XP13512, A Novel Gabapentin (Neurontin) Prodrug

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Research from J Pharmacol Exp Ther. 2004 May 14 2004

XP13512, A Novel Gabapentin Prodrug: 2. Improved Oral Bioavailability,

Dose Proportionality, and Colonic Absorption Compared to Gabapentin in

Rats and Monkeys.

Cundy KC, malai T, Bu L, De Vera J, Estrela J, Luo W, Shirsat P,

Torneros A, Yao F, Zou J, Barrett RW, Gallop MA.

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-([(alpha-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 (14)C-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.