Double-blind study of the actively transported levodopa prodrug XP21279 in Parkinson's disease.

The objective of this study was to assess the efficacy, safety, and pharmacokinetics of XP21279-carbidopa in patients with Parkinson's disease who experience motor fluctuations compared with immediate-release carbidopa-levodopa tablets. XP21279 is a levodopa prodrug that is actively absorbed by high-capacity nutrient transporters expressed throughout the gastrointestinal tract and then rapidly converted to levodopa by carboxylesterases. XP21279-carbidopa sustained-release bilayer tablets were developed to overcome pharmacokinetic limitations of levodopa by providing more continuous exposure. Patients with motor fluctuations who required carbidopa-levodopa four or five times daily were optimized for 2 weeks each on carbidopa-levodopa four or five times daily and XP21279-carbidopa three times daily in a randomized sequence. Next, they received each optimized treatment for 2 weeks in a double-blind/double-dummy, randomized sequence. The primary outcome measure was change from baseline in daily off time at the end of each double-blind treatment period. All patients at 2 sites underwent pharmacokinetic analyses. Twenty-eight of 35 enrolled patients completed both double-blind treatments. The mean total daily off time was reduced from baseline by a mean (± standard error) of 2.7 hours (± 0.48 hours) for immediate-release carbidopa-levodopa and 3.0 hours (± 0.57 hours) for XP21279-carbidopa (P = 0.49). Among 11 patients who completed pharmacokinetic sampling on each optimized treatment, the percentage deviation from the mean levodopa concentration was lower (P < 0.05) for XP21279-carbidopa than carbidopa-levodopa. Both treatments had a similar incidence of new or worsening dyskinesias. XP21279-carbidopa administered three times daily produced a reduction in off time similar to that of carbidopa-levodopa administered four or five times daily, and the difference was not statistically significant. XP21279-carbidopa significantly reduced variability in levodopa concentrations compared with carbidopa-levodopa.

Actively transported levodopa prodrug XP21279: a study in patients with Parkinson disease who experience motor fluctuations.

OBJECTIVE: 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. METHODS: Subjects received CD-LD 3 or 4 times daily for 2 weeks, followed by XP21279 plus CD 3 times daily for 2 weeks at fixed dosing times, allowing dose adjustment to optimize clinical response, in this multiple-dose, multicenter, open-label, 2-period, sequential-treatment study. Pharmacokinetic parameters, including LD exposure, were assessed over 16 hours on the last day of each treatment period. Levodopa exposure variability was assessed for each treatment using the absolute % deviation from average concentration (Cavg) in each subject. Efficacy assessments included daily self-ratings of OFF time, ON time, and dyskinesias. RESULTS: XP21279 provided significantly less variability in LD concentration compared with CD-LD (P < 0.05) in 10 PD subjects with motor fluctuations, consistent with lower peak-to-trough fluctuation for XP21279. Patterns of percentage of subjects OFF were consistent with the LD concentration-time profiles for each respective treatment. Compared with CD-LD treatment, 6 of 10 study completers experienced reduction of 30% or greater in average daily OFF time during the last 4 days in the XP21279 treatment period. XP21279 resulted in an increase in the time spent ON without troublesome dyskinesias, and the mean time to ON after the first morning XP21279 dose was not delayed, as compared with CD-LD. CONCLUSIONS: XP21279 provided improved pharmacokinetic performance (highlighted by reduction in variability of LD concentration) compared with CD-LD and therefore may provide better control of PD motor fluctuations.

Arbaclofen placarbil in GERD: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: It has been shown that arbaclofen placarbil (AP) inhibits reflux in gastroesophageal reflux disease (GERD) following single oral dosing. This study evaluated the efficacy and safety of AP over 4 weeks in subjects with symptomatic GERD. METHODS: One hundred fifty-six subjects with heartburn and/or regurgitation ≥3 days/week and either no history of taking proton pump inhibitors (PPIs naive, n=58) or at least partial symptom response to PPI therapy (PPI responsive, n=98) were enrolled in this randomized, double-blind, placebo-controlled trial. All GERD therapies including PPIs were discontinued 2 weeks before randomization to AP 20, 40, or 60 mg daily, 30 mg twice daily, or placebo for 4 weeks. Randomization was stratified by prior PPI use. RESULTS: In the primary analysis, change from baseline in weekly heartburn events between AP and placebo for the entire study group was not statistically significant. However, a significant interaction was observed between prior PPI use and response to AP treatment. In pre-planned secondary analyses of the PPI-responsive subgroup, percent reductions from baseline in weekly heartburn events were greater for each AP dose vs. placebo (P<0.05) and the percentage of subjects who reported complete resolution of heartburn during week 4 was higher in each AP treatment group (21, 28, 30, and 50% for AP 20, 40, 60 mg daily, and 30 mg twice daily, respectively) compared with placebo (6%) (P<0.05 for 30 mg twice daily). Corresponding analyses of the PPI-naive subgroup showed no significant differences. AP was well tolerated; withdrawals due to adverse events were infrequent. CONCLUSIONS: AP was not superior to placebo in reducing the number of weekly heartburn events over 4 weeks in the primary analysis of the entire study population. Exploratory subgroup analyses suggest that response to PPI treatment before the study was associated with a response to AP treatment.

Arbaclofen placarbil decreases postprandial reflux in patients with gastroesophageal reflux disease.

OBJECTIVES: 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). METHODS: We conducted a multicenter, randomized, double-blind, crossover study comparing single doses of AP with placebo. Different patients were enrolled at each of four escalating AP doses: 10, 20, 40, and 60 mg. Enrolled patients had GERD symptoms at least three times a week and 20 reflux episodes on impedance/pH monitoring over a period of 2 h. During study visits separated by periods of 3-7 days, patients received single doses of AP or placebo, followed by high-fat meals 2 and 6 h after treatment. The primary end point was the number of reflux episodes over 12 h after treatment. RESULTS: A total of 50 patients were treated; efficacy analysis included 44 patients who received both AP and placebo and had technically satisfactory impedance/pH data. For the combined data from all dose cohorts, there was a statistically significant (P=0.01) decrease in reflux episodes over 12 h after treatment with AP compared with placebo. The mean (s.d.) number of reflux episodes over 12 h after AP treatment was 50.5 (27.2), with a mean reduction of 10.4 (23.9) episodes (17%) compared with placebo, for which a mean (s.d.) number of 60.9 (35.3) episodes was observed. Heartburn events associated with reflux were reduced during treatment with AP compared with placebo. AP seemed to be the most efficacious in the 60-mg dose group, and was well tolerated at all dose levels. CONCLUSIONS: AP decreased reflux and associated symptoms with good tolerability in patients with GERD.