Kappelhoff Bregt S, van Leth Frank, Robinson Patrick A, MacGregor Thomas R, Baraldi Ezio, Montella Francesco, Uip David E, Thompson Melanie A, Russell Darren B, Lange Joep M A, Beijnen Jos H, Huitema Alwin D R
Department of Pharmacy et Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands.
Antivir Ther. 2005;10(4):489-98.
The relationships between adverse events (AEs) and plasma concentrations of nevirapine (NVP) and efavirenz (EFV) were investigated as part of the large, international, randomized 2NN study.
Treatment-naive, HIV-1-infected patients received NVP (once or twice daily), EFV or their combination, each in combination with lamivudine and stavudine. Blood samples were collected on day 3 and weeks 1, 2, 4, 24 and 48. Concentrations of NVP and EFV were quantitatively assessed by a validated HPLC assay. Individual Bayesian estimates of the area under the plasma concentration-time curve over 24 h (AUC24h), and minimum and maximum plasma concentrations (Cmin and Cmax) as measures for drug exposure of NVP and EFV, were generated using a previously developed population pharmacokinetic model. Pharmacokinetic parameters were compared for patients with and without central nervous system (CNS) and psychiatric AEs, hepatic events, liver enzyme elevations (LEEs) and rash. Furthermore, it was investigated whether a clear cut-off for a pharmacokinetic parameter could be identified above which the incidence of AEs was clearly increased. AEs were also related to demographic parameters and baseline characteristics.
In total, from 1077 patients, NVP (3024 samples) and EFV (1694 samples) plasma concentrations and AE data (825 observations) were available. For all patients Cmin, Cmax and AUC24h were determined. When corrected for known covariates of gender, CD4 cell count at baseline, region, hepatitis coinfection and possible interactions between these factors, no significant associations between AEs and any tested exposure parameter of NVP was observed. Also, no target Cmin value, above which patients were at increased risk for AEs, could be established. On the other hand, geographical region, hepatitis coinfection, CD4 cell count and gender were found to be significantly related with the incidence of CNS and psychiatric AEs, hepatic events, LEEs and rash during the treatment with NVP. The occurrence of elevated liver enzymes during the first 6 weeks in the EFV-containing arm was significantly (P = 0.036) correlated to the exposure of EFV (Cmin). Only hepatitis coinfection impacted on LEEs during the first 6 weeks of treatment. With an EFV Cmin above 2.18 mg/l during the induction phase, patients were 4.4 (range 1.3-15.5) times more at risk for elevated liver enzymes. No other correlations between AEs and EFV pharmacokinetics or patient characteristics could be identified.
Pharmacokinetic parameters of NVP did not have a relationship to AEs in the 2NN trial when corrected for known covariates. The value of periodical drug monitoring of NVP as a way to prevent toxicity is therefore limited. Treating physicians should instead focus on factors that are more predictive of AEs (gender, CD4 count and hepatitis coinfection). High EFV Cmin levels resulted in elevated liver enzyme values during the first 6 weeks of treatment. Regular measurement of EFV levels and liver enzymes at the start of therapy may therefore be advised.
作为大型国际随机2NN研究的一部分，研究了不良事件（AE）与奈韦拉平（NVP）和依非韦伦（EFV）血浆浓度之间的关系。
初治的HIV-1感染患者接受NVP（每日一次或两次）、EFV或它们的联合用药，每种药物均与拉米夫定和司他夫定联合使用。在第3天以及第1、2、4、24和48周采集血样。通过经过验证的高效液相色谱法对NVP和EFV的浓度进行定量评估。使用先前开发的群体药代动力学模型生成24小时血浆浓度-时间曲线下面积（AUC24h）以及NVP和EFV药物暴露量的测量指标——血浆最小和最大浓度（Cmin和Cmax）的个体贝叶斯估计值。比较了有和没有中枢神经系统（CNS）及精神方面AE、肝脏事件、肝酶升高（LEE）和皮疹的患者的药代动力学参数。此外，研究了是否能够确定一个药代动力学参数的明确界限，超过该界限AE的发生率会明显增加。AE还与人口统计学参数和基线特征相关。
总共获得了1077例患者的NVP（3024份样本）和EFV（1694份样本）血浆浓度以及AE数据（825次观察）。测定了所有患者的Cmin、Cmax和AUC24h。在校正了已知的性别、基线CD4细胞计数、地区、合并感染肝炎以及这些因素之间可能的相互作用等协变量后，未观察到AE与NVP的任何测试暴露参数之间存在显著关联。此外，无法确定一个使患者AE风险增加的目标Cmin值。另一方面，发现地理区域、合并感染肝炎、CD4细胞计数和性别与NVP治疗期间CNS及精神方面AE、肝脏事件、LEE和皮疹的发生率显著相关。在含EFV治疗组的前6周内，肝酶升高的发生与EFV暴露量（Cmin）显著相关（P = 0.036）。仅合并感染肝炎影响治疗的前6周内的LEE。在诱导期EFV Cmin高于2.18 mg/l时，患者肝酶升高的风险增加4.4倍（范围为1.3 - 15.5倍）。未发现AE与EFV药代动力学或患者特征之间的其他相关性。
在校正已知协变量后，2NN试验中NVP的药代动力学参数与AE无关。因此，将定期药物监测NVP作为预防毒性的一种方法的价值有限。治疗医生应转而关注更能预测AE的因素（性别、CD4计数和合并感染肝炎）。治疗的前6周内，EFV Cmin水平高会导致肝酶值升高。因此，建议在治疗开始时定期测量EFV水平和肝酶。
