Tissue disposition and pharmacokinetics of recombinant human nerve growth factor after acute and chronic subcutaneous administration in monkeys

In this study, we have characterized the metabolism, tissue disposition, ex cretion routes, and plasma pharmacokinetics of recombinant human nerve grow th factor after single and multiple s.c. administration in male cynomolgus monkeys. Unlabeled nerve growth factor (NGF; 2 mg/kg) was administered thre e times a week for 4 weeks and a full pharmacokinetic profile was obtained for doses 1 and 12. For the tissue distribution studies, 0.8 mu g/kg of tra ce I-125-labeled recombinant human nerve growth factor was dosed. Histologi cal analysis of emulsion-microautoradiography indicated that specific I-125 -NGF labeling was confined to sections of nerves most frequently localized adjacent to large vessels in sections of kidney, spleen, liver, and salivar y gland. A small percentage of large neurons within the sympathetic ganglia were intensely labeled, as well as large neurons within the dorsal root ga nglia. We found an increased disposition of I-125-NGF in parts of the perip heral nervous system (including sympathetic ganglia) from 8 to 24 h postdos e. In contrast, radioactivity in most non-neuronal tissues declined. This s uggests specific uptake in these target tissues known to express specific r eceptors for NGF. We also identified changes in pharmacokinetic parameters after single versus chronic s.c. administration. These studies demonstrated that s.c. administration of NGF at 0.8 mu g/kg doses in monkeys is capable of accessing and localizing in the target tissues.