Zhu Li, Butterton Joan, Persson Anna, Stonier Michele, Comisar Wendy, Panebianco Deborah, Breidinger Sheila, Zhang Jenny, Bertz Richard
Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, R&D, Hopewell, NJ, USA.
Antivir Ther. 2010;15(8):1107-14. doi: 10.3851/IMP1673.
Atazanavir plus raltegravir 300/400 mg twice daily is being explored as a ritonavir- and nucleoside-sparing treatment strategy. The pharmacokinetics and safety of this combination in healthy individuals were evaluated.
A total of 22 healthy individuals received raltegravir 400 mg on days 1-5, atazanavir 300 mg on days 6-12 and atazanavir plus raltegravir 300/400 mg on days 13-26, twice daily with a light meal. Serial blood samples were collected 12 h after the morning dose on days 5, 12 and 26; safety assessments, clinical laboratory data and serial electrocardiograms (ECGs) at 0, 2 and 6 h were obtained.
Raltegravir coadministration reduced atazanavir geometric mean maximum plasma concentration (C(max)), area under the plasma concentration-time curve from 0 to 12 h post-dose (AUC(0-12)) and trough plasma concentration (C(min)) by 11%, 17% and 29%, respectively, compared with atazanavir alone. Geometric mean atazanavir C(min) was 817 ng/ml (range 250-1,550) with raltegravir coadministration. Atazanavir increased raltegravir geometric mean C(max), AUC(0-12) and C(min) by 39%, 54% and 48%, respectively. All adverse events were of mild or moderate intensity. Hyperbilirubinaemia and ECG PR increases with atazanavir were similar to those of atazanavir/ritonavir once daily. No corrected QT prolongations were noted. Mean QRS increase from baseline was 11.0 ms (range 2-25) after receiving atazanavir for 7 days; no further QRS increase was noted and no QRS interval was >120 ms with raltegravir coadministration. No ECG changes were observed with raltegravir alone.
Coadministration of atazanavir and raltegravir 300/400 mg twice daily decreased atazanavir AUC(0-12) and C(min) relative to atazanavir alone, and increased AUC(0-12) of raltegravir relative to raltegravir alone. Atazanavir and raltegravir alone and coadministered appeared safe and well-tolerated.
阿扎那韦联合每日两次300/400mg的拉替拉韦正在作为一种节省利托那韦和核苷类药物的治疗策略进行探索。评估了该联合用药在健康个体中的药代动力学和安全性。
总共22名健康个体在第1 - 5天接受400mg拉替拉韦，在第6 - 12天接受300mg阿扎那韦，在第13 - 26天接受阿扎那韦联合300/400mg拉替拉韦，均每日两次并与清淡食物同服。在第5、12和26天晨服药物12小时后采集系列血样；获取0、2和6小时的安全性评估、临床实验室数据及系列心电图（ECG）。
与单独使用阿扎那韦相比，联合使用拉替拉韦使阿扎那韦的几何平均最大血浆浓度（C(max)）、给药后0至12小时的血浆浓度 - 时间曲线下面积（AUC(₀₋₁₂)）和谷浓度（C(min)）分别降低了11%、17%和29%。联合使用拉替拉韦时阿扎那韦的几何平均C(min)为817ng/ml（范围250 - 1550）。阿扎那韦使拉替拉韦的几何平均C(max)、AUC(₀₋₁₂)和C(min)分别增加了39%、54%和48%。所有不良事件均为轻度或中度。阿扎那韦导致的高胆红素血症和ECG的PR间期增加与阿扎那韦/利托那韦每日一次时相似。未观察到校正QT间期延长。接受阿扎那韦7天后，平均QRS相对于基线增加11.0ms（范围2 - 25）；联合使用拉替拉韦时未观察到QRS进一步增加，且无QRS间期>120ms。单独使用拉替拉韦时未观察到ECG变化。
与单独使用阿扎那韦相比，每日两次联合使用阿扎那韦和300/400mg拉替拉韦降低了阿扎那韦的AUC(₀₋₁₂)和C(min)，相对于单独使用拉替拉韦增加了拉替拉韦的AUC(₀₋₁₂)。单独使用及联合使用阿扎那韦和拉替拉韦似乎安全且耐受性良好。
