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Keywords:

  • Parkinson's disease;
  • levodopa;
  • motor fluctuations;
  • dyskinesias;
  • XP21279;
  • pharmacokinetics

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Author Roles
  8. Financial Disclosures
  9. References

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. © 2013 International Parkinson and Movement Disorder Society

The most effective and widely used approach to the treatment of Parkinson's disease (PD) involves restoring dopamine synthesis and release in the brain by administration of its precursor, levodopa (l-dopa).[1] Attempts to increase the constancy of plasma l-dopa concentration with sustained-release carbidopa (CD)-l-dopa or inhibitors of catechol-O-methyltransferase and monoamine oxidase type-B have been only partially effective. Therapy with these products, as with immediate-release CD-l-dopa (IR-CD-LD),[2] has clinical utility limited by delayed time to clinical effect and response variability.[3, 4]

Over time the clinical response of a patient with PD often mirrors fluctuations in blood l-dopa concentrations.[5] Approximately 40% of patients with PD experience motor fluctuations within 4 to 6 years of starting l-dopa treatment.[6] The pharmacokinetics of l-dopa explain its inability to provide consistent control of PD symptoms.[7, 8] The peripheral elimination of l-dopa shows a relatively rapid clearance half-life, requiring IR-CD-LD to be given four or more times per day for maintaining therapeutic l-dopa concentrations in the brain. l-Dopa is actively absorbed by low-capacity amino acid transporters primarily in the duodenum and jejunum. The absence of more distal absorption capability for l-dopa has limited the efficacy of sustained-release formulations.

XP21279 is a prodrug of l-dopa that was designed to address the pharmacokinetic limitations of IR-CD-LD. In animal studies, XP21279 is well absorbed from both small and large intestines. After absorption, it undergoes rapid metabolism to l-dopa. The capability for colonic absorption of XP21279 can extend the duration of maintaining therapeutic plasma concentrations of l-dopa. Consequently, the reduced fluctuation of plasma l-dopa concentrations with XP21279 should diminish off time without increasing dyskinesias, while decreasing dosing frequency. The promise of XP21279 was supported by a proof-of-concept pharmacokinetics study in PD patients for whom a sustained-release l-dopa formulation was coadministered with CD tablets[9] and compared with IR-CD-LD.[10]

Patients and Methods

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Author Roles
  8. Financial Disclosures
  9. References

This was a phase 2, randomized, double-blind, double-dummy, crossover efficacy, safety, and pharmacokinetic study of XP21279-CD and IR-CD-LD in patients with PD who were experiencing motor fluctuations. The objectives of the study were to assess the efficacy and safety of XP21279-CD compared with IR-CD-LD, to evaluate the pharmacokinetics of l-dopa after administration of XP21279-CD and IR-CD-LD and exposure-response relationships, and to estimate a dose-conversion ratio. The protocol for this multicenter study was approved by institutional review boards at participating institutions. Written informed consent was obtained from each patient before any study-related activities were performed. The study was registered at http://www.ClinicalTrials.gov (identifier: NCT01171313). Study recruitment started in July 2010, and data collection ended in October 2011. The study was sponsored by XenoPort, Inc. (Santa Clara, CA, USA).

The study design is illustrated in Figure 1. Open-label dosage-optimization periods for IR-CD-LD and XP21279-CD (2 weeks for each treatment in randomized sequence) were followed by randomized, 2-week, double-blind treatment periods. Patients entering the study were randomized to one of four possible sequences, using a 1:1:1:1 allocation, across the open-label and double-blind maintenance phases. All patients enrolled at two study sites underwent blood sampling for pharmacokinetic analysis on the last treatment day of each open-label period.

image

Figure 1. The study design is illustrated. W indicates week; V, clinic visit number; XP21279-CD, XP21279-carbidopa tablets; IR-CD-LD, immediate-release formulation of carbidopa-l-dopa; PK, pharmacokinetics.

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Eligible patients with PD were taking IR-CD-LD four or five times daily, with a total daily l-dopa dose of 400 to 1000 mg for at least 4 weeks, and were experiencing motor fluctuations, defined by wearing off in at least half of inter-dose intervals between the first and last daily doses averaged over 3 diary days and an average daily off time of ≥ 2 hours after the first daily on period through their awake time up to midnight. For at least 4 weeks before screening, patients who were receiving dopaminergic agonists, monoamine oxidase-B inhibitors, amantadine, or anticholinergics were required to maintain stable dosages that could not be changed during the study. Other l-dopa preparations were not permitted.

