Arbaclofen Placarbil, a Novel R-Baclofen Prodrug: Improved Absorption, Distribution, Metabolism, and Elimination Properties Compared with R-Baclofen

Abstract

Baclofen is a racemic GABA B receptor agonist that has a number of significant pharmacokinetic limitations, including a narrow window of absorption in the upper small intestine and rapid clearance from the blood. Arbaclofen placarbil is a novel transported prodrug of the pharmacologically active R-isomer of baclofen designed to be absorbed throughout the intestine by both passive and active mechanisms via the monocarboxylate type 1 transporter. Arbaclofen placarbil is rapidly converted to R-baclofen in human and animal tissues in vitro. This conversion seems to be primarily catalyzed in human tissues by human carboxylesterase-2, a major carboxylesterase expressed at high levels in various tissues including human intestinal cells. Arbaclofen placarbil was efficiently absorbed and rapidly converted to R-baclofen after oral dosing in rats, dogs, and monkeys. Exposure to R-baclofen was proportional to arbaclofen placarbil dose, whereas exposure to intact prodrug was low. Arbaclofen placarbil demonstrated enhanced colonic absorption, i.e., 5-fold higher R-baclofen exposure in rats and 12-fold higher in monkeys compared with intracolonic administration of R-baclofen. Sustained release formulations of arbaclofen placarbil demonstrated sustained R-baclofen exposure in dogs with bioavailability up to 68%. In clinical use, arbaclofen placarbil may improve the treatment of patients with gastroesophageal reflux disease, spasticity, and numerous other conditions by prolonging exposure and decreasing the fluctuations in plasma levels of R-baclofen.

Therapeutic options for refractory gastroesophageal reflux disease

“…This in turn may lead to potentially improved efficacy through a combination of greater duration of action, subject's convenience, and better safety profile compared with baclofen. 33,34 A recent study demonstrated that arbaclofen significantly reduced the total number of reflux episodes over 12 h in 44 patients with GERD. 34 The most efficacious dose of arbaclofen (60 mg) significantly reduced acid reflux episodes by 35% and heartburn episodes associated with reflux by 49%.…”

Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury

“…7 In preclinical studies, AP produced dose-proportional exposure to R-baclofen following oral dosing, with limited systemic exposure to intact prodrug. 7 Compared with immediate-release baclofen, AP has a flatter pharmacokinetic profile and more sustained plasma levels allowing less frequent dosing and improved patient convenience.…”

“…7 In preclinical studies, AP produced dose-proportional exposure to R-baclofen following oral dosing, with limited systemic exposure to intact prodrug. 7 Compared with immediate-release baclofen, AP has a flatter pharmacokinetic profile and more sustained plasma levels allowing less frequent dosing and improved patient convenience. After single 20-mg oral doses of a prototype extendedrelease formulation of AP (SR1) in 10 healthy human volunteers, the time to maximal R-baclofen blood concentration (T max ) was 5.05 h under fed conditions (unpublished data on file at XenoPort Inc.), which is longer than the comparable mean T max of 1.9 h after administration of racemic baclofen in a separate study.…”

“…It has not been possible to develop an extended-release formulation of baclofen because its absorption is limited to the upper small intestine. 7,8 Further, oral baclofen is associated with adverse events (AEs) of the central nervous system (for example, somnolence, dizziness, weakness and confusion) and gastrointestinal system (for example, nausea). 8 Rare but serious AEs include hallucinations, seizures and syncope.…”

“…Baclofen is a g-aminobutyric-acid-B agonist 6 that has been used in the United States for more than three decades 7 to alleviate the signs and symptoms of spasticity resulting from SCI or multiple sclerosis. 8 Oral racemic baclofen (R,S-baclofen)…”