Wendy Luo's research while affiliated with XenoPort, Inc. and other places

Publications (25)

Article
Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that provides sustained dose-proportional exposure to gabapentin and predictable bioavailability. Gabapentin enacarbil is approved by the US Food and Drug Administration for the treatment of moderate-to-severe primary restless legs syndrome (RLS) in adults. Using plasma gab...
Article
The objective of this study was to determine steady-state gabapentin exposures and corresponding relief of symptoms and safety profile produced by 4 dose levels of gabapentin enacarbil (GEn) in subjects with restless legs syndrome (RLS). Subjects with RLS (n = 217) were randomized to receive once-daily, orally administered GEn 600 (n = 48), 1200 (n...
Article
The objectives of this study were to assess the pharmacokinetic profile, efficacy, and safety of XP21279 administered with carbidopa (CD) in subjects with Parkinson disease (PD) experiencing motor fluctuations and explore dose correspondence between CD-levodopa (LD) and XP21279 administered with CD. Subjects received CD-LD 3 or 4 times daily for 2...
Article
Gabapentin enacarbil, a transported prodrug of gabapentin, was recently approved by the US Food and Drug Administration for the treatment of moderate to severe restless legs syndrome. As part of the overall safety evaluation of gabapentin enacarbil, the present definitive QT/QTc study was conducted to assess the effects of gabapentin enacarbil on c...
Article
Background: Gabapentin enacarbil, a transported acyloxyalkylcarbamate prodrug of gabapentin, provides predictable and dose-proportional gabapentin exposure (AUC). Gabapentin is cleared via renal excretion, and its elimination is proportional to creatinine clearance (CrCL); CrCL can, therefore, be used as a predictor of gabapentin renal clearance....
Article
Arbaclofen placarbil (AP), previously designated as XP19986, is an investigational prodrug of the active R-isomer of baclofen, a gamma-aminobutyric acid agonist reflux inhibitor. The aim of this study was to assess the efficacy and safety of AP for decreasing meal-induced reflux episodes in patients with gastroesophageal reflux disease (GERD). We c...
Article
Full-text available
Gabapentin enacarbil, a transported prodrug of gabapentin, provides sustained, dose-proportional exposure to gabapentin. Unlike gabapentin, the prodrug is absorbed throughout the intestinal tract by high-capacity nutrient transporters, including mono-carboxylate transporter-1 (MCT-1). Once absorbed, gabapentin enacarbil is rapidly hydrolyzed to gab...
Article
Gabapentin enacarbil is an actively transported prodrug of gabapentin that provides predictable dose-proportional gabapentin exposure with high (> or =68%) oral bioavailability. The aims of this study were to investigate the pharmacokinetics and tolerability of gabapentin enacarbil up to supratherapeutic doses and the effects of gabapentin enacarbi...
Article
Full-text available
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 through...
Article
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...
Article
The absorption of gabapentin (Neurontin) is dose-dependent and variable between patients. Rapid clearance of the drug necessitates dosing three or more times per day to maintain therapeutic levels. These deficiencies appear to result from the low capacity, limited intestinal distribution, and variable expression of the solute transporter responsibl...