Based on the previous study,[10] the initial dose conversion chosen for XP21279-CD in the present study provided a milligram-equivalent: l-dopa dose equal to approximately 130% to 150% of the total milligrams of l-dopa per day dosed as IR-CD-LD at baseline. During the optimization periods, investigators could make adjustments based on their clinical judgment or by the following guideline suggested in the study protocol: doses should be increased by 1 unit (ie, one tablet of XP21279-CD or one capsule of IR-CD-LD) at appropriate dose times if there is off time and no dyskinesia or other dose-limiting adverse events (AEs) in the interval prior to the next dose on 2 or more (≥ 2) days of a 3-day diary period. The present study used a sustained-release preparation formulated as a bilayer tablet of XP21279 combined with CD (XP21279-CD). The XP21279 layer contained 241 mg of XP21279 mesylate salt (equivalent to 190 mg free base or 104-mg equivalent of l-dopa), and the CD layer consisted of a 27-mg CD monohydrate (equivalent to 25 mg of anhydrous CD). The l-dopa comparator agent was an over-encapsulated commercial supply of IR-CD-LD,[2] each containing 25 mg CD and 100 mg l-dopa.

XP21279-CD (or XP21279-CD placebo) treatment was given three times daily at 5-hour intervals after the first morning dose. Patients entered the study on IR-CD-LD either four or five times daily; and, during the study, IR-CD-LD (or its matching placebo) treatment was dosed at the same dosing times as pre-study; no change in dosing time or frequency was allowed. All treatments in the study involved fixed dosing frequency; only the dose levels were allowed to change during the optimization phase. Throughout the study, the first morning dose was administered in a fasted state and at a fixed time for all treatments. For XP21279-CD, the subsequent daily doses were administered with food. For IR-CD-LD, the subsequent daily doses could be taken with or without food, and patients whose pre-study IR-CD-LD regimen involved administration with food at certain times of the day continued that practice during the study. In the double-blind maintenance treatment phase, patients were to maintain their optimized doses of IR-CD-LD and XP21279-CD. In a dosing diary, patients recorded the date and time of each dose and whether or not it was taken with food. Rescue doses of IR-CD-LD were allowed during the first 10 days of each treatment with the investigator's consent, but not on days for diary recording or clinic visits.

Efficacy assessments involved on-off diaries,[11] Unified Parkinson's Disease Rating Scale (UPDRS)[12] parts II (activities of daily living) and III (motor assessment), the Parkinson's Disease Questionnaire-39 (PDQ-39),[13] and the investigator-rated and patient-rated Clinical Global Impression Improvement (CGI-I) scale.[14] The primary efficacy endpoint was treatment difference for change from baseline in mean daily off time at the end of double-blind maintenance treatment periods. Secondary efficacy endpoints included: change in mean daily time on without and with troublesome dyskinesias, UPDRS subscales and PDQ-39 scores, and the proportion of responders scored “much improved” or “very much improved” on investigator-rated and patient-rated CGI-I scale at the end of double-blind maintenance treatment periods. Safety assessments included AEs, clinical laboratory findings, electrocardiograms, vital signs, and physical examination.

For patients in the pharmacokinetic substudy, doses were administered and recorded by study staff, and plasma samples were collected for estimating pharmacokinetic parameters at the end of open-label dose-optimization periods (days 14 and 28) through 16 hours after the morning dose. Plasma samples were analyzed to determine concentrations of l-dopa and CD. Estimated plasma pharmacokinetic parameters included maximum concentration (Cmax), area under the plasma concentration-time curve from hour 0 to hour 16 (AUC0–16), average concentration (Cavg; calculated as AUC0–16/16), minimum concentration (Cmin), and bioavailability relative to IR-CD-LD (%Frel AUC). An analysis of the percentage deviation from the l-dopa Cavg was performed according to methods used in previous studies.[10, 15]

The primary endpoint was analyzed using a repeated-measures analysis of covariance model with fixed effects for treatment sequence and treatment week and with baseline off time as a covariate. Statistical analysis was conducted using a two-sided significance level of 0.05. In consideration of the crossover design, the primary population for efficacy analyses was specified in advance as the per-protocol population, consisting of patients who completed visit 12 (see Fig. 1), had non-missing primary efficacy assessments during the double-blind phase, and had no major protocol violations. Only patients who complete both periods of the double-blind crossover provided adequate data for statistical analysis. Based on results from the previous study,[10] a sample size of 24 patients in the per-protocol population was estimated, assuming a mean difference in mean daily off time of 2.3 and a standard deviation (SD) of 3.57 hours, a Type-I error of 0.05, and power of 86%. A prospective outlier analysis was included in the statistical analysis plan. This plan, which was finalized before unblinding, specified sensitivity analyses for the primary endpoint, including the computation of Cook's distance[16] and a plan to repeat the primary endpoint analysis with outliers excluded.

