Section of Infectious Diseases, Imperial College London, United Kingdom.
Kirby Institute, University of New South Wales, Sydney, Australia.
Clin Infect Dis. 2015 Apr 1;60(7):1026-32. doi: 10.1093/cid/ciu976. Epub 2014 Dec 11.
The optimal penetration of antiretroviral agents into the central nervous system may be a balance between providing adequate drug exposure to inhibit human immunodeficiency virus (HIV) replication while avoiding concentrations associated with neuronal toxicities.
Cerebrospinal fluid (CSF) exposure of efavirenz and the metabolites 7-hydroxy (7OH) and 8-hydroxy (8OH) efavirenz were assessed after at least 12 weeks of therapy in HIV-infected subjects randomized to commence antiretroviral regimens containing efavirenz at either 400 mg or 600 mg once daily.
Of 28 subjects (14 and 14 on efavirenz 400 mg and 600 mg, respectively), CSF HIV RNA was undetectable in all. Geometric mean CSF efavirenz, 7OH-, and 8OH-efavirenz concentrations (with 90% confidence intervals [CIs]) for the 400-mg and 600-mg dosing groups were 16.5 (13-21) and 19.5 (15-25) ng/mL; 0.6 (.4-.9) and 0.6 (.4-1) ng/mL; and 5.1 (4.0-6.4) and 3.1 (2.1-4.4) ng/mL, respectively. Efavirenz concentration in CSF was >0.51 ng/mL (proposed CSF 50% maximal inhibitory concentration for wild-type virus) in all subjects, and 8OH-efavirenz concentration in CSF was >3.3 ng/mL (a proposed toxicity threshold) in 11 of 14 and 7 of 14 subjects randomized to the 400 mg and 600 mg doses of efavirenz, respectively. Whereas CSF efavirenz concentration was significantly associated with plasma concentration (P < .001) and cytochrome P450 2B6 genotype (CSF efavirenz GG to GT/TT geometric mean ratio, 0.56 [90% CI, .42-.74]), CSF 8OH-efavirenz concentration was not (P = .242 for association and CSF 8OH-efavirenz GG to GT/TT geometric mean ratio, 1.52 [90% CI, .97-2.36]).
With both doses of efavirenz studied, CSF concentrations were considered adequate to inhibit HIV replication, although concentrations of 8OH-efavirenz were greater than those reportedly associated with neuronal toxicity. CSF exposure of 8OH-efavirenz was not dependent on plasma exposure and, as we postulate, may be subject to saturable pharmacokinetic effects.
NCT01011413.
抗逆转录病毒药物在中枢神经系统中的最佳渗透可能是在提供足够的药物暴露以抑制人类免疫缺陷病毒（HIV）复制与避免与神经元毒性相关的浓度之间取得平衡。
在接受至少 12 周治疗的感染 HIV 的受试者中，评估依非韦伦及其代谢物 7-羟基（7OH）和 8-羟基（8OH）依非韦伦在开始含依非韦伦的抗逆转录病毒方案时的脑脊液（CSF）暴露情况，方案中的依非韦伦剂量分别为每日 400mg 或 600mg。
在 28 名受试者（每日接受依非韦伦 400mg 和 600mg 的各 14 名）中，所有受试者的脑脊液 HIV RNA 均无法检测到。400mg 和 600mg 剂量组的脑脊液依非韦伦、7OH-和 8OH-依非韦伦的几何均数浓度（90%置信区间[CI]）分别为 16.5（13-21）和 19.5（15-25）ng/mL；0.6（0.4-0.9）和 0.6（0.4-1）ng/mL；和 5.1（4.0-6.4）和 3.1（2.1-4.4）ng/mL。所有受试者的脑脊液中依非韦伦浓度均>0.51ng/mL（野生型病毒的建议 CSF 50%最大抑制浓度），在随机分配至依非韦伦 400mg 和 600mg 剂量的 14 名受试者中，有 11 名和 7 名受试者的脑脊液中 8OH-依非韦伦浓度>3.3ng/mL（建议毒性阈值）。虽然脑脊液中依非韦伦浓度与血浆浓度显著相关（P<0.001）和细胞色素 P450 2B6 基因型相关（CSF 依非韦伦 GG 至 GT/TT 几何均数比值，0.56[90%CI，0.42-0.74]），但脑脊液中 8OH-依非韦伦浓度并无显著相关性（与关联的 P=0.242，CSF 8OH-依非韦伦 GG 至 GT/TT 几何均数比值，1.52[90%CI，0.97-2.36]）。
在研究的依非韦伦两种剂量下，脑脊液浓度被认为足以抑制 HIV 复制，尽管 8OH-依非韦伦的浓度高于据报道与神经元毒性相关的浓度。8OH-依非韦伦的脑脊液暴露与血浆暴露无关，正如我们推测的那样，可能受到饱和药代动力学效应的影响。
NCT01011413。