Citations

... AP is developed in a sustained-release formulation, allowing for decreased dosing frequency with reduced fluctuation in R-baclofen exposure due to its absorption in the lower GI tract. 9 This may lead to improved efficacy and a decreased incidence of adverse effects compared with racemic baclofen. Therefore, this present study assessed the efficacy of AP for decreasing the total number of reflux episodes in patients with GERD, in whom substantial baseline incidence of meal-induced reflux was confirmed by impedance/pH measurements. ...
... 4 While the mechanism of absorption of gabapentin enacarbil differs from that of gabapentin, the distribution and elimination PK of gabapentin subsequently released into the bloodstream are identical; gabapentin, when dosed either as gabapentin or gabapentin enacarbil, is not metabolized and is thus excreted unchanged in the urine. 10,15 In contrast to gabapentin, the absorption pathway of gabapentin enacarbil does not become saturated at clinically relevant doses, allowing greater bioavailability of the active drug. 13,16 Gabapentin enacarbil is absorbed through the gastrointestinal (GI) tract and has dose-proportional and predictable PK over a wide dose range, resulting in lower variability of gabapentin exposure compared with the administration of other gabapentin formulations. ...
... These results suggest treatment with GEn could reduce dosing frequency, improve compliance, and have prolonged effects in patients compared to those treated with GBP. In 2011, the FDA approved the use of the extended-release formulation of GEn (Horizant) to treat moderate-to-severe primary restless legs syndrome (RLS), for which this prodrug has shown efficacy in several clinical trials [109,110], and in 2012, for the management of postherpetic neuralgia. As there is no therapeutically equivalent version of Horizant available in the USA (i.e., generic product), the costs of Horizant are significantly higher than GBP. ...
... Though carbamazepine has sodium-channel blocking properties, at least one study suggests decreasing QTc interval with increasing carbamazepine concentrations (103). In a double-blind, placebo-and active-controlled trial, gabapentin enacarbil, a transported prodrug of gabapentin, was not associated with QTc interval prolongation in healthy adults (104). ...
... Levodopa is primarily absorbed in the upper part of the small intestine (duodenum and jejunum) with the help of amino acid transporters [100]. XP21279 is a prodrug of levodopa that can be absorbed in both the small and the large intestine by nutritional transporters that can provide sustained levels of levodopa and avoid fluctuations [100]. ...
... Altogether, these results suggest that gabapentin is an effective therapy for RLS in ESRD patients with acceptable risk of side effects. However, the studies addressing the pharmacokinetics and pharmacodynamics of gabapentinoids in ESRD patients are limited [50][51][52], and gabapentin should still be used with caution for RLS treatment in ESRD patients. As of now, no available studies have investigated the impact of pregabalin and gabapentin enacarbil on RLS in ESRD patients. ...
... This variability is due to the GAB dose-dependent bioavailability and the saturation of active transport during the absorption (Stewart et al., 1993;Gidal et al., 1998). Furthermore, age/glomerular filtration rate or renal drug transporters activity can influence GAB pharmacokinetics (Boyd et al., 1999;Urban et al., 2008;Lal et al., 2010;Ahmed et al., 2017;Yamamoto et al., 2019). In this study, patients using OCT2 and OCTN1 inhibitors were excluded, since these drug transporters were reported to be involved in GAB elimination (Urban et al., 2008;Lal et al., 2010). ...
... The gamma-aminobutyric acid type B (GABA-B) receptor agonist, baclofen, significantly reduces the occurrence of TLOSRs, thereby significantly decreasing reflux episodes after a meal in both healthy controls and patients with GERD. [7][8][9][10][11] Furthermore, in patients with duodeno-gastrooesophageal reflux (DGOR) that persisted during PPI treatment, add-on therapy with baclofen improved both the objectively measured DGOR and a composite reflux symptom score. 12,13 GABA-B agonists, therefore, have the potential to provide a next step in the treatment approach of GERD, when reflux symptoms are refractory to PPI use. ...
... 10,15 In contrast to gabapentin, the absorption pathway of gabapentin enacarbil does not become saturated at clinically relevant doses, allowing greater bioavailability of the active drug. 13,16 Gabapentin enacarbil is absorbed through the gastrointestinal (GI) tract and has dose-proportional and predictable PK over a wide dose range, resulting in lower variability of gabapentin exposure compared with the administration of other gabapentin formulations. 16,17 Hence, the same doses of gabapentin enacarbil and gabapentin formulations cannot be regarded clinically as bioequivalent and interchangeable. ...
... notably, previous studies have suggested that VPa rodent models exhibit GaBaergic signalling dysfunction, extensive alterations in neuronal morphology and local neocortical microcircuit disorder (24)(25)(26)(27)(28)(29)(30)(31)(32)(33). The GaBaB receptor (GaBaBr2) agonist STX209 is an exploratory drug comprising the single, active r-enantiomer of baclofen (r-baclofen) and has the advantage of being a biologically defined and active enantiomer (34,35). The potential of STX209 to treat autism symptoms in VPa model mice has attracted our attention. ...