Results

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Author Roles
  8. Financial Disclosures
  9. References

In the safety-set population (35 enrolled patients), 34 patients were white, and 11 were women. The mean age was 60.9 years. The mean (± SD) duration of PD was 8.8 years (± 4.9 years), and the mean (± SD) duration of motor fluctuations was 5.7 years (± 5.5 years). Hoehn and Yahr stage was 2 or 3 for 34 patients. Of the 35 patients, 30 completed the open-label phase and entered the double-blind phase; and, of the 28 patients who completed treatment (the per-protocol population), five were taking IR-CD-LD five times daily, and 23 were taking IR-CD-LD four times daily (Fig. 2). Among the seven patients who withdrew from the study, two withdrew because of AEs, and one withdrew for lack of efficacy. The five patients who discontinued before the double-blind treatment had no data available for the primary analysis. The two patients who entered but did not complete the double-blind treatment had double-blind data available for one of the treatments, but not for the other.

image

Figure 2. This is a Consolidated Standards of Reporting Trials (CONSORT) diagram of the current study. ABAB, BAAB, ABBA, BABA represent the sequences illustrated in Figure 1 (A indicates the immediate-release formulation of carbidopa-l-dopa; B, XP21279-carbidopa tablets). OL indicates open label; AE, adverse event; CC, continuation criteria; LOE, lack of efficacy; DB, double blind.

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In the per-protocol population, the mean (± SD) total daily l-dopa dose administered as IR-CD-LD increased 20% from 673 mg (± 236 mg) at baseline to 809 mg (± 267 mg) at the end of the open-label period. The mean (± SD) total daily l-dopa milligram-equivalent dose administered as XP21279-CD was 1181 mg-equivalent (± 441 mg-equivalent) at the end of the open-label period (46% higher than the mean l-dopa dose at the end of the IR-CD-LD open-label period and 75% higher than the baseline dose).

Across 3 baseline diary days for patients in the per-protocol population, the mean total daily off time was 6.4 hours. At the end of the double-blind period, the mean (± standard error [SE]) total daily off time was reduced from baseline by a mean of 2.7 hours (± 0.48 hours) for IR-CD-LD and 3.0 hours (± 0.57 hours) for XP21279-CD (Fig. 3). The mean (± SE) difference of 0.3 hours (± 0.43 hours) in favor of XP21279-CD was not significant (P = 0.49) in the primary analysis. The primary analysis indicated no significant effect on the treatment difference in mean daily off time for baseline daily l-dopa dose, baseline daily off time, sequence of IR-CD-LD and XP21279-CD, or frequency of IR-CD-l-dopa dosing.

image

Figure 3. Efficacy results at the end of double-blind maintenance treatment. For each endpoint, the left chart shows the results for all per-protocol patients, and the right graph shows the results for the sensitivity analysis excluding outliers. XP21279-carbidopa tablets (XP21279-CD) were administered 3 times daily, and the immediate-release formulation of carbidopa-l-dopa (IR-CD-LD) was administered 4 or 5 times daily. LS indicates least squares; SE, standard error.

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Model-based analysis revealed a significant clinical site effect; four patients (two at each of two sites) had appreciable (≥ 0.3) Cook's distance, suggesting an impact as outliers on the mean treatment effect. A prospectively planned sensitivity analysis was performed to assess the primary endpoint with the four outliers excluded. Among the remaining 24 patients in the per-protocol population, the mean (± SE) daily off time was reduced from baseline by least-squares mean of 3.3 hours (± 0.41 hours) at the end of the double-blind period for XP21279-CD, compared with 2.4 hours (± 0.41 hours) for the IR-CD-LD double-blind period (Fig. 3). The least-squares mean difference of −0.9 hours (± 0.37 hours) reflected a greater reduction in total daily off time for XP21279-CD compared with IR-CD-LD (P = 0.016). Deviations from the protocol may explain the outlier patients: two patients did not take the second and third doses of XP21279-CD with food on diary days during the double-blind periods, and one patient took frequent rescue IR-CD-LD on diary days during the double-blind periods.

