University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, San Diego, CA, USA.
J Antimicrob Chemother. 2011 Feb;66(2):354-7. doi: 10.1093/jac/dkq434. Epub 2010 Nov 23.
HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF.
CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF).
Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2-17] of therapy were 2145 ng/mL in plasma (IQR 1384-4423) and 13.9 ng/mL in CSF (IQR 4.1-21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026-0.0076; n = 69). The CSF/IC(50) ratio was 26 (IQR 8-41) using the published IC(50) for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC(50) for wild-type HIV.
Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC(50) in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.
尽管使用了高效抗逆转录病毒疗法（ART），但与 HIV 相关的神经认知障碍仍然很常见。由于抗病毒药物在中枢神经系统中的分布不佳，导致病毒持续复制，这可能会增加 HIV 相关神经认知障碍的风险。本研究的目的是确定常用抗逆转录病毒药物依非韦伦进入脑脊液（CSF）的穿透情况。
CHARTER 是一项正在进行的北美多中心观察性研究，旨在确定 ART 对与 HIV 相关的神经疾病的影响。2003 年 9 月至 2007 年 7 月期间，每位接受依非韦伦治疗的受试者在彼此 1 小时内抽取了单次随机血浆和 CSF 样本。使用高效液相色谱法或高效液相色谱/质谱法对样本进行检测，检测限为 39ng/mL（血浆）和 <0.1ng/mL（CSF）。
80 名参与者（年龄 44±8 岁；79±15kg；20 名女性）在给药后 12.5±5.4 小时抽取样本。在中位数为 7 个月（IQR 2-17）的治疗后，血浆中依非韦伦的中位数浓度为 2145ng/mL（IQR 1384-4423），CSF 中的浓度为 13.9ng/mL（IQR 4.1-21.2）。在彼此 1 小时内抽取的配对样本中，CSF 与血浆浓度的比值为 0.005（IQR 0.0026-0.0076；n=69）。使用已发表的野生型 HIV 的 IC50（0.51ng/mL），CSF/IC50 比值为 26（IQR 8-41）。有 2 份 CSF 样本的浓度低于野生型 HIV 的依非韦伦 IC50。
CSF 中的依非韦伦浓度仅为血浆浓度的 0.5%，但在几乎所有个体中均超过野生型的 IC50。由于 CSF 药物浓度反映了脑间质液中的浓度，因此依非韦伦在脑组织中达到了治疗浓度。
