孕期伴或不伴替诺福韦时阿扎那韦的药代动力学。
Atazanavir pharmacokinetics with and without tenofovir during pregnancy.
机构信息
Department of Pediatrics, Boston University School of Medicine, Boston, MA, USA.
出版信息
J Acquir Immune Defic Syndr. 2011 Apr 15;56(5):412-9. doi: 10.1097/QAI.0b013e31820fd093.
BACKGROUND
Few data are available describing atazanavir exposure during pregnancy, especially when used in combination with tenofovir, whose coadministration with atazanavir results in decreased atazanavir exposure.
DESIGN
International Maternal Pediatric Adolescent AIDS Clinical Trials 1026 s is an ongoing, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included 2 cohorts receiving atazanavir/ritonavir 300 mg/100 mg once daily, either with or without tenofovir.
METHODS
Intensive steady-state 24-hour pharmacokinetic profiles were performed during the third trimester and at 6-12 weeks postpartum. Atazanavir was measured by reverse-phase high-performance liquid chromatography (detection limit 0.047 mcg/mL). Pharmacokinetic targets were the estimated 10th percentile atazanavir area under the concentration versus time curve [(AUC): 29.4 mcg · hr · mL-1] in nonpregnant historical controls (mean AUC = 57 mcg · hr · mL-1) and a trough concentration of 0.15 mcg/mL, the concentration target used in therapeutic drug monitoring programs.
RESULTS
Median atazanavir AUC was reduced during the third trimester compared with postpartum for subjects not receiving tenofovir (41.9 vs. 57.9 mcg · hr · mL-1, P = 0.02) and for subjects receiving tenofovir (28.8 vs. 39.6 mcg · hr · mL-1, P = 0.04). During the third trimester, AUC was below the target in 33% (6 of 18) of women not receiving tenofovir and 55% (11 of 20) of women receiving tenofovir. Trough concentration was below the target in 6% (1 of 18) of women not receiving tenofovir and 15% (3 of 20) of women receiving tenofovir. The median (range) ratio of cord blood/maternal atazanavir concentration in 29-paired samples was 0.18 (0-0.45).
CONCLUSIONS
Atazanavir exposure is reduced by pregnancy and by concomitant tenofovir use. A dose increase of atazanavir/ritonavir to 400 mg/100 mg may be necessary in pregnant women to ensure atazanavir exposure equivalent to that seen in nonpregnant adults.
背景
关于阿扎那韦在孕期的暴露情况，目前仅有少量数据可供描述，尤其是当它与替诺福韦联合使用时，因为替诺福韦的存在会降低阿扎那韦的暴露水平。
设计
国际母婴青少年艾滋病临床试验 1026s 是一项正在进行的、前瞻性的、非盲法研究，旨在评估 HIV 感染孕妇的抗逆转录病毒药药代动力学，该研究纳入了两个队列，均接受每日一次阿扎那韦/利托那韦 300mg/100mg 治疗，其中一个队列联合使用替诺福韦，另一个不联合使用。
方法
在妊娠晚期和产后 6-12 周时进行强化稳态 24 小时药代动力学研究。采用反相高效液相色谱法（检测下限为 0.047 mcg/mL）检测阿扎那韦。药代动力学目标为非妊娠历史对照人群中第 10 百分位数的阿扎那韦 AUC（AUC：29.4 mcg·hr·mL-1）（平均 AUC = 57 mcg·hr·mL-1）和谷浓度 0.15 mcg/mL，这是治疗药物监测项目中使用的浓度目标。
结果
与产后相比，未接受替诺福韦治疗的患者（41.9 vs. 57.9 mcg·hr·mL-1，P = 0.02）和接受替诺福韦治疗的患者（28.8 vs. 39.6 mcg·hr·mL-1，P = 0.04）在妊娠晚期的阿扎那韦 AUC 降低。在妊娠晚期，未接受替诺福韦治疗的患者中有 33%（6/18）的 AUC 低于目标值，接受替诺福韦治疗的患者中有 55%（11/20）的 AUC 低于目标值。未接受替诺福韦治疗的患者中有 6%（1/18）的谷浓度低于目标值，接受替诺福韦治疗的患者中有 15%（3/20）的谷浓度低于目标值。29 对配对样本的脐带血/母体阿扎那韦浓度中位数（范围）比值为 0.18（0-0.45）。
结论
妊娠和同时使用替诺福韦会降低阿扎那韦的暴露水平。为了确保在妊娠女性中达到与非妊娠成人相当的阿扎那韦暴露水平，可能需要将阿扎那韦/利托那韦剂量增加至 400mg/100mg。
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