Among all per-protocol patients, the 0.5-hour greater increase for XP21279-CD compared with IR-CD-LD in mean daily on time without troublesome dyskinesias from baseline to the end of the double-blind period was not statistically significant (Fig. 3). With outliers excluded, however, a 1.1-hour greater increase in mean daily on time without troublesome dyskinesias was observed for XP21279-CD compared with IR-CD-LD (P = 0.027).

There were no statistically significant treatment differences for change from baseline in the mean daily time on with troublesome dyskinesias in either the per-protocol population or the per-protocol population excluding the outliers (Fig. 3). There were no significant treatment differences in the per-protocol population at the end of the double-blind treatment periods for other secondary outcome measures. At the end of double-blind periods, the mean (± SE) time to on after the first dose of the day for XP21279-CD of 1.0 hours (± 0.13 hours) was not significantly different from the 0.9 hours (± 0.10 hours) for IR-CD-LD in the per-protocol population.

The mean (± SE) total daily off time decreased from baseline to the end of the open-label period by a mean of 2.0 hours (± 0.39 hours) for IR-CD-LD and 3.4 hours (± 0.42 hours) for XP21279-CD in the per-protocol population (Fig. 4). There was a mean greater reduction of 1.4 hours (± 0.29 hours) for XP21279-CD compared with IR-CD-LD.

image

Figure 4. Changes from baseline in the mean daily off during the open-label (OL) optimization period are illustrated in the per-protocol population. LS indicates least squares; SE, standard deviation; IR-CD-LD, immediate-release formulation of carbidopa-l-dopa; XP21279-CD, XP21279-carbidopa tablets.

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Of the 28 patients who completed the study through the double-blind maintenance treatment phase, 11 participated in the pharmacokinetic sub-study (eight patients on IR-CD-LD four times daily and three patients on IR-CD-LD five times daily). Among pharmacokinetic sub-study patients, the mean (± SD) total daily l-dopa dose administered as IR-CD-LD increased from 691 mg (± 270 mg) at baseline to 805 mg (± 259 mg) at the end of the open-label period; and the mean (± SD) total daily l-dopa milligram-equivalent dose administered as XP21279-CD was 1203 mg-equivalent (± 394 mg-equivalent) at end of the open-label period, similar to the overall per-protocol population. An analysis of the l-dopa concentration-time profiles (Table 1) indicated that variability of l-dopa exposure (% absolute deviation from Cavg) was significantly reduced for XP21279-CD (39.4%) compared with IR-CD-LD (52.5%). Table 1 indicates that, across patients, Cavg values were significantly higher with XP21279-CD compared with IR-CD-LD. This difference was not associated with higher mean l-dopa peak concentrations (Cmax) for XP21279-CD than for IR-CD-LD. The mean minimum l-dopa concentrations (Cmin) for XP21279-CD were higher than those for IR-CD-LD. XP21279-CD treatment had overall l-dopa mean bioavailability, measured by the area under the concentration versus time curve (%Frel AUC), of approximately 91% compared with IR-CD-LD treatment. The mean CD Cavg was 0.177 μg/mL for XP21279-CD and 0.124 μg/mL for IR-CD-LD; and the mean CD Cmax was 0.359 μg/mL for XP21279-CD and 0.211 μg/mL for IR-CD-LD.

Table 1. Mean overall pharmacokinetic parameters for l-dopa in plasma after oral dosing with an immediate-release formulation of carbidopa-levodopa or with XP21279-carbidopa tablets in patients from the pharmacokinetic substudy
  Pharmacokinetic parameters for l-dopa in plasmaa 
TreatmentNo. of patientsCmax, μg/mLAUC0–16, μg*h/mLCavg, μg/mLCmin, μg/mL%Frel AUC% Absolute deviation from Cavgb
  1. a

    Values in parentheses are standard deviations except for % absolute deviation from Cavg, for which values in parentheses are standard errors of the mean.

  2. b

    Calculations excluded predose concentration.

  3. c

    Statistically significant difference compared with IR-CD-LD treatment (P < .05).

  4. l-dopa, levodopa; Cmax, maximum concentration; AUC0–16, area under the concentration-time curve from hour 0 to hour 16; Cavg, average concentration; Cmin, minimum concentration; %Frel AUC, bioavailability area under the concentration-time curve relative to IR-CD-LD; IR-CD-LD, immediate-release formulation of carbidopa-l-dopa; NA, not applicable; XP21279-CD, XP21279-carbidopa tablets.

