Hirt Déborah, Treluyer Jean-Marc, Jullien Vincent, Firtion Ghislaine, Chappuy Hélène, Rey Elisabeth, Pons Gérard, Mandelbrot Laurent, Urien Saïk
Pharmacologie Clinique, Hôpital Saint Vincent de Paul, Paris, France.
Antimicrob Agents Chemother. 2006 Jun;50(6):2079-86. doi: 10.1128/AAC.01596-05.
A relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established. As physiological changes associated with pregnancy have a large impact on the pharmacokinetics of many drugs, a nelfinavir population study with women was developed, and the large intersubject variability was analyzed in order to optimize individual treatment schedules for this drug during pregnancy. A population pharmacokinetic model was developed in order to describe the concentration time course of nelfinavir and its metabolite M8 in pregnant and nonpregnant women. Individual characteristics, such as age, body weight, and weeks of gestation or delivery, which may influence nelfinavir-M8 pharmacokinetics were investigated. Data from therapeutic drug monitoring in 133 women treated with nelfinavir were retrospectively analyzed with NONMEM. Nelfinavir pharmacokinetics was described by a one-compartment model with linear absorption and elimination and M8 produced from the nelfinavir central compartment. Mean pharmacokinetic estimates and the corresponding intersubject percent variabilities for a nonpregnant woman were the following: absorption rate, 0.83 h(-1); absorption lag time, 0.85 h; apparent nelfinavir elimination clearance (CL(10)/F), 35.5 liters/h (50%); apparent volume of distribution (V/F), 596 liters (118%); apparent formation clearance to M8 (CL(1M)/F), 0.65 liters/h (69%); and M8 elimination rate constant (k(M0)), 3.3 h(-1) (59%). During pregnancy, we observed significant increases in nelfinavir (44.4 liters/h) and M8 (5 h(-1)) elimination but unchanged nelfinavir transformation clearance to M8, suggesting an induction of CYP3A4 but no effect on CYP2C19. Apparent nelfinavir clearance and volume showed a twofold increase on the day of delivery, suggesting a decrease in bioavailability on this day. The M8 elimination rate was increased by concomitant administration of nonnucleoside reverse transcriptase inhibitors. A trough nelfinavir plasma concentration above 1 mg/liter was previously shown to improve the antiretroviral response. The Bayesian individual pharmacokinetic estimates suggested that the dosage should not be changed in pregnant women but may be doubled on the day of delivery.
奈非那韦的抗逆转录病毒疗效与血浆浓度之间的关系此前已得到确立。由于与妊娠相关的生理变化对许多药物的药代动力学有很大影响，因此开展了一项针对女性的奈非那韦群体研究，并分析了较大的个体间变异性，以便在妊娠期间优化该药物的个体化治疗方案。为描述奈非那韦及其代谢物M8在孕妇和非孕妇体内的浓度-时间过程，建立了群体药代动力学模型。研究了可能影响奈非那韦-M8药代动力学的个体特征，如年龄、体重、妊娠周数或分娩周数。使用NONMEM对133例接受奈非那韦治疗的女性的治疗药物监测数据进行了回顾性分析。奈非那韦的药代动力学由具有线性吸收和消除的单室模型描述，M8由奈非那韦中央室产生。非孕妇的平均药代动力学估计值及相应的个体间变异百分比如下：吸收速率，0.83 h⁻¹；吸收滞后时间，0.85 h；奈非那韦表观消除清除率（CL₁₀/F），35.5升/小时（50%）；表观分布容积（V/F），596升（118%）；M8的表观生成清除率（CL₁M/F），0.65升/小时（69%）；以及M8消除速率常数（kM₀），3.3 h⁻¹（59%）。在妊娠期间，我们观察到奈非那韦（44.4升/小时）和M8（5 h⁻¹）的消除显著增加，但奈非那韦向M8的转化清除率未变，提示CYP3A4被诱导，但对CYP2C19无影响。奈非那韦的表观清除率和容积在分娩日增加了两倍，提示该日生物利用度降低。同时给予非核苷类逆转录酶抑制剂可增加M8的消除速率。先前显示，奈非那韦血浆谷浓度高于1毫克/升可改善抗逆转录病毒反应。贝叶斯个体药代动力学估计表明，孕妇的剂量无需改变，但在分娩日剂量可能需加倍。
