奈非那韦与齐多夫定和拉米夫定联合用于HIV感染孕妇时的药代动力学及安全性：儿科艾滋病临床试验组（PACTG）353号方案
Pharmacokinetics and safety of nelfinavir when used in combination with zidovudine and lamivudine in HIV-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol 353.
作者信息
Bryson Y J, Mirochnick M, Stek A, Mofenson L M, Connor J, Capparelli E, Watts D H, Huang S, Hughes M D, Kaiser K, Purdue L, Asfaw Y, Keller M, Smith E
机构信息
David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1752, USA.
出版信息
HIV Clin Trials. 2008 Mar-Apr;9(2):115-25. doi: 10.1310/hct0902-115.
BACKGROUND
Combination antiretroviral regimens including nelfinavir (NFV) are commonly used in pregnancy. We studied the safety, antiviral effect, and pharmacokinetics of NFV and its M8 metabolite with two dosing regimens in combination with zidovudine (ZDV) and lamivudine (3TC) in HIV-infected pregnant women.
METHOD
HIV-infected pregnant women between 14 and 34 weeks gestation received NFV (Cohort 1: 750 mg tid, n = 10; Cohort 2: 1250 mg bid, n = 23) with ZDV and 3TC. Serial blood sampling for NFV concentrations was performed antepartum (AP) and 6 weeks postpartum (PP). Maternal and cord blood samples were also obtained at delivery. NFV and M8 levels were determined by high-performance liquid chromatography. The pharmacokinetic (PK) target was an extrapolated NFV AUC0-24 > 30 mug . h/mL. Mothers were followed frequently for potential clinical and laboratory toxicity.
RESULTS
Overall, NFV in combination with ZDV and 3TC was well tolerated. The PK target was met in 3/8 AP and 5/7 PP in Cohort 1 and 17/21 AP and 16/17 PP in Cohort 2. When Cohort 2 NFV PK parameters AP and PP were compared, median Cmax (3.90 microg/mL vs. 5.01 microg/mL, p < .05) and AUC0-24 (56.6 vs. 86.8 microg . h/mL, p < .05) were increased PP and oral clearance (Cl/F; 44.2 vs. 28.8 L/h, p < .05) was decreased PP. The average M8/NFV ratio was increased PP compared to AP (0.085 vs. 0.29, p < .001). Placental transfer of NFV was low with a median cord blood:maternal plasma ratio at delivery of 0.05. Maternal mean CD4+ T cell counts increased significantly and plasma HIV-1 RNA levels decreased from entry to delivery and 6 to 12 weeks postpartum.
CONCLUSION
NFV used in combination with ZDV and 3TC was well tolerated in pregnant HIV-infected women and produced a significant improvement in HIV disease parameters. NFV drug exposure is inadequate in most pregnant women receiving 750 mg tid but is much improved with 1250 mg bid. NFV crosses the placenta poorly. The AP increase in NFV oral clearance and decrease in M8/NFV ratio suggest that CYP3A activity increases relative to CYP2C19 activity during pregnancy.
背景
包括奈非那韦（NFV）在内的联合抗逆转录病毒疗法常用于孕期。我们研究了在感染HIV的孕妇中，两种给药方案的NFV及其M8代谢产物与齐多夫定（ZDV）和拉米夫定（3TC）联合使用时的安全性、抗病毒效果及药代动力学。
方法
妊娠14至34周的感染HIV的孕妇接受NFV（队列1：750mg每日三次，n = 10；队列2：1250mg每日两次，n = 23）与ZDV和3TC联合治疗。在产前（AP）和产后6周（PP）进行系列血样采集以测定NFV浓度。分娩时还获取了母血和脐血样本。通过高效液相色谱法测定NFV和M8水平。药代动力学（PK）目标是推算的NFV AUC0 - 24 > 30μg·h/mL。对母亲进行频繁随访以观察潜在的临床和实验室毒性。
结果
总体而言，NFV与ZDV和3TC联合使用耐受性良好。队列1中3/8例产前和5/7例产后达到PK目标，队列2中17/21例产前和16/17例产后达到PK目标。比较队列2产前和产后的NFV PK参数时，中位数Cmax（3.90μg/mL对5.01μg/mL，p <.05）和AUC0 - 24（56.6对86.8μg·h/mL，p <.05）产后升高，口服清除率（Cl/F；44.2对28.8L/h，p <.05）产后降低。与产前相比，产后M8/NFV平均比值升高（0.085对0.29，p <.001）。NFV的胎盘转运率较低，分娩时脐血与母血浆的中位数比值为0.05。母亲的平均CD4 + T细胞计数显著增加，血浆HIV - 1 RNA水平从入组至分娩以及产后6至12周均下降。
结论
在感染HIV的孕妇中，NFV与ZDV和3TC联合使用耐受性良好，并使HIV疾病参数有显著改善。大多数接受750mg每日三次治疗的孕妇NFV药物暴露不足，但1250mg每日两次治疗时情况有很大改善。NFV通过胎盘的能力较差。产前NFV口服清除率增加和M8/NFV比值降低表明孕期CYP3A活性相对于CYP2C19活性增加。
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