一起给予）和屈螺酮/炔雌醇的平均血浆浓度-时间曲线相似。当与 GSK2248761 联合使用时，洛匹那韦（LPV）的血浆 AUC（0，τ）、C（max）和 Cτ分别下降 23%、14%和 40%。当给予 GSK2248761 时，阿托伐他汀、瑞舒伐他汀和辛伐他汀的 AUC（0，∞）和 C（max）增加，其中辛伐他汀的变化最大（3.7 倍和 4.3 倍）。与 GSK2248761 单独给药相比，与 GSK2248761 联合给药时，阿扎那韦、TDF/FTC 和拉替拉韦的最大和程度的 GSK2248761 暴露变化均较小。与 GSK2248761 单独给药相比，与 GSK2248761 联合给药时，DRV/RTV 和 LPV/RTV 增加了 GSK2248761 的血浆暴露，增加了 1.25-至≤2 倍，并且与多次剂量相比，DRV/RTV 或 LPV/RTV 的单次剂量联合给药时，GSK2248761 的暴露增加更高。药物相关不良事件很少，血液化学、血液学、尿液分析、生命体征或心电图结果无治疗相关趋势。
在这些研究中，GSK2248761 在接受评估的治疗剂量和治疗时间范围内，在接受这些研究治疗的健康成年人中是安全且耐受良好的。
