Mordenti J, Thomsen K, Licko V, Berleau L, Kahn J W, Cuthbertson R A, Duenas E T, Ryan A M, Schofield C, Berger T W, Meng Y G, Cleland J
Department of Experimental Therapeutics, Genentech, Inc., South San Francisco, California 94080, USA.
Toxicol Sci. 1999 Nov;52(1):101-6. doi: 10.1093/toxsci/52.1.101.
Poly(lactic-co-glycolic) acid (PLGA) bioresorbable microspheres are used for controlled-release drug delivery and are particularly promising for ocular indications. The objective of the current study was to evaluate the pharmacokinetics and safety of a recombinant human monoclonal antibody (rhuMAb HER2) in rabbits after bolus intravitreal administration of a solution or a PLGA-microsphere formulation. On Day 0, forty-eight male New Zealand white rabbits (2.3-2.6 kg) were immobilized with intramuscular ketamine/xylazine, and the test materials were injected directly into the vitreous compartment. Group 1 animals received rhuMAb HER2 in 50:50 lactide: glycolide PLGA microspheres; Group 2 animals received rhuMAb HER2 in solution (n = 24/group). The dose for each eye was 25 microg (50 microl). After dosing, animals were sacrificed at 2 min, and on 1, 2, 4, 7, 14, 23, 29, 37, 44, 50, and 56 days (n = 2/timepoint/group). Safety assessment included direct ophthalmoscopy, clinical observations, body weight, and hematology and clinical chemistry panels. At necropsy, vitreous and plasma were collected for pharmacokinetics and analysis for antibodies to rhuMAb HER2, and the vitreal pellet (Group 1) was prepared for histologic evaluation. All animals completed the study per protocol-both treatments were well tolerated, and no suppurative or mixed inflammatory cell reaction was observed in the vitreal samples (Group 1) at any of the time points examined. Antibodies to rhuMAb HER2 were detected in plasma samples by Day 7 in both treatment groups, but infrequently in vitreous samples. There were no safety implications associated with this immune response. The in vitro characterization of the PLGA microspheres provided reasonable projections of the in vivo rhuMAb HER2 release kinetics (Group 1). The total amount of antibody that was released was similar in vitro (25.9%) and in vivo (32.4%). RhuMAb HER2 (Group 2) was cleared slowly from the vitreous compartment, with initial and terminal half-lives of 0.9 and 5.6 days, respectively. The volume of distribution approximated the vitreous volume in a rabbit eye.
聚乳酸-乙醇酸共聚物（PLGA）生物可吸收微球用于控释给药，尤其在眼部适应症方面前景广阔。本研究的目的是评估重组人单克隆抗体（rhuMAb HER2）溶液或PLGA微球制剂经玻璃体腔一次性给药后在兔体内的药代动力学和安全性。在第0天，48只雄性新西兰白兔（体重2.3 - 2.6 kg）通过肌肉注射氯胺酮/赛拉嗪进行麻醉，然后将受试材料直接注射到玻璃体腔。第1组动物接受含50:50丙交酯:乙交酯PLGA微球的rhuMAb HER2；第2组动物接受溶液形式的rhuMAb HER2（每组n = 24）。每只眼的剂量为25微克（50微升）。给药后，在2分钟以及第1、2、4、7、14、23、29、37、44、50和56天处死动物（每组每个时间点n = 2）。安全性评估包括直接检眼镜检查、临床观察、体重以及血液学和临床化学指标检测。尸检时，收集玻璃体和血浆用于药代动力学研究以及检测抗rhuMAb HER2抗体，并且制备玻璃体沉淀物（第1组）用于组织学评估。所有动物均按方案完成研究——两种治疗耐受性良好，在任何检测时间点，玻璃体样本（第1组）均未观察到化脓性或混合性炎症细胞反应。在两个治疗组中，到第7天时血浆样本中均检测到抗rhuMAb HER2抗体，但玻璃体样本中很少检测到。这种免疫反应未产生安全性问题。PLGA微球的体外特性对体内rhuMAb HER2释放动力学（第1组）提供了合理预测。体外释放的抗体总量（25.9%）与体内（32.4%）相似。rhuMAb HER2（第2组）从玻璃体腔清除缓慢，初始半衰期和终末半衰期分别为0.9天和5.6天。分布容积接近兔眼的玻璃体容积。
