Bonora Stefano, Gonzalez de Requena Daniel, D'Avolio Antonio, Calcagno Andrea, Tettoni Mariacristina, Siccardi Marco, Baietto Lorena, Simiele Marco, Trentini Laura, Di Perri Giovanni
Department of Infectious Diseases of the University of Torino, Amedeo di Savoia Hospital, Torino, Italy.
Antivir Ther. 2011;16(4):499-504. doi: 10.3851/IMP1802.
Use of unboosted atazanavir (ATV) with tenofovir disoproxil fumarate (TDF), although attractive from a clinical view point, has not been tested in trials and is not currently recommended because of the risk of suboptimal ATV pharmacokinetics (PK). In order to improve ATV exposure, plasma and intracellular (IC) PK of ATV in patients administered with ATV 400 mg once daily and TDF/emtricitabine (FTC) and switched to ATV 200 mg twice daily were studied.
On day 0, 10 subjects on ATV 400 mg plus TDF/FTC once daily underwent intensive plasma and IC PK evaluation and bilirubin measurement. Patients were subsequently switched to ATV 200 mg twice daily for 10 days. On day 11, they once again underwent intensive PK and bilirubin evaluation.
Switch to 200 mg twice daily led (in plasma) to a significant increase of the observed concentration at the end of dosing interval (C(trough); ratio twice daily/once daily 2.20; P=0.005), with a decrease from 60% to 20% of suboptimal values, a significant decrease of the maximum concentration (C(max); ratio twice daily/once daily 0.47; P=0.022), whereas no differences of other PK parameters or bilirubin were observed. IC ATV concentrations at 400 once daily showed higher C(trough) (ratio peripheral blood mononuclear cells [PBMCs]/plasma 2.86; P=0.005) and longer half-life (ratio PBMCs/plasma 1.44; P=0.007) as compared with plasma. After the switch, IC ATV accumulation showed changes similar to plasma.
Switch to 200 mg twice daily appeared to optimize plasma and IC ATV PK, by increasing the determinant of efficacy (C(trough)) and decreasing C(max), without significant effect on total ATV plasma exposure and bilirubin. Dosage of 200 mg might provide an option to patients showing suboptimal ATV exposure with standard unboosted dosing.
虽然从临床角度来看，使用未增强的阿扎那韦（ATV）联合富马酸替诺福韦二吡呋酯（TDF）很有吸引力，但尚未在试验中进行测试，且由于存在阿扎那韦药代动力学（PK）不理想的风险，目前不推荐使用。为了提高阿扎那韦的暴露量，对每日一次服用400mg阿扎那韦及TDF/恩曲他滨（FTC），随后改为每日两次服用200mg阿扎那韦的患者的阿扎那韦血浆和细胞内（IC）PK进行了研究。
在第0天，10名每日一次服用400mg阿扎那韦加TDF/FTC的受试者接受了强化血浆和IC PK评估以及胆红素测量。患者随后改为每日两次服用200mg阿扎那韦，持续10天。在第11天，他们再次接受了强化PK和胆红素评估。
改为每日两次服用200mg导致（血浆中）给药间隔结束时的观察浓度（C（谷））显著增加（每日两次/每日一次的比值为2.20；P = 0.005），次优值从60%降至20%，最大浓度（C（max））显著降低（每日两次/每日一次的比值为0.47；P = 0.022），而未观察到其他PK参数或胆红素的差异。与血浆相比，每日一次服用400mg时的IC阿扎那韦浓度显示出更高的C（谷）（外周血单核细胞[PBMCs]/血浆比值为2.86；P = 0.005）和更长的半衰期（PBMCs/血浆比值为1.44；P = 0.007）。换药后，IC阿扎那韦的蓄积变化与血浆相似。
改为每日两次服用200mg似乎优化了血浆和IC阿扎那韦的PK，通过增加疗效决定因素（C（谷））并降低C（max），而对阿扎那韦的总血浆暴露量和胆红素无显著影响。200mg的剂量可能为标准未增强给药时阿扎那韦暴露不理想的患者提供一种选择。
