Time

Executive Director, Clinical Pharmacology, PK/ADME, Xenoport, Inc.

Clinical Pharmacology of Gabapentin Enacarbil (XP13512): A Novel Transported Prodrug of Gabapentin

Dec 12, 2008

Gabapentin absorption occurs in only a limited region of the small intestine and saturates at doses used clinically, resulting in dose-dependent pharmacokinetics, high inter-patient variability in pharmacokinetics, and potentially ineffective response. Gabapentin enacarbil is a novel Transported Prodrug of gabapentin that is absorbed throughout the entire length of the intestine by high-capacity nutrient transporters, monocarboxylate transporter-1 (MCT-1) and sodium dependent multi vitamin transporter (SMVT). In preclinical studies, gabapentin enacarbil demonstrated dose-proportional exposures and absorption throughout the GI tract, including the colon. Gabapentin enacarbil has been formulated as an extended release tablet and is under investigation for the treatment of Restless Legs Syndrome (RLS), neuropathic pain due to diabetic peripheral neuropathy, post herpetic neuralgia and prophylaxis of migraine headache. In clinical studies, gabapentin enacarbil extended release tablets were well absorbed and produced approximately dose-proportional gabapentin exposures up to the highest dose evaluated of 6000 mg. Gabapentin enacarbil is almost completely converted to gabapentin by carboxylesterases, with intact prodrug levels in the systemic circulation ≤2% of gabapentin exposures. Prolonged absorption of gabapentin to the systemic circulation was delivered by the gabapentin enacarbil extended-release formulation. The time to reach maximum blood concentrations of gabapentin released from gabapentin enacarbil is 7–9 hr. The elimination half-life is consistent with that of oral gabapentin. Food, regardless of fat/caloric content, increased the bioavailability of gabapentin following administration of gabapentin enacarbil. Gabapentin enacarbil is not a substrate, inhibitor, or inducer for cytochrome P450s. Also, there were no clinically relevant drug-drug interactions with MCT-1 and OCT2 substrates. Gabapentin enacarbil, therefore, provides more predictable dose-proportional gabapentin exposure, with low inter-subject variability and allow once daily administration for the indication of RLS.

11:30-12:00 PM: Registration/lunch

12:00 – 1:00 PM: Presentation

$25 (includes lunch)

CVT

Address: 1651 Page Mill Road,  Palo Alto, CA 94304

12:30 PM: Authors put up posters

1 PM: Registration and Poster Social with refreshments

2-4 PM: Podium presentations

4-5 PM: Poster Social with light snacks and refreshments

$25

TBD

Mar./Apr., 2009

“Introduction to Physiologically-based PK/PD Modeling and Case Studies”

Lunch included

12:30 – 500 PM

Crowne Plaza

Foster, City