Abstract
The absorption of gabapentin (Neurontin®) is dose-dependent and variable
between patients. Rapid clearance of the drug necessitates dosing 3 or more times per
day to maintain therapeutic levels. These deficiencies appear to result from the low
capacity, limited intestinal distribution, and variable expression of the solute transporter
responsible for gabapentin absorption. Saturation of this transporter at doses used
clinically leads to unpredictable drug exposure and potentially ineffective therapy in
some patients. XP13512 [(±)-1-([( -isobutanoyloxyethoxy)carbonyl]aminomethyl)-1-
cyclohexane acetic acid] is a novel prodrug of gabapentin designed to be absorbed by
high capacity nutrient transporters located throughout the intestine. XP13512 was
efficiently absorbed and rapidly converted to gabapentin after oral dosing in rats and
monkeys. Exposure to gabapentin was proportional to prodrug dose, while exposure to
intact XP13512 was low. In rats, >95% of an oral dose of 14C-XP13512 was excreted in
urine in 24 hours as gabapentin. In monkeys, oral bioavailability of gabapentin from
XP13512 capsules was 84.2% compared to 25.4% after a similar oral Neurontin dose.
Compared to intracolonic gabapentin, intracolonic XP13512 gave a 17-fold higher
gabapentin exposure in rats and 34-fold higher in monkeys. XP13512 may therefore be
incorporated into a sustained release formulation to provide extended gabapentin
exposure. XP13512 demonstrated improved gabapentin bioavailability, increased dose-
proportionality, and enhanced colonic absorption. In clinical use, XP13512 may improve
the treatment of neuropathic pain, epilepsy, and numerous other conditions by increasing
efficacy, reducing inter-patient variability, and decreasing frequency of dosing.
