Clinical pharmacokinetics of XP13512, a novel transported prodrug of gabapentin.
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.
Cundy
Kenneth C
KC
XenoPort Inc, 3410 Central Expressway, Santa Clara, CA 95051, USA. kcundy@xenoport.com
Sastry
Srikonda
S
Luo
Wendy
W
Zou
Joan
J
Moors
Tristen L
TL
Canafax
Daniel M
DM
D000328:Adult; D000368:Aged; D000588:Amines / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002214:Capsules; D002219:Carbamates / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003509:Cyclohexanecarboxylic Acids / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D000077206:Gabapentin; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D008970:Molecular Weight; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D012893:Sleep Wake Disorders / Q000139:chemically induced; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
C493250:1-(((alpha-isobutanoyloxyethoxy)carbonyl)aminomethyl)-1-cyclohexaneacetic acid; D000588:Amines; D002214:Capsules; D002219:Carbamates; D003509:Cyclohexanecarboxylic Acids; D011355:Prodrugs; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin