IAME, UMR 1137, Université Paris Diderot, Sorbonne Paris Cité and INSERM, Paris, France.
AP-HP, Hôpital Bichat-Claude Bernard, Laboratoire de Pharmacologie-Toxicologie, Paris, France.
J Antimicrob Chemother. 2018 Aug 1;73(8):2120-2128. doi: 10.1093/jac/dky193.
In the ANRS 165 DARULIGHT study (NCT02384967) carried out in HIV-infected patients, the use of a darunavir/ritonavir-containing regimen with a switch to a reduced dose of darunavir maintained virological efficacy (≤50 copies/mL) for 48 weeks with a good safety profile.
To assess the total and unbound blood plasma pharmacokinetics of darunavir and associated antiretrovirals, and their penetration into semen before and after dose reduction.
Patients receiving a darunavir/ritonavir (800/100 mg q24h)-containing regimen for >6 months with plasma HIV-RNA ≤50 copies/mL for >12 months were switched to 400/100 mg darunavir/ritonavir q24h at week 0. A 24 h intensive pharmacokinetic blood sampling and a trough seminal sampling were performed before (week 0) and after (week 12) dose reduction. Individual pharmacokinetic parameter estimates were obtained using non-linear mixed-effect modelling for darunavir/ritonavir in blood plasma and used to test for bioequivalence, whereas darunavir/ritonavir in seminal plasma and NRTIs were analysed using a non-compartmental approach.
Fifteen patients completed the intensive pharmacokinetic analysis. There was no significant decrease in total and unbound darunavir blood plasma exposure despite a 50% decrease in darunavir daily dose from 800 to 400 mg (AUC0-24 = 65 563 versus 52 518 ng·h/mL; P = 0.25). A decrease in apparent oral clearance (CL/F) of both darunavir and ritonavir at week 12 suggests a modification of the initial darunavir/ritonavir daily dose balance (800/100 to 400/100 mg), in favour of a reduced inducer effect of darunavir on cytochrome P450 and efflux transporters compared with the standard dose.
在 ANRS 165 DARULIGHT 研究（NCT02384967）中，对感染 HIV 的患者进行了一项研究，结果表明，使用含达芦那韦/利托那韦的方案，并将达芦那韦的剂量减少至原来的一半，可在 48 周内保持病毒学疗效（≤50 拷贝/mL），且安全性良好。
评估达芦那韦及其相关抗逆转录病毒药物的总血浆和游离血浆药代动力学，以及剂量减少前后进入精液中的药物渗透情况。
接受达芦那韦/利托那韦（800/100mg，每 24 小时 1 次）治疗方案超过 6 个月且血浆 HIV-RNA＜50 拷贝/mL 超过 12 个月的患者，在第 0 周时转换为 400/100mg 达芦那韦/利托那韦，每 24 小时 1 次。在剂量减少前（第 0 周）和后（第 12 周）进行 24 小时密集药代动力学采血和精液低谷采样。使用非线性混合效应模型对达芦那韦/利托那韦在血浆中的个体药代动力学参数进行估算，并进行生物等效性检验，而达芦那韦/利托那韦在精液中的浓度和 NRTIs 则采用非房室模型进行分析。
15 名患者完成了密集的药代动力学分析。尽管达芦那韦的日剂量从 800mg 减少到 400mg，减少了 50%，但总血浆暴露和游离达芦那韦血浆暴露并没有显著下降（AUC0-24=65563 与 52518ng·h/mL；P=0.25）。第 12 周时，达芦那韦和利托那韦的表观口服清除率（CL/F）下降，提示初始达芦那韦/利托那韦日剂量平衡（800/100 至 400/100mg）发生改变，与标准剂量相比，达芦那韦对细胞色素 P450 和外排转运体的诱导作用降低。
