von Hentig Nils, Babacan Errol, Lennemann Tessa, Knecht Gabi, Carlebach Amina, Harder Sebastian, Staszewski Schlomo, Haberl Annette
Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Johann Wolfgang Goethe University, Frankfurt, Germany.
J Antimicrob Chemother. 2008 Sep;62(3):579-82. doi: 10.1093/jac/dkn204. Epub 2008 May 13.
Pharmacokinetic differences, contributing to drug-related side effects, between men and women have been reported for HIV protease inhibitors. As only limited and inconclusive data on ritonavir-boosted atazanavir are available, we evaluated the respective steady-state pharmacokinetics in 48 male and 26 female HIV-1-infected adults receiving atazanavir/ritonavir 300/100 mg once-daily as part of their antiretroviral therapy.
Pharmacokinetic profiles (24 h) of atazanavir/ritonavir were assessed and measured by HPLC/tandem mass spectrometry. Geometric mean (GM; ANOVA) of minimum and maximum plasma drug concentrations (C(min) and C(max)), area under the concentration-time curve (AUC) and total clearance (CL(total)) were compared between the sexes and correlated to demographic (age, gender and ethnicity), physiological (weight and body mass index) and clinical (CD4+ cell count, HIV-RNA, co-medication and hepatitis serology) co-factors.
The GM of the atazanavir AUC, C(max) and C(min) of men versus women were 32 643 versus 36 232 ng.h/mL [GM ratio (GMR) = 1.11, P = 0.435], 2802 versus 3211 ng/mL (GMR = 1.15, P = 0.305) and 398 versus 470 ng/mL (GMR = 1.18, P = 0.406), respectively. Although weight (80.6 versus 63.9 kg, P = 0.001) and body weight-adjusted atazanavir dose (3.84 versus 4.60 mg/kg, P = 0.013) were different between the sexes, no significant correlation to atazanavir pharmacokinetics was observed. A linear regression analysis detected significant correlations of atazanavir C(min) with ritonavir AUC (P < 0.001) and the co-administration of methadone oral solution (P = 0.032), and inverse correlations with the time since the first HIV infection diagnosis (P = 0.003) and the number of previous antiretroviral treatments (P = 0.022).
Atazanavir/ritonavir steady-state pharmacokinetics was comparable in men and women, despite gender-related significant differences in atazanavir dose/body weight. The administration of atazanavir/ritonavir is pharmacokinetically safe; 95% of all trough samples were above the recommended plasma concentration of 150 ng/mL.
已有报告指出，男性和女性在使用HIV蛋白酶抑制剂时存在药代动力学差异，这可能导致与药物相关的副作用。由于关于利托那韦增强的阿扎那韦的可用数据有限且尚无定论，我们评估了48名接受阿扎那韦/利托那韦300/100mg每日一次作为抗逆转录病毒治疗一部分的男性和26名感染HIV-1的成年女性的各自稳态药代动力学。
通过高效液相色谱/串联质谱法评估并测量阿扎那韦/利托那韦的药代动力学曲线（24小时）。比较了两性之间血浆药物最低和最高浓度（C(min)和C(max)）、浓度-时间曲线下面积（AUC）和总清除率（CL(total)）的几何平均值（GM；方差分析），并将其与人口统计学（年龄、性别和种族）、生理学（体重和体重指数）和临床（CD4+细胞计数、HIV-RNA、合并用药和肝炎血清学）协变量相关联。
男性与女性的阿扎那韦AUC、C(max)和C(min)的GM分别为32643对36232 ng.h/mL [GM比率（GMR）=1.11，P = 0.435]、2802对3211 ng/mL（GMR = 1.15，P = 0.305）和398对470 ng/mL（GMR = 1.18，P = 0.406）。尽管两性之间体重（80.6对63.9 kg，P = 0.001）和体重调整后的阿扎那韦剂量（3.84对4.60 mg/kg，P = 0.013）不同，但未观察到与阿扎那韦药代动力学有显著相关性。线性回归分析检测到阿扎那韦C(min)与利托那韦AUC（P < 0.001）以及美沙酮口服溶液的联合使用（P = 0.032）之间存在显著相关性，与首次诊断HIV感染后的时间（P = 0.003）和既往抗逆转录病毒治疗次数（P = 0.022）呈负相关。
尽管阿扎那韦剂量/体重存在与性别相关的显著差异，但阿扎那韦/利托那韦的稳态药代动力学在男性和女性中具有可比性。阿扎那韦/利托那韦的给药在药代动力学上是安全的；所有谷值样本的95%高于推荐的血浆浓度150 ng/mL。
