Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers
Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers
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DOI：
10.1128/aac.44.6.1667-1673.2000
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发表时间：
2000-06-01
影响因子：
4.9
通讯作者：
Henson, GW
中科院分区：
文献类型：
--
作者：
Hendrix, CW;Flexner, C;Henson, GW
AMD-3100是一种双环类药物，它通过选择性阻断趋化因子CXCR-4受体，独特地抑制人类免疫缺陷病毒1型（HIV-1）进入CD 4（+）T细胞。12名健康志愿者以10、20、40或80 μ g/kg的剂量单次静脉输注AMD-3100 15分钟。五名受试者还接受了AMD-3100（40或80 μ g/kg）的单次皮下注射。3名受试者分别接受了两次递增口服剂量（80和160 μ g/kg）。所有受试者均对剂量耐受良好，无任何2级毒性或剂量调整。6例受试者出现轻度、一过性症状，主要为胃肠道症状，与剂量无关。所有受试者的白色血细胞计数均出现剂量相关性升高，从基线的1.5倍升高至3.1倍，在给药后24小时恢复至基线水平，AMD-3100显示出血清最大药物浓度（C-max）和从0小时至无穷大的浓度-时间曲线下面积的剂量比例性整个剂量范围内的AUC（0-无穷大），最高静脉给药剂量（80 μ g/kg），中位C-max为515（范围：470 - 521）ng/ml，AUC（0-无穷大）为1，044（范围：980 - 1，403）ng-h/ml，皮下给药后的中位全身吸收为87%（范围：67 - 106%）。经口给药后，血液中未检出药物。使用二室模型，中位药代动力学参数估计值（范围）如下：分布容积，0.34（0.27 - 0.36）L/kg;清除率，1.30（0.97 - 1.34）L/h;消除半衰期，3.6（3.5 - 4.9）h。在接受耐受性良好的AMD 3100单次静脉给药后，浓度持续高于体外抗逆转录病毒90%抑制浓度12 h，并持续高于HIV感染的SCID-hu Thy/Liv小鼠模型中确定的抗病毒浓度8 h。
AMD-3100, a bicyclam, is a novel agent that uniquely inhibits the entry of human immunodeficiency virus type 1 (HIV-1) into CD4(+) T cells via selective blockade of the chemokine CXCR-4 receptor, Twelve healthy volunteers were given AMD-3100 as a single 15-min intravenous infusion at 10, 20, 40, or 80 mu g/kg. Five subjects also received a single subcutaneous injection of AMD-3100 (40 or 80 mu g/kg). Three subjects received two escalating oral doses each (80 and 160 mu g/kg). All subjects tolerated their dose(s) well without any grade 2 toxicity or dose adjustment. Six subjects experienced mild, transient symptoms, primarily gastrointestinal in nature and not dose related. All subjects experienced a dose-related elevation of the white blood cell count, from 1.5 to 3.1 times the baseline, which returned to the baseline 24 h after dosing, AMD-3100 demonstrated dose proportionality for the maximum drug concentration in serum (C-max) and the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)) over the entire dose range, At the highest intravenous dose (80 mu g/kg), the median C-max was 515 (range, 470 to 521) ng/ml and the AUC(0-infinity) was 1,044 (range, 980 to 1,403) ng-h/ml, The median systemic absorption after subcutaneous dosing was 87% (range, 67 to 106%). No drug was detectable in the blood following oral dosing. Using a two-compartment model, the median pharmacokinetic parameter estimates (ranges) were as follows: volume of distribution, 0.34 (0.27 to 0.36) liter/kg; clearance, 1.30 (0.97 to 1.34) liters/h; elimination half-life, 3.6 (3.5 to 4.9) h. After a single, well-tolerated intravenous dose of AMD3100, concentrations were sustained for 12 h above the in vitro antiretroviral 90% inhibitory concentrations and for 8 h above antiviral concentrations identified in the SCID-hu Thy/Liv mouse model of HIV infection.