Clinical pharmacokinetics of XP13512, a novel transported prodrug of gabapentin

• Published in: Journal of clinical pharmacology Vol. 48; no. 12; p. 1378
• Main Authors: Cundy, Kenneth C, Sastry, Srikonda, Luo, Wendy, Zou, Joan, Moors, Tristen L, Canafax, Daniel M
• Format: Journal Article
• Language: English
• Published: England 01.12.2008
• Subjects: Adult; Aged; Amines - adverse effects; Amines - metabolism; Amines - pharmacokinetics; Area Under Curve; Biological Availability; Capsules; Carbamates - adverse effects; Carbamates - metabolism; Carbamates - pharmacokinetics; Cross-Over Studies; Cyclohexanecarboxylic Acids - adverse effects; Cyclohexanecarboxylic Acids - metabolism; Cyclohexanecarboxylic Acids - pharmacokinetics; Dizziness - chemically induced; Dose-Response Relationship, Drug; Double-Blind Method; Female; gamma-Aminobutyric Acid - adverse effects; gamma-Aminobutyric Acid - analogs & derivatives; gamma-Aminobutyric Acid - metabolism; gamma-Aminobutyric Acid - pharmacokinetics; Half-Life; Headache - chemically induced; Humans; Male; Middle Aged; Molecular Structure; Molecular Weight; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - pharmacokinetics; Sleep Wake Disorders - chemically induced; Young Adult
• ISSN: 0091-2700
• DOI: 10.1177/0091270008322909

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.