XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] 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

Abstract

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 [(Ϯ)-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, Ͼ95% of an oral dose of 14 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) (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., 1998Gidal et al., , 2000Boyd 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, (Ϯ)-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; t 1/2 , elimination half-life; T max , time to maximum concentration; AUC (0-inf) , area under the concentration versus time curve extrapolated to infinity; AUC, area under the curve.

XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane Acetic Acid], A Novel Gabapentin Prodrug: I. Design, Synthesis, Enzymatic Conversion to Gabapentin, and Transport by Intestinal Solute Transporters

“…The purpose of the current work was to evaluate in vitro the metabolism and transport properties of XP13512 in comparison with gabapentin. A companion manuscript describes the effect of the superior transport properties of XP13512 on the resulting oral bioavailability, dose proportionality, colonic absorption, and tissue distribution of gabapentin in preclinical species (Cundy et al, 2004). 14 C]-gabapentin (162 mCi/mmol) was from PerkinElmer Life and Analytical Sciences (Boston, MA).…”

Drugability of Extracellular Targets: Discovery of Small Molecule Drugs Targeting Allosteric, Functional, and Subunit-Selective Sites on GPCRs and Ion Channels

“…(Comprehensive review of the development of drug-like ligands for a 2 d.) The prodrug XP13512 (compound 25, Figure 8) has been shown to improve exposure in two different species compared to dosing gabapentin itself. XP13512 has been demonstrated to increase plasma levels of gabapentin by 9-fold in the monkey and by 17-fold in the rat following oral administration, and 34-fold in the monkey following direct intracolonic administration compared to gabapentin by the same route (Cundy et al, 2004). Compound 26 (Figure 8) is an example of a compound with a tetrazole as a carboxylic acid bioisostere, which was shown to have potent binding to a 2 d and demonstrated robust anticonvulsant activity in vivo.…”

A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Tolerability of Gabapentin Enacarbil in Subjects with Restless Legs Syndrome

“…17 GEn delivers predictable and sustained gabapentin exposure (bioavailability ≥ 68% based on urinary recovery of gabapentin in healthy adults) compared with mgequivalent doses of gabapentin. 16,18,19 In a 12-week, placebo-controlled study, subjects with moderate-to-severe primary RLS reported significantly improved RLS symptoms with GEn 1200 mg compared with placebo. 20 A shorter 2-week study demonstrated significant treatment benefit in subjects with primary RLS with GEn 1200 mg compared with placebo, but not with GEn 600 mg. 21 The present study evaluated the efficacy and tolerability of GEn 1200 mg and 600 mg compared with placebo in subjects with moderate-tosevere primary RLS, to confirm the previous findings for GEn 1200 mg and to further evaluate whether 12-week exposure to GEn 600 mg provided significant treatment benefits.…”

“…13,15 Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that overcomes the pharmacokinetic limitations of gabapentin through absorption by high-capacity nutrient transporters located throughout the large and small intestine. 16,17 After absorption, GEn is rapidly converted to gabapentin by non-specific carboxylesterases, primarily in intestinal epithelial cells. 17 GEn delivers predictable and sustained gabapentin exposure (bioavailability ≥ 68% based on urinary recovery of gabapentin in healthy adults) compared with mgequivalent doses of gabapentin.…”