Convective delivery of glial cell line-derived neurotrophic factor in the human putamen.
OBJECTIVE
The authors conducted an analysis of the distribution of glial cell line-derived neurotrophic factor in the human striatum following convection-enhanced delivery.


METHODS
Computational examinations of the effects of differing catheters, infusion rates, infusate concentrations, and target placement on distribution were completed based on the protocols of three recent clinical trials.


RESULTS
Similar drug distributions around on-target end-hole catheters were predicted in two of the trials (AmgenUT study and Bristol study), although there was slightly deeper penetration for one of the trials (Bristol) due to a higher infusate concentration. However, when positioning uncertainly located catheter tips close to gray-white matter interfaces, backflow could diminish delivery, shunting infusate across the interfaces. For delivery via a multiport catheter at a constant base infusion rate plus a periodic bolus inflow rate (Kentucky study), base inflow alone generated a somewhat smaller distribution volume relative to those in the other trials, was positioned more anteriorly in the putamen, and was somewhat elongated axially; the bolus component extended this putaminal distribution to a larger relative volume but may have been reduced by backflow loss.


CONCLUSIONS
Results of these computations indicated that for catheters placed exactly on the intended target, ideal drug distributions were similar for two of the trials (AmgenUT and Bristol) and different in terms of location and extent in the third study (Kentucky); yet the pattern of trial outcomes did not reflect these same groupings. This finding suggests that other factors are at play, widely varying statistical power and the possible effects of not excluding data from patients who experienced large drug losses across gray tissue boundaries due to variation in catheter placement.
Morrison
Paul F
PF
Division of Bioengineering and Physical Science, Office of Research Services, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA. Morrison@mail.nih.gov
Lonser
Russell R
RR
Oldfield
Edward H
EH
D002408:Catheters, Indwelling; D003342:Corpus Striatum / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D006801:Humans; D008959:Models, Neurological; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology; D011699:Putamen / Q000378:metabolism*
D051100:Glial Cell Line-Derived Neurotrophic Factor