Veldkamp A I, van Heeswijk R P, Mulder J W, Meenhorst P L, Hoetelmans R M, Lange J M, Beijnen J H
Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands.
Ther Drug Monit. 2001 Dec;23(6):606-11. doi: 10.1097/00007691-200112000-00002.
The objective of this study was to develop and validate a limited sampling strategy (LSS) that allows accurate and precise estimation of the area under the plasma concentration versus time curve (AUC) of nevirapine, when used in the licensed dosage of 200 mg twice daily. Because nevirapine has a long plasma elimination half-life and the plasma concentration shows little variation within the 12-hour dosing interval, the authors also wanted to explore whether a time frame exists for which a single-sample LSS can be applied. Twenty HIV-1-infected individuals receiving steady-state treatment with nevirapine (200 mg twice daily) were enrolled. For the development of the LSS, 10 patients were randomly selected from the study population (index set). The pharmacokinetic results from the other 10 patients (validation set) were used for prospective validation of the proposed LSS. Blood samples were obtained before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after ingestion. The relationship between the nevirapine concentration at each of the designated time points and the AUC 12h was evaluated by univariate and multivariate linear regression analysis. At each of the sampling times, a strong correlation was observed between the nevirapine concentration and the corresponding AUC 12h (r > 0.97). This allows for a single-sample LSS, using any time point during the dosing interval. When a single equation is preferred, the concentration of nevirapine in a random sample drawn 2 to 4 hours after ingestion of nevirapine (C 2-4h; in microg/mL) can be used for accurate estimation of the AUC 12h (in h x microg/mL) by using the equation AUC 12h (h x microg/mL) = 11.699 (h) x C 2-4h (microg/mL) - 4.381 (h x microg/mL). Validation of this equation resulted in a predicted AUC 12h that was nonbiased and very precise. These data show that the nevirapine concentration at each time point during the dosing interval can be used for accurate estimation of the AUC 12h. Even more practical, a sample obtained at any time between 2 and 4 hours after ingestion of nevirapine can be used. The authors therefore conclude that less intensive sampling (i.e., a single sample) can readily be used to assess the AUC 12h of nevirapine when used in a dosage of 200 mg twice daily.
本研究的目的是开发并验证一种有限采样策略（LSS），该策略能够在奈韦拉平按每日两次、每次200 mg的许可剂量使用时，准确且精确地估算其血浆浓度-时间曲线下面积（AUC）。由于奈韦拉平具有较长的血浆消除半衰期，且血浆浓度在12小时给药间隔内变化不大，作者还想探索是否存在一个时间段可应用单样本LSS。招募了20名接受奈韦拉平（每日两次，每次200 mg）稳态治疗的HIV-1感染个体。为开发LSS，从研究人群（索引集）中随机选择10名患者。另外10名患者（验证集）的药代动力学结果用于对所提出的LSS进行前瞻性验证。在服药前以及服药后0.5、1、1.5、2、2.5、3、3.5、4、5、6、8、10和12小时采集血样。通过单变量和多变量线性回归分析评估每个指定时间点的奈韦拉平浓度与AUC12h之间的关系。在每个采样时间，均观察到奈韦拉平浓度与相应的AUC12h之间存在强相关性（r > 0.97）。这使得可以在给药间隔内的任何时间点采用单样本LSS。当更倾向于使用单个方程时，在服用奈韦拉平后2至4小时采集的随机样本中的奈韦拉平浓度（C2 - 4h；单位为μg/mL）可用于通过以下方程准确估算AUC12h（单位为h x μg/mL）：AUC12h（h x μg/mL） = 11.699（h）× C2 - 4h（μg/mL） - 4.381（h x μg/mL）。对该方程的验证得出的预测AUC12h无偏差且非常精确。这些数据表明，给药间隔内每个时间点的奈韦拉平浓度均可用于准确估算AUC12h。更具实用性的是，服用奈韦拉平后2至4小时之间的任何时间采集的样本均可使用。因此，作者得出结论，当奈韦拉平按每日两次、每次200 mg的剂量使用时，可轻松采用强度较低的采样（即单样本）来评估其AUC12h。
