Combination therapy with saquinavir soft gelatin capsules in children with human immunodeficiency virus infection.
Combination therapy with saquinavir soft gelatin capsules in children with human immunodeficiency virus infection.
复制标题
沙奎那韦软明胶胶囊联合治疗人类免疫缺陷病毒感染儿童。
DOI：
10.1097/00006454-200107000-00006
复制
发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Duff,F
中科院分区：
文献类型：
--
作者：
Kline,MW;Brundage,RC;Fletcher,CV;Schwarzwald,H;Calles,NR;Buss,NE;Snell,P;DeLora,P;Eason,M;Jorga,K;Craig,C;Duff,F
目的：评价HIV蛋白酶抑制剂沙奎那韦（SQV-SGC）与核苷类抗逆转录病毒药物（NRTI）联合治疗HIV感染儿童的药代动力学、耐受性、安全性和抗病毒活性。在研究的第1部分中，14名儿童口服SQV-SGC（最初每天给予3次33 mg/kg剂量;根据初始药代动力学将剂量调整为50 mg/kg，每天3次）和2种NRTI。对于未达到预定稳态目标血浆沙奎那韦暴露量的儿童，允许添加奈非那韦。在第2部分中，一组新的13名儿童接受SQV-SGC（33 mg/kg，每日三次）联合奈非那韦和一种或两种NRTI。在首次给药后和治疗4周后（稳态）评估药代动力学。在第1部分和第2部分中，患者分别接受了72周和48周的治疗。结果：大多数不良事件是轻度的，最常见的是腹泻、腹部不适和头痛。两名儿童因与研究治疗相关的不良事件（恶心和吞咽困难各1例）退出研究。未发生归因于研究药物的死亡或严重不良事件。第1部分和第2部分的稳态沙奎那韦血药浓度-时间曲线下面积（AUC 24）分别为6210和11010 ng/h/ml。与基线测量值相比，第1部分和第2部分血浆HIV RNA浓度的中位变化分别为− 2.12 log 10拷贝/ml [14例中的5例（36%）HIV RNA< 50拷贝/ml）（第72周）]和− 2.58 log 10拷贝/ml [13例中的8例（62%）< 50拷贝/ml）（第48周）]。第1部分和第2部分的CD 4+淋巴细胞计数的中位变化分别为+ 292和+ 154个细胞/μl。基因型耐药检测显示，治疗48周后沙奎那韦相关耐药突变发生率较低，27例患儿中仅有2例发生48 V和/或90 M位点的替换。结论：SQV-SGC联合治疗HIV感染儿童耐受性好，安全性高，并观察到抗病毒活性。沙奎那韦血浆浓度低于预期，尤其是第1部分（SQV-SGC + NRTI），但添加奈非那韦增加了沙奎那韦暴露。
Objectives.To evaluate the pharmacokinetics, tolerance, safety and antiviral activity of the HIV protease inhibitor, saquinavir, formulated as soft gelatin capsules (SQV-SGC), given in combination with nucleoside antiretroviral agents (NRTIs) with or without nelfinavir in HIV-infected children.Methods.This was an open label study of HIV-infected children ages 3 to 16 years, conducted in two parts. In Part 1 of the study 14 children were treated orally with SQV-SGC (initially given in three 33-mg/kg doses daily; dosage adjusted to 50 mg/kg three times daily based on initial pharmacokinetics) and two NRTIs. Addition of nelfinavir was permitted for children who did not achieve a predetermined steady state target plasma saquinavir exposure. In Part 2 a new group of 13 children received SQV-SGC (33 mg/kg three times daily) in combination with nelfinavir and one or two NRTIs. Pharmacokinetics were assessed after the first dose and 4 weeks into treatment (steady state). Patients were treated for 72 and 48 weeks in Parts 1 and 2, respectively.Results.Most adverse events were mild; the most commonly reported were diarrhea, abdominal discomfort and headache. Two children were withdrawn from the study because of adverse events (one each of nausea and dysphagia) related to the study treatment. There were no deaths or serious adverse events attributed to the study medication. Steady state saquinavir area under the plasma concentration vs. time curves (AUC 24) were 6210 and 11 010 ng/h/ml for Parts 1 and 2, respectively. Compared with baseline measurements median changes in plasma HIV RNA concentrations were− 2.12 log 10 copies/ml [5 of 14 (36%) with HIV RNA< 50 copies/ml)(Week 72)] and− 2.58 log 10 copies/ml [8 of 13 (62%)< 50 copies/ml)(Week 48)] in Parts 1 and 2, respectively. The median changes in CD4+ lymphocyte count were+ 292 and+ 154 cells/μl for Parts 1 and 2, respectively. Genotypic resistance assays revealed a low frequency of saquinavir-associated resistance mutations after 48 weeks of therapy, with only 2 of 27 children having substitutions at positions 48V and/or 90M.Conclusions.Combination therapy with SQV-SGC was well-tolerated and safe in HIV-infected children, and antiviral activity was observed. Saquinavir plasma concentrations were lower than expected, particularly for Part 1 (SQV-SGC plus NRTIs), but addition of nelfinavir increased saquinavir exposures.