IR-CD-LD113.43 (1.68)19.0 (9.94)1.19 (0.621)0.43 (0.23)NA52.5 (3.24)
XP21279-CD112.91 (1.23)24.5 (9.97)c1.53 (0.623)c0.81(0.38)c90.9 (18.6)39.4 (2.98)c

Figure 5A displays the percentage deviation from each patient's l-dopa Cavg on each treatment, as computed for each time point in relation to dosing, and Figure 5B shows the percentage of patients who were off over time in relation to dosing IR-CD-LD and XP21279-CD. The time course of changes in the fraction of patients who were off was consistent with the l-dopa pharmacokinetic profile for each respective treatment. The reduced fraction of patients with between-dose wearing-off while taking XP21279-CD is consistent with the less variable l-dopa pharmacokinetic profile compared with IR-CD-LD treatment.

image

Figure 5. (A) For individual patients (n = 11) undergoing pharmacokinetic evaluation, the percentage deviation from each patient's average levodopa (l-dopa) concentration (Cavg) on each treatment is plotted at every time point in relation to the first dose, which was given to fasted patients at hour zero for both treatments. The immediate-release formulation of carbidopa-l-dopa (IR-CD-LD) was dosed 4 or 5 times daily at the same dosing times that were used pre-study for each patient. XP21279-carbidopa tablets (XP21279-CD) were given 3 times daily at 5-hour intervals, and the doses at 5 hours and at 10 hours were given with food. (B) The percentages of patients in the pharmacokinetic population who were off medication over time are illustrated after the first dose of the day for each treatment.

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Two patients had an AE (a fall) leading to discontinuation: one on IR-CD-LD in the open-label phase and the other on XP21279-CD during the double-blind treatment phase. The most frequent AE was dyskinesia. New/worsening dyskinesia occurred in seven of 34 patients (21%) on XP21279-CD and in five of 35 patients (14%) on IR-CD-LD in the open-label phase and in four of 30 patients (13%) on XP21279-CD and in three of 28 patients (11%) on IR-CD-LD during the double-blind phase. Other frequent treatment-emergent AEs in the open-label phase were dizziness for IR-CD-LD (5.7%) and insomnia, gastroesophageal reflux disease, and somnolence for XP21279-CD (5.9% each). All AEs were mild or moderate in intensity. There were no treatment-related effects observed in laboratory tests, vital signs, or electrocardiogram results.

Discussion

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Author Roles
  8. Financial Disclosures
  9. References

For the primary study endpoint, the difference between XP21279-CD and IR-CD-LD in total daily off time was not significant in the per-protocol population at end of the double-blind period. The results indicated a similar reduction in total daily off time for XP21279-CD administered three times daily compared with IR-CD-LD administered four or five times daily.

A secondary analysis used Cook's distance,[16] an estimate of the impact of removing a patient from the analysis that identifies statistical outliers with high impact on the mean treatment effect and may be useful for interpreting the results of an exploratory study. When the four patients identified as outliers were excluded in the prespecified sensitivity analysis, XP21279-CD showed significant improvement versus IR-CD-LD. The mean 0.9-hour difference between the two treatments in total daily off time is within the range observed in registration trials for other PD therapies[17-19] and occurred while reducing dosing from four or five times per day to three times per day. The off time improvement with XP21279-CD was not accompanied by increased on time with troublesome dyskinesias compared with IR-CD-LD.

Among the four outlier patients, two did not take the second and third doses of XP21279-CD with food on diary days during the double-blind periods. All IR-CD-LD doses were consistent with the label,[2] which does not specify a requirement for dosing with or without food. The first daily dose of XP21279-CD (administered without food) provided a rapid initial effect similar to that of IR-CD-LD. Subsequent doses, administered with food, achieved a more sustained pharmacokinetic profile compared with IR-CD-LD. In future studies of XP21279-CD, more intensive monitoring for correct dosing in relation to food may help to clarify the potential advantages of this l-dopa prodrug.

At the end of optimization, XP21279-CD achieved a total mean total daily off-time reduction from baseline by 3.4 hours (1.4 hours greater than the reduction for IR-CD-LD in the per-protocol population). The mean 2.0-hour benefit on off time of the titration of IR-CD-LD during the open-label phase suggests that some patients were undertreated at study entry. We found no effect of the open-label treatment sequence on the study outcome. The final optimized doses support the conversion to a total daily dose of XP21279-CD providing 50% greater l-dopa milligram-equivalents than the total daily l-dopa dose at the end of the IR-CD-LD dose-optimization period.

