aminomethyl )-1-cyclohexane Acetic Acid ] , A Novel Gabapentin Prodrug : II . Improved Oral Bioavailability , Dose Proportionality , and Colonic Absorption Compared with Gabapentin in Rats and Monkeys

The absorption of gabapentin (Neurontin) is dose-dependent and variable between patients. Rapid clearance of the drug necessitates dosing three 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 highcapacity 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, whereas exposure to intact XP13512 was low. In rats, 95% of an oral dose of C-XP13512 was excreted in urine in 24 h as gabapentin. In monkeys, oral bioavailability of gabapentin from XP13512 capsules was 84.2% compared with 25.4% after a similar oral Neurontin dose. Compared with 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 interpatient variability, and decreasing frequency of dosing. Gabapentin (Fig. 1) is a structural analog of GABA with demonstrated therapeutic utility in epilepsy (McLean, 1999), neuropathic pain (Backonja et al., 1998; Rowbotham et al., 1998; Rice and Maton, 2001), restless legs syndrome (GarciaBorreguero et al., 2002), anxiety disorders (Pollack et al., 1998), hot flashes (Guttoso et al., 2003), and numerous other indications. The drug is currently marketed in the United States under the brand name Neurontin as an adjunctive therapy for partial seizures in adults with epilepsy and for management of postherpetic neuralgia. The mechanism of action of gabapentin in most indications remains undefined, but the drug does not directly interact with GABA receptors (Kelly, 1998). Its efficacy in neuropathic pain and epilepsy may involve binding of the drug to the 2 subunit of a voltage-dependent calcium channel (Gee et al., 1996; Marais et al., 2001). The clinical pharmacokinetics of gabapentin have been studied in healthy volunteers and patients with epilepsy (McLean, 1995; Gidal et al., 1998, 2000; Boyd et al., 1999). Gabapentin bioavailability is dose-dependent, decreasing from an average of about 60% at a 300-mg dose to about 35% or less at doses used to treat neuropathic pain. The underlyArticle, publication date, and citation information can be found at http://jpet.aspetjournals. org. doi:10.1124/jpet.104. 067959. ABBREVIATIONS: XP13512, ( )-1-([( -isobutanoyloxyethoxy)carbonyl]aminomethyl)-1-cyclohexane acetic acid; SMVT, sodium-dependent multivitamin transporter; MCT-1, monocarboxylate transporter type 1; HPLC, high-pressure liquid chromatography; GP, gabapentin; LC/MS/MS, liquid chromatography-tandem mass spectrometry; CSF, cerebrospinal fluid; t1/2, elimination half-life; Tmax, time to maximum concentration; AUC(0-inf), area under the concentration versus time curve extrapolated to infinity; AUC, area under the curve. 0022-3565/04/3111-324–333$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 311, No. 1 Copyright © 2004 by The American Society for Pharmacology and Experimental Therapeutics 67959/1166481 JPET 311:324–333, 2004 Printed in U.S.A.