Biopharmaceutics of intrathecal baclofen-loaded microparticles in a goat model

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 μg 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 μg/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 μg/l. In conclusion, a large animal model was developed and allowed the biopharmaceutic evaluation of baclofen microparticles injected via intrathecal route.