TY - JOUR
T1 - Point source concentration of GDNF may explain failure of phase II clinical trial
AU - Salvatore, Michael F.
AU - Ai, Yi
AU - Fischer, Brent
AU - Zhang, Amanda M.
AU - Grondin, Richard C.
AU - Zhang, Zhiming
AU - Gerhardt, Greg A.
AU - Gash, Don M.
PY - 2006/12
Y1 - 2006/12
N2 - Significant differences have been reported in results from three clinical trials evaluating intraputamenal infusion of glial cell line-derived neurotrophic factor (GDNF) for the treatment of Parkinson's disease. To determine if problems in drug bioavailability could have contributed to the discrepancies between studies, we have analyzed the distribution of intraputamenally infused GDNF in the rhesus monkey brain using the delivery system and infusion protocol followed in a phase 2 clinical trial that failed to achieve its primary endpoint. I125-GDNF was unilaterally infused into the putamen of three adult rhesus monkeys for 7 days. Three age- and sex-matched animals received vehicle infusions following identical procedures. GDNF levels in the brain, peripheral organs, blood and CSF were quantified and mapped by GDNF immunocytochemistry, GDNF ELISAs and I125 measurements. Infused GDNF was found to be unevenly concentrated around the catheter, with tissue levels dropping exponentially with increasing distance from the point source of the single opening in the catheter tip. The volume of distribution of GDNF around the catheter, as determined by immunocytochemistry, varied over four-fold between animals ranging from 87 to 369 mm3. The concentration of GDNF around the catheter tip and limited diffusion into surrounding brain parenchyma support the hypothesis that drug bioavailability was limited to a small portion (2-9%) of the human putamen in the clinical trial using this catheter and infusion protocol.
AB - Significant differences have been reported in results from three clinical trials evaluating intraputamenal infusion of glial cell line-derived neurotrophic factor (GDNF) for the treatment of Parkinson's disease. To determine if problems in drug bioavailability could have contributed to the discrepancies between studies, we have analyzed the distribution of intraputamenally infused GDNF in the rhesus monkey brain using the delivery system and infusion protocol followed in a phase 2 clinical trial that failed to achieve its primary endpoint. I125-GDNF was unilaterally infused into the putamen of three adult rhesus monkeys for 7 days. Three age- and sex-matched animals received vehicle infusions following identical procedures. GDNF levels in the brain, peripheral organs, blood and CSF were quantified and mapped by GDNF immunocytochemistry, GDNF ELISAs and I125 measurements. Infused GDNF was found to be unevenly concentrated around the catheter, with tissue levels dropping exponentially with increasing distance from the point source of the single opening in the catheter tip. The volume of distribution of GDNF around the catheter, as determined by immunocytochemistry, varied over four-fold between animals ranging from 87 to 369 mm3. The concentration of GDNF around the catheter tip and limited diffusion into surrounding brain parenchyma support the hypothesis that drug bioavailability was limited to a small portion (2-9%) of the human putamen in the clinical trial using this catheter and infusion protocol.
KW - Clinical trial
KW - Drug delivery
KW - GDNF
KW - Nonhuman primates
KW - Putamen
KW - Tissue levels
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UR - http://www.scopus.com/inward/citedby.url?scp=33750609664&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2006.07.015
DO - 10.1016/j.expneurol.2006.07.015
M3 - Article
C2 - 16962582
AN - SCOPUS:33750609664
SN - 0014-4886
VL - 202
SP - 497
EP - 505
JO - Experimental Neurology
JF - Experimental Neurology
IS - 2
ER -
