Nettles Richard E, Kieffer Tara L, Parsons Teresa, Johnson James, Cofrancesco Joseph, Gallant Joel E, Carson Kathryn A, Siliciano Robert F, Flexner Charles
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Clin Infect Dis. 2006 Apr 15;42(8):1189-96. doi: 10.1086/501458. Epub 2006 Mar 7.
Effective therapeutic drug monitoring for antiretrovirals requires a better understanding of intraindividual variability in pharmacokinetics.
We determined concentrations of human immunodeficiency virus (HIV) protease and nonnucleoside reverse-transcriptase inhibitors for 10 patients with undetectable plasma HIV RNA levels who had been receiving stable regimens for > or = 11 months. Plasma samples were collected at the same time of day 3 times per week for up to 4 months. Patients were instructed to take their antiretrovirals at the same time every day. Plasma protease and nonnucleoside reverse-transcriptase inhibitor concentrations were determined using high-performance liquid chromatographic methods. Pharmacokinetic variability was expressed as intraindividual percentage coefficient of variation (ICV), which was calculated as the patient's standard deviation divided by the mean drug concentration for that patient.
ICV was determined for 6 drugs for 10 patients, for a total of 17 different patient-drug combinations, using 600 total samples. ICV was unexpectedly high for most patients who were receiving protease inhibitors (ICVs for individual patients taking lopinavir/ritonavir were 24%, 33%, 51%, and 92%; for patients taking nelfinavir/M8 metabolite, they were 30%/44% and 39%/54%; for patients taking ritonavir, they were 34% and 43%; for patients taking saquinavir, they were 52% and 55%). ICVs for patients receiving nonnucleoside reverse-transcriptase inhibitors were lower (for patients receiving efavirenz, they were 7%, 13%, 29%, and 51%; for a patient receiving nevirapine, it was 25%). The median ICV for all patients receiving protease inhibitors (n = 12) was 43.5%, and for all patients receiving nonnucleoside reverse-transcriptase inhibitors (n = 5), the median ICV was 25%.
Intraindividual variability in concentrations of antiretrovirals was surprisingly high in virologically suppressed patients. Possible contributors include food effects, concomitant use of prescription and herbal medications, assay variability, or medication timing, which was assessed by self-report. High intraindividual pharmacokinetic variability may limit the utility of single measurements in therapeutic drug monitoring for some antiretroviral agents.
对抗逆转录病毒药物进行有效的治疗药物监测需要更好地了解药代动力学的个体内变异性。
我们测定了10例血浆中人类免疫缺陷病毒（HIV）RNA水平检测不到的患者的HIV蛋白酶和非核苷类逆转录酶抑制剂浓度，这些患者接受稳定治疗方案已达11个月及以上。每周3次在一天中的同一时间采集血浆样本，持续4个月。指导患者每天在同一时间服用抗逆转录病毒药物。使用高效液相色谱法测定血浆蛋白酶和非核苷类逆转录酶抑制剂浓度。药代动力学变异性以个体内变异系数百分比（ICV）表示，计算方法为患者的标准差除以该患者的药物平均浓度。
使用总共600个样本，对10例患者的6种药物进行了ICV测定，共有17种不同的患者 - 药物组合。对于大多数接受蛋白酶抑制剂的患者，ICV出乎意料地高（服用洛匹那韦/利托那韦的个体患者的ICV分别为24%、33%、51%和92%；服用奈非那韦/M8代谢物的患者，ICV分别为30%/44%和39%/5%；服用利托那韦的患者，ICV分别为34%和43%；服用沙奎那韦的患者，ICV分别为52%和55%）。接受非核苷类逆转录酶抑制剂的患者的ICV较低（接受依非韦伦的患者，ICV分别为7%、13%、29%和51%；接受奈韦拉平的1例患者，ICV为25%）。所有接受蛋白酶抑制剂的患者（n = 12）的ICV中位数为43.5%，所有接受非核苷类逆转录酶抑制剂的患者（n = 5）的ICV中位数为25%。
在病毒学抑制的患者中，抗逆转录病毒药物浓度的个体内变异性高得出奇。可能的影响因素包括食物效应、同时使用处方药和草药、检测变异性或用药时间（通过自我报告评估）。高个体内药代动力学变异性可能会限制单次测量在某些抗逆转录病毒药物治疗药物监测中的效用。
