Pharmacokinetic and behavioral characterization of a long-term antipsychotic delivery system in rodents and rabbits.
BACKGROUND
Non-adherence with medication remains the major correctable cause of poor outcome in schizophrenia. However, few treatments have addressed this major determinant of outcome with novel long-term delivery systems.


OBJECTIVE
The aim of this study was to provide biological proof of concept for a long-term implantable antipsychotic delivery system in rodents and rabbits.


METHODS
Implantable formulations of haloperidol were created using biodegradable polymers. Implants were characterized for in vitro release and in vivo behavior using prepulse inhibition of startle in rats and mice, as well as pharmacokinetics in rabbits.


RESULTS
Behavioral measures demonstrate the effectiveness of haloperidol implants delivering 1 mg/kg in mice and 0.6 mg/kg in rats to block amphetamine (10 mg/kg) in mice or apomorphine (0.5 mg/kg) in rats. Additionally, we demonstrate the pattern of release from single polymer implants for 1 year in rabbits.


CONCLUSIONS
The current study suggests that implantable formulations are a viable approach to providing long-term delivery of antipsychotic medications in vivo using animal models of behavior and pharmacokinetics. In contrast to depot formulations, implantable formulations could last 6 months or longer. Additionally, implants can be removed throughout the delivery interval, offering a degree of reversibility not available with depot formulations.
Metzger
Kayla L
KL
Stanley Center for Experimental Therapeutics in Psychiatry, Translational Research Laboratories, University of Pennsylvania, Philadelphia, PA 19104, USA.
Shoemaker
Jody M
JM
Kahn
Jonathan B
JB
Maxwell
Christina R
CR
Liang
Yuling
Y
Tokarczyk
Jan
J
Kanes
Stephen J
SJ
Hans
Meredith
M
Lowman
Anthony M
AM
Dan
Nily
N
Winey
Karen I
KI
Swerdlow
Neal R
NR
Siegel
Steven J
SJ
D000161:Acoustic Stimulation; D000661:Amphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001143:Arousal / Q000187:drug effects* / Q000502:physiology; D001672:Biocompatible Materials; D004343:Drug Implants; D006220:Haloperidol / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007266:Inhibition, Psychological; D019344:Lactic Acid; D008134:Long-Term Care; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology
D014150:Antipsychotic Agents; D001672:Biocompatible Materials; D004343:Drug Implants; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000661:Amphetamine; D006220:Haloperidol; D001058:Apomorphine