Elsherbiny Doaa, Cohen Karen, Jansson Britt, Smith Peter, McIlleron Helen, Simonsson Ulrika S H
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, P.O. Box 591 BMC, 75124 Uppsala, Sweden.
Eur J Clin Pharmacol. 2009 Jan;65(1):71-80. doi: 10.1007/s00228-008-0481-y. Epub 2008 Aug 27.
The aim was to develop a model to describe the population pharmacokinetics of nevirapine in South African human immunodeficiency virus (HIV)-infected patients who were taking nevirapine-based antiretroviral therapy concomitantly or in the absence of rifampicin-based tuberculosis therapy.
Patients were divided into two groups: (1) patients receiving nevirapine-containing antiretroviral regimen (200 mg twice daily) and continuation phase rifampicin-containing tuberculosis therapy (n = 27) in whom blood samples were obtained before and not less than 14 days after they completed tuberculosis therapy; (2) patients without tuberculosis who were receiving a nevirapine-containing antiretroviral regimen for at least 3 weeks (n = 26). The population pharmacokinetics of nevirapine was described using nonlinear mixed effects modelling with NONMEM software. Based on the developed model, plasma concentration profiles after 300, 400 and 500 mg of nevirapine twice daily were simulated.
Concomitant administration of rifampicin increased nevirapine oral clearance (CL/F) by 37.4% and reduced the absorption rate constant (k(a)) by almost sixfold. Rifampicin reduced the nevirapine average minimum concentration by 39%. Simulated doses of 300 mg twice daily elevated nevirapine concentrations above subtherapeutic levels in most patients, with minimum exposure above the recommended maximum concentration. The area under the concentration-time curve of 12-hydroxynevirapine was not different in the presence of rifampicin. 2-, 3- and 8-Hydroxynevirapine were not detectable (LLOQ = 0.025 mg/L).
The developed model adequately describes nevirapine population pharmacokinetics in a South African population when taken with/and in the absence of rifampicin treatment. The simulations suggest that an increased dose of 300 mg twice daily would achieve adequate nevirapine concentrations in most patients during rifampicin-containing treatment for tuberculosis.
本研究旨在建立一个模型，以描述在南非接受基于奈韦拉平的抗逆转录病毒治疗的人类免疫缺陷病毒（HIV）感染患者中，无论是否同时接受基于利福平的抗结核治疗时奈韦拉平的群体药代动力学。
患者被分为两组：（1）接受含奈韦拉平的抗逆转录病毒方案（每日两次，每次200毫克）并在继续期接受含利福平的抗结核治疗的患者（n = 27），在完成抗结核治疗前及治疗结束后不少于14天采集血样；（2）未患结核病且接受含奈韦拉平的抗逆转录病毒方案至少3周的患者（n = 26）。使用NONMEM软件通过非线性混合效应模型描述奈韦拉平的群体药代动力学。基于所建立的模型，模拟了每日两次服用300、400和500毫克奈韦拉平后的血药浓度曲线。
利福平的同时给药使奈韦拉平的口服清除率（CL/F）提高了37.4%，并使吸收速率常数（k(a)）降低了近六倍。利福平使奈韦拉平的平均最低浓度降低了39%。模拟的每日两次300毫克剂量使大多数患者的奈韦拉平浓度升高至亚治疗水平以上，最低暴露量高于推荐的最高浓度。在存在利福平的情况下，12 - 羟基奈韦拉平的浓度 - 时间曲线下面积没有差异。未检测到2 -、3 - 和8 - 羟基奈韦拉平（LLOQ = 0.025毫克/升）。
所建立的模型能够充分描述南非人群在接受/未接受利福平治疗时奈韦拉平的群体药代动力学。模拟结果表明，在含利福平的抗结核治疗期间，每日两次增加至300毫克的剂量将使大多数患者达到足够的奈韦拉平浓度。
