Zhou X J, Havlir D V, Richman D D, Acosta E P, Hirsch M, Collier A C, Tebas P, Sommadossi J P
Department of Clinical Pharmacology, Birmingham Veteran Affairs Medical Center, Center for AIDS Research, University of Alabama at Birmingham School of Medicine, USA.
AIDS. 2000 Dec 22;14(18):2869-76. doi: 10.1097/00002030-200012220-00008.
To evaluate plasma population pharmacokinetics and penetration into cerebrospinal fluid (CSF) by indinavir (IDV) in HIV-infected individuals receiving IDV, zidovudine and lamivudine.
Plasma population pharmacokinetic analysis was performed on 805 IDV plasma values from 171 patients, using a non-linear mixed-effects modeling approach. CSF data from 19 patients were analyzed using an individual approach.
Mean individual Bayesian estimates for oral clearance (CL) and volume of distribution (V) by the final model that incorporated interoccasion variability were 0.75 l/h per kg [coefficient of variation (CV) 54.8%] and 1.74 l/kg (CV 82.7%), respectively. Mean model-predicted plasma IDV level at 8 h, maximal level, area under the plasma level-time curve up to 8 h and plasma half-life were 0.42 micromol/l (CV 57.5%), 9.51 micromol/l (CV 47.3%), 29.56 micromol/l x h (CV 46.9%) and 1.50 h (CV 20.9%), respectively. The mean IDV CSF level was 0.11 micromol/l (CV 49.7%) and the mean CSF:plasma concentration ratio was 0.017.
Population estimates of pharmacokinetic parameters of IDV and its CSF penetration were in excellent agreement with previously reported data from individual analyses. Intraindividual interoccasion variability of IDV pharmacokinetics was estimated to be of similar order of magnitude to its interindividual variability, which may affect response to long-term antiretroviral therapy involving IDV. CSF levels of IDV exceeded its in vitro 95% inhibitory concentration of HIV replication. Given that CSF is virtually free of protein, viral suppression in the central nervous system should be achievable with an IDV-containing regimen.
评估茚地那韦(IDV)在接受IDV、齐多夫定和拉米夫定治疗的HIV感染个体中的血浆群体药代动力学及脑脊液(CSF)渗透情况。
采用非线性混合效应建模方法,对171例患者的805个IDV血浆值进行血浆群体药代动力学分析。对19例患者的CSF数据采用个体分析方法进行分析。
纳入给药间隔间变异性的最终模型得出的口服清除率(CL)和分布容积(V)的平均个体贝叶斯估计值分别为每千克0.75升/小时[变异系数(CV)54.8%]和1.74升/千克(CV 82.7%)。模型预测的8小时平均血浆IDV水平、最高水平、8小时内血浆水平-时间曲线下面积和血浆半衰期分别为0.42微摩尔/升(CV 57.5%)、9.51微摩尔/升(CV 47.3%)、29.56微摩尔/升·小时(CV 46.9%)和1.50小时(CV 20.9%)。IDV的平均CSF水平为0.11微摩尔/升(CV 49.7%),平均CSF:血浆浓度比为0.017。
IDV药代动力学参数的群体估计值及其CSF渗透情况与先前个体分析报告的数据高度一致。IDV药代动力学的个体内给药间隔间变异性估计与个体间变异性处于相似的数量级,这可能会影响对包含IDV的长期抗逆转录病毒治疗的反应。IDV的CSF水平超过了其体外对HIV复制的95%抑制浓度。鉴于CSF几乎不含蛋白质,含IDV方案应可实现中枢神经系统中的病毒抑制。