Fabbiani Massimiliano, Di Giambenedetto Simona, Bracciale Laura, Bacarelli Alessandra, Ragazzoni Enzo, Cauda Roberto, Navarra Pierluigi, De Luca Andrea
Institute of Clinical Infectious Diseases, Catholic University, Rome, Italy.
J Antimicrob Chemother. 2009 Jul;64(1):109-17. doi: 10.1093/jac/dkp132. Epub 2009 Apr 27.
To assess the inter-individual and intra-individual plasma concentration variabilities of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in routine clinical practice and to investigate their relationships with virological failure.
We retrospectively enrolled HIV-infected patients undergoing therapeutic drug monitoring (TDM) of NNRTIs and PIs during routine outpatient visits. Plasma drug concentrations were measured by HPLC-UV and were considered therapeutic if above the proposed minimum efficacy trough concentration. Inter-individual and intra-individual variabilities were evaluated through the coefficient of variation (CV).
A total of 457 PI and 172 NNRTI plasma concentrations were measured from 363 patients (HIV-RNA <50 copies/mL in 70.8%, median CD4 count 434 cells/mm(3)). NNRTIs showed less inter-individual (CV(inter) 54.8% versus 84.3%) and intra-individual (CV(intra) 19.0% versus 38.1%) pharmacokinetic variabilities than PIs. Intra-individual variability was constantly lower than inter-individual variability for each drug. Subtherapeutic drug concentrations were observed in 106 samples (16.9%). Older age (P = 0.020) and higher viral load (P = 0.013) were associated with subtherapeutic levels. Patients with therapeutic levels had a viral load of <50 copies/mL more frequently than those with subtherapeutic levels (74.8% versus 63.2%, P = 0.020). The estimated proportion with virological failure at 24 weeks was 0.21 in patients with suboptimal baseline drug levels and 0.08 in those with optimal levels (P < 0.001). In the multivariate analysis, therapeutic drug levels showed an independent negative association with virological failure (P = 0.004).
A wide inter-individual and limited intra-individual pharmacokinetic variabilities, together with the demonstration of a concentration-response relationship, suggest that TDM is a useful tool for the clinical management of patients treated with NNRTIs or PIs.
评估非核苷类逆转录酶抑制剂（NNRTIs）和蛋白酶抑制剂（PIs）在常规临床实践中的个体间和个体内血浆浓度变异性，并研究它们与病毒学失败的关系。
我们回顾性纳入了在常规门诊就诊期间接受NNRTIs和PIs治疗药物监测（TDM）的HIV感染患者。通过高效液相色谱-紫外检测法测定血浆药物浓度，如果高于建议的最低有效谷浓度则视为治疗有效。通过变异系数（CV）评估个体间和个体内变异性。
共测量了363例患者的457份PI和172份NNRTI血浆浓度（70.8%的患者HIV-RNA<50拷贝/mL，CD4细胞计数中位数为434个/mm³）。与PIs相比，NNRTIs的个体间（CV(inter) 54.8%对84.3%）和个体内（CV(intra) 19.0%对38.1%）药代动力学变异性较小。每种药物的个体内变异性始终低于个体间变异性。在106份样本（16.9%）中观察到药物浓度低于治疗水平。年龄较大（P = 0.020）和病毒载量较高（P = 0.013）与低于治疗水平相关。治疗水平的患者病毒载量<50拷贝/mL的频率高于低于治疗水平的患者（74.8%对63.2%，P = 0.020）。基线药物水平不理想的患者在24周时病毒学失败的估计比例为0.21，而基线水平理想的患者为0.08（P < 0.001）。在多变量分析中，治疗药物水平与病毒学失败呈独立负相关（P = 0.004）。
个体间药代动力学变异性大而个体内变异性有限，以及浓度-反应关系的证明，表明TDM是用于接受NNRTIs或PIs治疗患者临床管理的有用工具。
