title: Biopharmaceutics of intrathecal baclofen-loaded microparticles in a goat model.
abstract: The goal of this study was to develop a goat model allowing reliable pharmacokinetic (PK) studies of intrathecal baclofen (ITB) sustained release dosage forms using an implanted silicone catheter. ITB PK parameters (clearance, volume of distribution) following intrathecal bolus injection were determined for doses ranging from 100 to 560 microg and a comparison to human data was made. Baclofen-loaded microparticles were then implanted in the intrathecal space of goats and the resulting baclofen levels were determined during 28 days. Finally, PK parameters were used to predict cerebrospinal fluid (CSF) baclofen rates from in vitro release profiles of baclofen-loaded microspheres. The catheter was well tolerated and did not interfere with behavioral testings. Baclofen CSF clearance (mean = 8.59+/-2.43 ml/h) and volume of distribution (21.06+/-13.32 ml) were not significantly affected by the increase of the dose (p > 0.05). In vivo, the baclofen levels in CSF were stabilized at 200 microg/l after a period of 3 days. The predictive value of the in vitro release studies was good since the theoretical levels ranged between 128 and 257 microg/l. In conclusion, a large animal model was developed and allowed the biopharmaceutic evaluation of baclofen microparticles injected via intrathecal route.
authors.affiliation: Inserm U 646, 10 rue A Boquel, 49100 Angers, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Lagarce
authors.forename: Nathalie
authors.initials: N
authors.lastname: Faisant
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Desfontis
authors.forename: Laurent
authors.initials: L
authors.lastname: Marescaux
authors.forename: Freddy
authors.initials: F
authors.lastname: Gautier
authors.forename: Delphine
authors.initials: D
authors.lastname: Holopherne
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Rousselet
authors.forename: Philippe
authors.initials: P
authors.lastname: Menei
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Benoit
mesh_terms: D000818:Animals; D001418:Baclofen / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D006041:Goats; D006801:Humans; D007278:Injections, Spinal; D008863:Microspheres; D023421:Models, Animal
chemical_list: D003692:Delayed-Action Preparations; D001418:Baclofen