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0091270008322909v1
48/12/1378    most recent
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PHARMACOKINETICS

Clinical Pharmacokinetics of XP13512, a Novel Transported Prodrug of Gabapentin

Kenneth C. Cundy, PhD, Srikonda Sastry, PhD, Wendy Luo, MS, Joan Zou, BS, Tristen L. Moors, MS and Daniel M. Canafax, PharmD

From XenoPort Inc, Santa Clara, California.

Gabapentin absorption occurs in only a limited region of the small intestine and saturates at doses used clinically, resulting in dose-dependent pharmacokinetics, high interpatient variability, and potentially ineffective drug exposure. XP13512/GSK1838262 is a novel transported prodrug of gabapentin that is absorbed throughout the entire length of the intestine by high-capacity nutrient transporters. In 4 studies of healthy volunteers (136 subjects total), the pharmacokinetics of XP13512 immediate- and extended-release formulations were compared with those of oral gabapentin. XP13512 immediate-release (up to 2800 mg single dose and 2100 mg twice daily) was well absorbed (>68%, based on urinary recovery of gabapentin), converted rapidly to gabapentin, and provided dose-proportional exposure, whereas absorption of oral gabapentin declined with increasing doses to <27% at 1200 mg. Compared with 600 mg gabapentin, an equimolar XP13512 extended-release dose provided extended gabapentin exposure (time to maximum concentration, 8.4 vs 2.7 hours) and superior bioavailability (74.5% vs 36.6%). XP13512 may therefore provide more predictable gabapentin exposure and decreased dosing frequency.

Key Words: XP13512 • GSK1838262 • gabapentin • bioavailability • pharmacokinetics

Address for reprints: Kenneth C. Cundy, PhD, XenoPort Inc, 3410 Central Expressway, Santa Clara, CA 95051; e-mail: kcundy{at}xenoport.com.


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