Bertrand Julie, Treluyer Jean-Marc, Panhard Xavière, Tran Agnes, Auleley Solange, Rey Elisabeth, Salmon-Céron Dominique, Duval Xavier, Mentré France
UMR 738, INSERM, Université Paris Diderot, UFR de Médecine, 16, rue Henri Huchard, 75018, Paris, France.
Eur J Clin Pharmacol. 2009 Jul;65(7):667-78. doi: 10.1007/s00228-009-0660-5. Epub 2009 May 14.
To assess the relationship between genetic polymorphisms and indinavir pharmacokinetic variability and to study the link between concentrations and short-term response or metabolic safety.
Forty protease inhibitor-naive patients initiating highly active antiretroviral therapy (HAART) including indinavir/ritonavir and enrolled in the COPHAR 2-ANRS 111 trial were studied. At week 2, four blood samples were taken before and up to 6 h following drug intake. A population pharmacokinetic analysis was performed using the stochastic approximation expectation maximization (SAEM) algorithm implemented in MONOLIX software. The area under the concentration-time curve (AUC) and maximum (C(max)) and trough concentrations (C(trough)) of indinavir were derived from the population model and tested for their correlation with short-term viral response and safety measurements, while for ritonavir, these same three parameters were tested for their correlation with short-term biochemical safety
A one-compartment model with first-order absorption and elimination best described both indinavir and ritonavir concentrations. For indinavir, the estimated clearance and volume of distribution were 22.2 L/h and 97.3 L, respectively. The eight patients with the *1B/*1B genotype for the CYP3A4 gene showed a 70% decrease in absorption compared to those with the *1A/*1B or *1A/*1A genotypes (0.5 vs. 2.1, P = 0.04, likelihood ratio test by permutation). The indinavir AUC and C(trough) were positively correlated with the decrease in human immunodeficiency virus RNA between week 0 and week 2 (r = 0.4, P = 0.03 and r = -0.4, P = 0.03, respectively). Patients with the *1B/*1B genotype also had a significantly lower indinavir C(max) (median 3.6, range 2.1-5.2 ng/mL) than those with the *1A/*1B or *1A/*1A genotypes (median 4.4, range 2.2-8.3 ng/mL) (P = 0.04) and a lower increase in triglycerides during the first 4 weeks of treatment (median 0.1, range -0.7 to 1.4 vs. median 0.6, range -0.5 to 1.7 mmol/L, respectively; P = 0.02). For ritonavir, the estimated clearance and volume of distribution were 8.3 L/h and 60.7 L, respectively, and concentrations were not found to be correlated to biochemical safety. Indinavir and ritonavir absorption rate constants were found to be correlated, as well as their apparent volumes of distribution and clearances, indicating correlated bioavailability of the two drugs.
The CYP3A4*1B polymorphism was found to influence the pharmacokinetics of indinavir and, to some extent, the biochemical safety of indinavir.
评估基因多态性与茚地那韦药代动力学变异性之间的关系，并研究血药浓度与短期疗效或代谢安全性之间的联系。
对40例初治患者进行研究，这些患者开始接受包含茚地那韦/利托那韦的高效抗逆转录病毒治疗（HAART），并参与了COPHAR 2-ANRS 111试验。在第2周，于服药前及服药后6小时内采集4份血样。使用MONOLIX软件中实现的随机近似期望最大化（SAEM）算法进行群体药代动力学分析。茚地那韦的血药浓度-时间曲线下面积（AUC）、峰浓度（C(max)）和谷浓度（C(trough)）由群体模型得出，并测试它们与短期病毒学应答及安全性指标的相关性；对于利托那韦，测试这三个参数与短期生化安全性的相关性。
具有一级吸收和消除的单室模型能最好地描述茚地那韦和利托那韦的血药浓度。对于茚地那韦，估计清除率和分布容积分别为22.2 L/h和97.3 L。CYP3A4基因*1B/1B基因型的8例患者与1A/1B或1A/*1A基因型患者相比，吸收降低了70%（0.5对2.1，P = 0.04，通过置换进行似然比检验）。茚地那韦的AUC和C(trough)与第0周和第2周期间人类免疫缺陷病毒RNA的降低呈正相关（r = 0.4，P = 0.03和r = -0.4，P = 0.03）。*1B/1B基因型患者的茚地那韦C(max)也显著低于1A/1B或1A/*1A基因型患者（中位数3.6，范围2.1 - 5.2 ng/mL对中位数4.4，范围2.2 - 8.3 ng/mL）（P = 0.04），且在治疗的前4周甘油三酯升高幅度较低（中位数0.1，范围 -0.7至1.4对中位数0.6，范围 -0.5至1.7 mmol/L；P = 0.02）。对于利托那韦，估计清除率和分布容积分别为8.3 L/h和60.7 L，且未发现血药浓度与生化安全性相关。发现茚地那韦和利托那韦的吸收速率常数相关，其表观分布容积和清除率也相关，表明两种药物的生物利用度相关。
发现CYP3A4*1B多态性影响茚地那韦的药代动力学，并在一定程度上影响茚地那韦的生化安全性。
