Taylor Claribel P, Tummala Sanjeev, Molrine Deborah, Davidson Lisa, Farrell Richard J, Lembo Anthony, Hibberd Patricia L, Lowy Israel, Kelly Ciaran P
Beth Israel Deaconess Medical Center, University of Massachusetts Medical School, Boston, Massachusetts, USA.
Vaccine. 2008 Jun 25;26(27-28):3404-9. doi: 10.1016/j.vaccine.2008.04.042. Epub 2008 May 7.
Recent data suggest that Clostridium difficile-associated diarrhea is becoming more severe and difficult to treat. Antibody responses to C. difficile toxin A are protective against symptomatic disease and recurrence. We examined the safety and pharmacokinetics (pk) of a novel neutralizing human monoclonal antibody against C. difficile toxin A (CDA1) in healthy adults.
Five cohorts with 6 subjects each received a single intravenous infusion of CDA1 at escalating doses of 0.3, 1, 5, 10, and 20 mg/kg. Safety evaluations took place on days 1, 2, 3, 7, 14, 28, and 56 post-infusion. Samples for pk analysis were obtained before and after infusion, and at each safety evaluation. Serum CDA1 antibody concentrations and human anti-human antibody (HAHA) titers were measured with enzyme-linked immunosorbent assays. A noncompartmental model was used for pk analysis.
Thirty subjects were enrolled. The median age was 27.5 yrs. There were no serious adverse events (AE) related to CDA1. Twenty-one of the 48 reported non-serious adverse events were possibly related to CDA1, and included transient blood pressure changes requiring no treatment, nasal congestion, headache, abdominal cramps, nausea, and self-limited diarrhea. Serum CDA1 concentrations increased with escalating doses: mean C(max) ranged from 6.82 microg/ml for the 0.3 mg/kg cohort to 511 microg/ml for the 20 mg/kg cohort. The geometric mean values of the half-life of CDA1 ranged between 25.3 and 31.8 days, and the volume of distribution approximated serum. No subject formed detectable HAHA titers.
Administration of CDA1 as a single intravenous infusion was safe and well tolerated. C(max) increased proportionally with increasing doses. A randomized study of CDA1 in patients with C. difficile associated diarrhea is underway.
近期数据表明，艰难梭菌相关性腹泻正变得愈发严重且难以治疗。针对艰难梭菌毒素A的抗体反应可预防症状性疾病及复发。我们研究了一种新型抗艰难梭菌毒素A人源化单克隆抗体（CDA1）在健康成年人中的安全性及药代动力学（PK）。
五个队列，每个队列6名受试者，分别接受0.3、1、5、10和20mg/kg递增剂量的CDA1单次静脉输注。在输注后第1、2、3、7、14、28和56天进行安全性评估。在输注前后及每次安全性评估时采集用于PK分析的样本。采用酶联免疫吸附测定法测量血清CDA1抗体浓度及人抗人抗体（HAHA）滴度。采用非房室模型进行PK分析。
共纳入30名受试者。中位年龄为27.5岁。未发生与CDA1相关的严重不良事件（AE）。48例报告的非严重不良事件中有21例可能与CDA1相关，包括无需治疗的短暂血压变化、鼻塞、头痛、腹部绞痛、恶心和自限性腹泻。血清CDA1浓度随剂量递增而升高：0.3mg/kg队列的平均C(max)为6.82μg/ml，20mg/kg队列的平均C(max)为511μg/ml。CDA1半衰期的几何平均值在25.3至31.8天之间，分布容积接近血清。无受试者形成可检测到的HAHA滴度。
单次静脉输注CDA1安全且耐受性良好。C(max)随剂量增加成比例升高。一项关于CDA1治疗艰难梭菌相关性腹泻患者的随机研究正在进行中。
