Pham Paul A, Flexner Charles, Parsons Teresa, Vasist Lakshmi, Fuchs Edward, Carson Kathryn, Agarwala Sangeeta, Barditch-Crovo Patricia
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Acquir Immune Defic Syndr. 2007 Jun 1;45(2):201-5. doi: 10.1097/QAI.0b013e318050d632.
The combination of lopinavir/ritonavir (LPV/r) and atazanavir (ATV) with nucleoside reverse transcriptase inhibitors has been used as a salvage regimen in HIV-infected patients. Because these agents, to various degrees, are substrates, inducers, and inhibitors of CYP450 3A4, there is concern for alterations in the pharmacokinetics (PK) of these combined agents.
To determine the steady-state PK interactions between ATV, ritonavir (RTV), and LPV when coadministered at various doses.
HIV-negative subjects (n = 15) received a combination of ATV, RTV, and LPV in the following sequence: period I (days 1-10), ATV/r at a dose of 300/100 mg once daily; period II (days 11-24), ATV at a dose of 300 mg once daily plus LPV/r at a dose of 400/100 mg twice daily; and period III (days 25-34), ATV/r at a dose of 300/100 mg once daily plus LPV/r at a dose of 400/100 mg twice daily. Intensive PK analysis was performed on days 10, 24, and 34. A paired t test was used for pairwise comparison of log-transformed PK parameters of ATV and LPV.
In period II, the ATV minimum concentration (Cmin) geometric mean (GM) was higher compared with period I (GM: 0.75 vs. 0.51 microg/mL, geometric mean ratio (GMR) = 1.45, 90% confidence interval [CI]: 1.19 to 1.77; P = 0.006). The ATV area under the concentration-time curve from dosing to 24 hours after the dose (AUC0-24; GM: 36.40 vs. 39.62 microg.h/mL, GMR = 0.92, 90% CI: 0.80 to 1.05; P = 0.28) did not differ, however. The addition of 100 mg of RTV in period III did not significantly increase the ATV Cmin (GM: 0.84 vs. 0.75 microg/mL, GMR = 1.13, 90% CI: 0.91 to 1.40; P = 0.34) or ATV AUC0-24 (GM: 39.59 vs. 36.40 microg.h/mL, GMR = 1.09, 90% CI: 0.99 to 1.20; P = 0.14) compared with period II. The additional RTV in period III resulted in a higher LPV Cmin (GM: 5.12 vs. 3.99 microg/mL, GMR = 1.28, 90% CI: 1.15 to 1.43; P = 0.001), but the LPV areas under the concentration-time curve from dosing to 12 hours after the dose and maximum concentration were not significantly different. LPV PK parameters in period II were comparable to those of historical control subjects receiving LPV/r at a dose of 400/100 mg twice daily. All studied regimens were well tolerated. Indirect hyperbilirubinemia was the only grade 3 and 4 abnormality reported, which was expected given that ATV competitively inhibits UGTIA1 and has not been shown to result in other hepatic abnormalities.
The combination of ATV at a dose of 300 mg once daily plus LPV/r at a dose of 400/100 mg twice daily resulted in an appropriate PK profile for ATV and LPV and could be further evaluated in treatment-experienced patients requiring a dual-boosted protease inhibitor-containing regimen.
洛匹那韦/利托那韦（LPV/r）与阿扎那韦（ATV）联合核苷类逆转录酶抑制剂已被用作HIV感染患者的挽救治疗方案。由于这些药物在不同程度上是细胞色素P450 3A4的底物、诱导剂和抑制剂，因此人们担心这些联合药物的药代动力学（PK）会发生改变。
确定不同剂量共同给药时ATV、利托那韦（RTV）和LPV之间的稳态PK相互作用。
HIV阴性受试者（n = 15）按以下顺序接受ATV、RTV和LPV联合用药：第I阶段（第1 - 10天），ATV/r剂量为300/100 mg，每日1次；第II阶段（第11 - 24天），ATV剂量为300 mg，每日1次，加LPV/r剂量为400/100 mg，每日2次；第III阶段（第25 - 34天），ATV/r剂量为300/100 mg，每日1次，加LPV/r剂量为400/100 mg，每日2次。在第10、24和34天进行强化PK分析。采用配对t检验对ATV和LPV的对数转换PK参数进行两两比较。
在第II阶段，与第I阶段相比，ATV最低浓度（Cmin）几何均值（GM）更高（GM：0.75 vs. 0.51 μg/mL，几何均值比（GMR） = 1.45，90%置信区间[CI]：1.19至1.77；P = 0.006）。然而，给药后至24小时的浓度 - 时间曲线下面积（AUC0 - 24；GM：36.40 vs. 39.62 μg·h/mL，GMR = 0.92，90% CI：0.80至1.05；P = 0.28）并无差异。第III阶段添加100 mg RTV后，与第II阶段相比，ATV Cmin（GM：0.84 vs. 0.75 μg/mL，GMR = 1.13，90% CI：0.91至1.40；P = 0.34）或ATV AUC0 - 24（GM：39.59 vs. 36.40 μg·h/mL，GMR = 1.09，90% CI：0.99至1.20；P = 0.14）无显著增加。第III阶段额外添加的RTV使LPV Cmin更高（GM：5.12 vs. 3.99 μg/mL，GMR = 1.28，90% CI：1.15至1.43；P = 0.001），但给药后至12小时的浓度 - 时间曲线下面积和LPV最高浓度并无显著差异。第II阶段LPV的PK参数与每日2次接受400/100 mg LPV/r的历史对照受试者相当。所有研究方案耐受性良好。间接高胆红素血症是唯一报告的3级和4级异常，鉴于ATV竞争性抑制UGTIA1且未显示会导致其他肝脏异常，这是预期的。
每日1次300 mg ATV加每日2次400/100 mg LPV/r的联合用药方案使ATV和LPV具有合适的PK特征，对于需要含双重增强蛋白酶抑制剂方案的经治患者可进一步评估。
