Boffito Marta, Hoggard Patrick G, Lindup W Edward, Bonora Stefano, Sinicco Alessandro, Khoo Saye H, Di Perri Giovanni, Back David J
Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
Ther Drug Monit. 2004 Feb;26(1):35-9. doi: 10.1097/00007691-200402000-00008.
Most protease inhibitors available for the treatment of human immunodeficiency virus (HIV) infection are highly bound to plasma proteins, mainly alpha-1 acid glycoprotein. Therapeutic drug monitoring (TDM) of total protease inhibitor (PI) concentrations has been increasing in the past few years; however, the pharmacological activity of the PIs is dependent on unbound drug entering cells harboring HIV. There is little information available on unbound drug concentrations of these drugs in vivo. The aim of the study was to measure unbound plasma concentrations of lopinavir (LPV) and to relate them to the total plasma concentrations to establish the unbound percentage in vivo during a full dosage interval. A pharmacokinetic study was performed in HIV-infected subjects (n = 23; median CD4 cell count = 290 x 10(6) cells x L(-1); viral load < 50 copies x mL(-1)) treated with a LPV/ritonavir (RTV)-containing regimen. Ultrafiltration was used to separate unbound LPV in all plasma samples (n = 115). Equilibrium dialysis was also used to compare with ultrafiltration measurements in 10/23 patients at baseline and 2 hours after drug intake. Total and unbound LPV concentrations were measured by a fully validated method using high-performance liquid chromatography-mass spectometry (HPLC-MS/MS). Based on a comparison of AUC(unbound)AUC(total), the mean (+/- SD) unbound percentage of LPV from all the samples studied (n = 115) was 0.92% (+/- 0.22) when measured with ultrafiltration and 1.32% (+/- 0.44) when equilibrium dialysis was used (n = 20), showing a higher drug recovery (P = 0.048). The unbound percentage of LPV was found to be significantly higher after 2 h than at baseline (P < 0.05 with both methods), suggesting a concentration-dependent binding of LPV that has not been observed in vitro. However, the clinical significance of such phenomena is still unclear.
大多数可用于治疗人类免疫缺陷病毒（HIV）感染的蛋白酶抑制剂与血浆蛋白高度结合，主要是与α-1酸性糖蛋白结合。在过去几年中，对总蛋白酶抑制剂（PI）浓度的治疗药物监测（TDM）一直在增加；然而，PI的药理活性取决于未结合的药物进入携带HIV的细胞。关于这些药物在体内的未结合药物浓度的信息很少。该研究的目的是测量洛匹那韦（LPV）的未结合血浆浓度，并将其与总血浆浓度相关联，以确定在整个给药间隔期间体内的未结合百分比。对接受含LPV/利托那韦（RTV）方案治疗的HIV感染受试者（n = 23；CD4细胞计数中位数 = 290×10⁶个细胞/L；病毒载量 < 50拷贝/mL）进行了一项药代动力学研究。使用超滤法分离所有血浆样本（n = 115）中的未结合LPV。还使用平衡透析法在10/23例患者的基线和服药后2小时与超滤测量结果进行比较。使用高效液相色谱-质谱法（HPLC-MS/MS）通过完全验证的方法测量总LPV浓度和未结合LPV浓度。基于AUC（未结合）/AUC（总）的比较，在用超滤法测量时，所有研究样本（n = 115）中LPV的平均（±标准差）未结合百分比为0.92%（±0.22），使用平衡透析法时为1.32%（±0.44）（n = 20），表明药物回收率更高（P = 0.048）。发现LPV的未结合百分比在2小时后显著高于基线（两种方法均P < 0.05），表明LPV存在浓度依赖性结合，这在体外尚未观察到。然而，这种现象的临床意义仍不清楚。
