Hodges T L, Kahn J O, Kaplan L D, Groopman J E, Volberding P A, Amman A J, Arri C J, Bouvier L M, Mordenti J, Izu A E
New England Deaconess Hospital, Boston, Massachusetts 02215.
Antimicrob Agents Chemother. 1991 Dec;35(12):2580-6. doi: 10.1128/AAC.35.12.2580.
The safety and pharmacokinetics of recombinant CD4-immunoglobulin G (rCD4-IgG) were evaluated in a phase 1 study with dose escalation. A total of 16 patients, 6 with AIDS and 10 with AIDS-related complex, were evaluated at two university-affiliated hospital clinics. rCD4-IgG was administered once weekly for 12 weeks to four patients each at doses of 0.03, 0.1, 0.3, and 1.0 mg/kg of body weight. Dosing was intravenous for two patients in the 1.0-mg/kg dose group and intramuscular for the remaining patients. Dosing was intravenous for two patients in the 1.0-mg/kg dose group and intramuscular for the remaining patients. Pharmacokinetic, toxicity, and immunologic variables were monitored with all patients. Administration of rCD4-IgG was well tolerated, with no important clinical or immunologic toxicities noted. No subjects required dose reduction or discontinuation of therapy due to toxicity. No consistent changes were seen in human immunodeficiency virus antigen levels in serum or CD4 lymphocyte populations. The volume of distribution was small, and compared with that of rCD4, the half-life of the hybrid molecule was markedly prolonged following intramuscular or intravenous administration. The rate and extent of absorption following intramuscular dosing were variable. Intramuscular administration of rCD4-IgG appears to be inferior to intravenous dosing from a pharmacokinetic standpoint, with lower peak concentrations and variable absorption. After intravenous administration, peak concentrations of rCD4-IgG in serum (20 to 24 micrograms/ml) that have shown antiviral activity in vitro against more sensitive clinical isolates of human immunodeficiency virus were achieved. The peak concentrations in serum after intramuscular administration were below these levels. Treatment with rCD4-IgG was well tolerated at the doses administered to patients in this study but did not result in significant changes in CD4 lymphocyte counts or p24 antigen levels in serum.
在一项剂量递增的1期研究中评估了重组CD4-免疫球蛋白G（rCD4-IgG）的安全性和药代动力学。在两家大学附属医院诊所对总共16名患者进行了评估，其中6名患有艾滋病，10名患有艾滋病相关综合征。rCD4-IgG以0.03、0.1、0.3和1.0mg/kg体重的剂量每周给药一次，共12周，每组4名患者。1.0mg/kg剂量组的两名患者采用静脉给药，其余患者采用肌肉注射。对所有患者监测药代动力学、毒性和免疫学变量。rCD4-IgG的给药耐受性良好，未观察到重要的临床或免疫毒性。没有受试者因毒性需要降低剂量或停止治疗。血清中的人类免疫缺陷病毒抗原水平或CD4淋巴细胞群体未见一致变化。分布容积较小，与rCD4相比，该杂交分子在肌肉注射或静脉给药后的半衰期明显延长。肌肉注射后的吸收速率和程度各不相同。从药代动力学角度来看，rCD4-IgG的肌肉注射给药似乎不如静脉给药，其峰值浓度较低且吸收变化不定。静脉给药后，血清中rCD4-IgG的峰值浓度（20至24微克/毫升）在体外对更敏感的人类免疫缺陷病毒临床分离株显示出抗病毒活性。肌肉注射后血清中的峰值浓度低于这些水平。在本研究中给予患者的剂量下，rCD4-IgG治疗耐受性良好，但未导致血清中CD4淋巴细胞计数或p24抗原水平发生显著变化。