The pharmacokinetic sub-study results indicate that XP21279-CD three times daily reduced variability in l-dopa concentrations compared with IR-CD-LD four or five times daily, and mean l-dopa concentrations were increased for XP21279-CD compared with IR-CD-LD without higher maximum exposures. Although the primary statistical analysis was negative in the present study, and the small number of patients presents limitations for extrapolating to clinical implications, improvement of wearing-off responses and peak-effect dyskinesias would be a logical outcome of less variability in plasma l-dopa concentration.

Acknowledgments

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Author Roles
  8. Financial Disclosures
  9. References

We thank Daniel Bonzo, PhD, Yongmei Zhou, MS, and Amy Bian, ME, for statistical analysis and review. The following investigators, in addition to Peter A. LeWitt, MD, MMSc, enrolled patients into the study: Victor Biton, MD, John Campbell, MD, Aaron Ellenbogen, DO, MPH, Kevin Klos, MD, Grace Liang, MD, Abraham Lieberman, MD, Margery Mark, MD, Paul Nausieda, MD, PhD, Omid Omidvar, MD, William Ondo, MD, and Rajesh Pahwa, MD. Editorial assistance on the article was provided by The Curry Rockefeller Group, LLC.

Author Roles

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Author Roles
  8. Financial Disclosures
  9. References

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

P.A.L.: 1A, 1B, 1C, 2A, 2B, 3A

F.J.H.: 1A, 1B, 1C, 2A, 2B, 3A

R.A.H.: 1A, 1B, 2A, 2B, 3A

D.C.: 1A, 1B, 1C, 2A, 2B, 3A

D.L.: 2B, 3A

K.Z.: 1C

K.C.C.: 1A, 1B, 1C, 2A, 2B, 3A

Financial Disclosures

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Author Roles
  8. Financial Disclosures
  9. References

Dr. LeWitt has served on scientific advisory boards for Civitas, Depomed, Impax, Intec, Ipsen, Knopp Biosciences, Merck, Merz, NeuroDerm, Noven, ProStrakan, Teva, USWorldMeds, and XenoPort and has received speaker honoraria from Ipsen, Lundbeck, Novartis, Teva, and USWorldMeds; he is compensated for services as Editor-in-Chief of Clinical Neuropharmacology and also serves on the editorial boards (without compensation) of Journal of Neurotransmission, Translational Neurodegeneration, and Journal of Parkinson's Disease; in addition, the Parkinson's Disease and Movement Disorders Program that Dr. LeWitt directs has received research grant support (for conducting clinical trial and other research) from Adamas, Addex, Allergan, Biotie, Great Lakes Neurotechnologies, the Michael J. Fox Foundation for Parkinson's Research, Merz, Parkinson Study Group, Phytopharm, Teva, UCB, USWorldMeds, and XenoPort. Dr. Huff is currently a consultant and previously was an employee of XenoPort; he is a consultant and a Clinical Advisory Board member for Epiomed; and he owns stock and stock options in XenoPort. Dr. Hauser has received personal compensation for activities with Boehringer Ingelheim, Teva, Impax, ICB, GE Healthcare, Ipsen, Novartis, Parkinson Study Group, Solvay, Quintiles, Biogen Idec, Allergan, GlaxoSmithKline, BIAL, Lundbeck, Chelsea, Santhera, Merck Serono/EMD Serono, SYNOVIA, Schering-Plough, Shire, XenoPort, Medivation, Addex, Adamas, and Noven; he has also consulted in litigation with lawyers representing various current and former manufacturers of welding consumables; and he has received research support from Pico-Tesla, Schwarz, Genzyme, Acadia, Solvay, Impax, Teva, Merck-Serono, Schering-Plough, Novartis, Ipsen, XenoPort, Chelsea, Allergan, Molecular Biometrics, the Michael J. Fox Foundation for Parkinson's Research, and the National Parkinson Foundation. Drs. Chen, Lissin, Zomorodi, and Cundy are employees of and stockholders of XenoPort.

References

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Author Roles
  8. Financial Disclosures
  9. References
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    Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001;16:448-458.
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    Nyholm D. Pharmacokinetic optimisation in the treatment of Parkinson's disease: an update. Clin Pharmacokinet 2006;45:109-136.
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