*Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome; †Department of Pharmacology, Fondazione IRCCS, Policlinico San Matteo, Pavia; ‡Department of Infectious Diseases and Hepatology, Azienda Ospedaliera di Parma, Parma; §Division of Infectious Disease, University of Bari, Bari; ¶Division of Infectious Diseases, Department of Experimental Medicine, University of Perugia, Perugia; ‖Infectious Diseases Unit, Pistoia Hospital, Pistoia; **Infectious Disease Unit, Pescara General Hospital, Pescara; ††Department of Internal Medicine, Geriatrics and Nephrologic Diseases, Section of Infectious Diseases, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, Bologna; ‡‡Clinic of Infectious Diseases, Ospedali Riuniti, Marche Polytechnic University, Ancona; and §§Department of Infectious Diseases, S. Anna Hospital, Ferrara, Italy.
Ther Drug Monit. 2013 Dec;35(6):785-90. doi: 10.1097/FTD.0b013e31829ad690.
There is no consensus on darunavir (DRV) target levels in plasma for clinical use, and information about variability in plasma concentrations is limited.
: To investigate the variability in DRV plasma trough concentrations in the clinical setting, evaluating interindividual and intraindividual variabilities of plasma drug levels among HIV-infected patients receiving ritonavir (RTV)-boosted DRV (DRV/r) within salvage regimens, and evaluate the potential correlation between variability and virological response.
Sixty-two patients taking DRV/r (600/100 mg twice a day) were evaluated for trough plasma concentrations and immunovirological parameters after 6 months from the start of the regimen. A subgroup of patients (n = 21) was also evaluated for intraindividual variability (expressed as coefficient of variation) on 2 samples taken at different time points. Drug concentrations were assayed by high-performance liquid chromatography with ultraviolet detection, and the values were expressed as medians with interquartile range (IQR). Genotypic sensitivity score and genotypic inhibitory quotient were calculated.
DRV/r was used with a median of 3 other antiretroviral drugs (raltegravir use 88.7%). Median plasma concentrations were 3.22 mcg/mL (IQR, 2.04-5.69) for DRV and 0.44 mcg/mL (IQR, 0.21-0.70) for RTV. Both drugs showed a high interindividual variability in plasma concentrations (61% and 99.3%, respectively). Only 3 patients (4.8%) had undetectable DRV plasma levels. DRV plasma concentrations showed a significant positive correlation with age (r = 0.298, P = 0.019), but no significant correlation between DRV genotypic inhibitory quotient and HIV-RNA plasma levels (P = 0.614) was found. Intraindividual coefficients of variation were 58.4% for DRV and 47.1% for RTV. Patients with undetectable HIV-RNA showed a trend for lower intraindividual coefficients of variation compared with patients with detectable HIV-RNA (55.9% versus 83.8%, P = 0.156). No major interaction effects with other antiretroviral drugs were found.
In a context of salvage therapy, both DRV and RTV plasma levels showed high interindividual and intraindividual variabilities. Lower intraindividual variability could be beneficial in maintaining viral suppression.
目前尚无用于临床的达芦那韦（DRV）血浆靶标水平的共识，且关于血浆浓度变异性的信息有限。
探究临床环境下 DRV 血药谷浓度的变异性，评估接受利托那韦（RTV）增强的 DRV（DRV/r）挽救治疗方案的 HIV 感染患者个体间和个体内的血浆药物水平差异，并评估变异性与病毒学应答之间的潜在相关性。
62 例接受 DRV/r（600/100mg 每日两次）治疗的患者在开始治疗后 6 个月评估血药谷浓度和免疫病毒学参数。其中一个亚组（n=21）还在不同时间点采集 2 个样本，评估个体内变异性（以变异系数表示）。通过高效液相色谱法-紫外检测法测定药物浓度，用中位数和四分位间距（IQR）表示。计算基因型敏感性评分和基因型抑制商。
DRV/r 与中位数为 3 种其他抗逆转录病毒药物（阿扎那韦使用率 88.7%）联合使用。DRV 的中位血浆浓度为 3.22 mcg/mL（IQR，2.04-5.69），RTV 的中位血浆浓度为 0.44 mcg/mL（IQR，0.21-0.70）。两种药物的血浆浓度均表现出较高的个体间变异性（分别为 61%和 99.3%）。仅 3 例患者（4.8%）的 DRV 血药谷浓度无法检测到。DRV 血浆浓度与年龄呈显著正相关（r=0.298，P=0.019），但未发现 DRV 基因型抑制商与 HIV-RNA 血浆水平之间存在显著相关性（P=0.614）。DRV 和 RTV 的个体内变异系数分别为 58.4%和 47.1%。无法检测到 HIV-RNA 的患者的个体内变异系数低于可检测到 HIV-RNA 的患者（55.9%比 83.8%，P=0.156），但无显著差异。未发现与其他抗逆转录病毒药物存在主要的相互作用效应。
在挽救治疗背景下，DRV 和 RTV 的血浆水平均表现出较高的个体间和个体内变异性。较低的个体内变异性可能有利于维持病毒抑制。
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