Colombo Sara, Telenti Amalio, Buclin Thierry, Furrer Hansjakob, Lee Belle L, Biollaz Jérôme, Decosterd Laurent A
Division of Clinical Pharmacology and Toxicology, University Hospital of Bern, Switzerland.
Ther Drug Monit. 2006 Jun;28(3):332-8. doi: 10.1097/01.ftd.0000211807.74192.62.
Total plasma concentrations are currently measured for therapeutic drug monitoring of HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). However, the pharmacological target of antiretroviral drugs reside inside cells. To study the variability of their cellular accumulation, and to determine to which extent total plasma concentrations (TPC) correlate with cellular concentrations (CC), plasma and peripheral blood mononuclear cells (PBMCs) were simultaneously collected at single random times after drug intake from 133 HIV infected patients. TPC levels were analysed by high-performance liquid chromatography with ultraviolet detection and CC by LC-MS/MS from peripheral blood mononuclear cells. The best correlations between TPC and CC were observed for nelfinavir (NFV, slope=0.93, r=0.85), saquinavir (SQV, slope=0.76, r=0.80) and lopinavir (LPV, slope=0.87, r=0.63). By contrast, TPC of efavirenz (EFV) exhibited a moderate correlation with CC (slope=0.69, r=0.58), while no correlation was found for nevirapine (NVP, slope=-0.3, r=0.1). Interindividual variability in the CC/TPC ratio was lower for protease inhibitors (coefficients of variation 76%, 61%, and 80% for SQV, NFV and LPV, respectively) than for nonnucleoside reverse transcriptase inhibitors (coefficients of variation 101% and 318%, for EFV and NVP). As routine CC measurement raises practical difficulties, well-correlated plasma concentrations (ie, NFV, SQV and LPV) can probably be considered as appropriate surrogates for cellular drug exposure. For drugs such as EFV or NVP, there may be room for therapeutic drug monitoring improvement using either direct CC determination or other predictive factors such as genotyping of transporters or metabolizing enzyme genes.
目前，通过测量血浆总浓度来进行HIV蛋白酶抑制剂（PIs）和非核苷类逆转录酶抑制剂（NNRTIs）的治疗药物监测。然而，抗逆转录病毒药物的药理靶点位于细胞内。为了研究其细胞内蓄积的变异性，并确定血浆总浓度（TPC）与细胞浓度（CC）的相关程度，在133例HIV感染患者服药后的单个随机时间点，同时采集血浆和外周血单核细胞（PBMC）。通过高效液相色谱-紫外检测分析TPC水平，通过液相色谱-串联质谱法分析PBMC中的CC。奈非那韦（NFV，斜率=0.93，r=0.85）、沙奎那韦（SQV，斜率=0.76，r=0.80）和洛匹那韦（LPV，斜率=0.87，r=0.63）的TPC与CC之间的相关性最佳。相比之下，依非韦伦（EFV）的TPC与CC呈中度相关（斜率=0.69，r=0.58），而奈韦拉平（NVP，斜率=-0.3，r=0.1）则未发现相关性。蛋白酶抑制剂的CC/TPC比值的个体间变异性低于非核苷类逆转录酶抑制剂（SQV、NFV和LPV的变异系数分别为76%、61%和80%，EFV和NVP的变异系数分别为101%和318%）。由于常规测量CC存在实际困难，相关性良好的血浆浓度（即NFV、SQV和LPV）可能被视为细胞药物暴露的合适替代指标。对于EFV或NVP等药物，使用直接测定CC或其他预测因素（如转运体或代谢酶基因的基因分型）可能会改善治疗药物监测。
