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1.  Long-Term Treatment with Extended-Release Carbidopa–Levodopa (IPX066) in Early and Advanced Parkinson’s Disease: A 9-Month Open-Label Extension Trial 
CNS Drugs  2015;29(4):341-350.
Background and Objective
IPX066 is a multiparticulate extended-release formulation of carbidopa–levodopa, designed to produce prolonged therapeutic levodopa plasma concentrations. This 9-month open-label extension study assessed its long-term safety and clinical utility in early and advanced Parkinson’s disease (PD).
Methods
Participants were enrolled from two phase III IPX066 studies and one open-label phase II study. Early PD patients were titrated to an appropriate dosing regimen while advanced patients started with regimens established in the antecedent studies. Adjustment was allowed throughout the extension. Clinical utility measures included the Unified Parkinson’s Disease Rating Scale (UPDRS) and Patient Global Impression (PGI) ratings.
Results
Among 268 early PD patients, 53.4 % reported adverse events (AEs) and 1.1 % (three patients) discontinued due to AEs; the most frequent AEs were nausea (5.6 %) and insomnia (5.6 %). Among 349 advanced patients, 60.2 % reported AEs and 3.7 % (13 patients) discontinued due to AEs; the most frequent AEs were dyskinesia (6.9 %) and fall (6.6 %). At month 9 (or early termination), 78.3 % of early patients were taking IPX066 three times daily (median: 720 mg/day) and 87.7 % of advanced patients were taking IPX066 three or four times daily (median: 1450 mg/day). Adjusting for 70 % bioavailability relative to immediate-release (IR) carbidopa–levodopa, the median dosages correspond to ~500 and ~1015 mg/day of IR levodopa in early and advanced PD, respectively. Based on the plasma profiles previously observed in PD patients, the IPX066 regimens in the extension can be estimated to provide a levodopa Cmax (maximum plasma drug concentration) similar to or lower than that provided by IR regimens during the antecedent trials. UPDRS and PGI findings showed sustained treatment effects throughout the extension.
Conclusion
During 9 months of extended use, IPX066 exhibited a safety/tolerability profile consistent with dopaminergic PD therapy.
doi:10.1007/s40263-015-0242-2
PMCID: PMC4555339  PMID: 25895021
2.  Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products: Workshop Summary Report 
The AAPS Journal  2010;12(3):371-377.
Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.
doi:10.1208/s12248-010-9201-5
PMCID: PMC2895434  PMID: 20440588
bioequivalence; interchangeability; modified release; pharmaceutical equivalence; therapeutic equivalence
3.  Pharmacokinetic profile of a 24-hour controlled-release OROS® formulation of hydromorphone in the presence and absence of food 
Background
The objective of this study was to compare the pharmacokinetic profile of a novel, once-daily, controlled-release formulation of hydromorphone (OROS® hydromorphone) under fasting conditions with that immediately after a high-fat breakfast in healthy volunteers. The effect of the opioid antagonist naltrexone on fasting hydromorphone pharmacokinetics also was evaluated.
Methods
In an open-label, three-way, crossover study, 30 healthy volunteers were randomized to receive a single dose of 16 mg OROS® hydromorphone under fasting conditions, 16 mg OROS® hydromorphone under fed conditions, or 16 mg OROS® hydromorphone under fasting conditions with a naltrexone 50-mg block. Plasma samples taken pre-dose and at regular intervals up to 48 hours post-dose were assayed for hydromorphone concentrations. Analysis of variance was performed on log-transformed data; for mean ratios of 0.8 to 1.2 (20%), differences were considered minimal. Bioequivalence was reached if 90% confidence intervals (CI) of treatment mean ratios were between 80% and 125%.
Results
The mean geometric ratios of the fed and fasting treatment groups for maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-t; AUC0-∞) were within 20%. Confidence intervals were within 80% to 125% for AUC0-t and AUC0-∞ but were slightly higher for Cmax (105.9% and 133.3%, respectively). With naltrexone block, the hydromorphone Cmax increased by 39% and the terminal half-life decreased by 4.5 hours. There was no significant change in Tmax, AUC0-t or AUC0-∞.
Conclusion
Standard bioavailability measures show minimal effect of food on the bioavailability of hydromorphone from OROS® hydromorphone. Naltrexone co-administration results in a slight increase in the rate of absorption but not the extent of absorption.
Trial Registration
Clinical Trials.gov NCT00399295
doi:10.1186/1472-6904-7-2
PMCID: PMC1810515  PMID: 17270055
4.  Pharmacokinetic investigation of dose proportionality with a 24-hour controlled-release formulation of hydromorphone 
Background
The purpose of this study was investigate the dose proportionality of a novel, once-daily, controlled-release formulation of hydromorphone that utilizes the OROS® Push-Pull™ osmotic pump technology.
Methods
In an open-label, four-way, crossover study, 32 healthy volunteers were randomized to receive a single dose of OROS® hydromorphone 8, 16, 32, and 64 mg, with a 7-day washout period between treatments. Opioid antagonism was provided by three or four doses of naltrexone 50 mg, given at 12-hour intervals pre- and post-OROS® hydromorphone dosing. Plasma samples for pharmacokinetic analysis were collected pre-dose and at regular intervals up to 48 hours post-dose (72 hours for the 64-mg dose), and were assayed for hydromorphone concentration to determine peak plasma concentration (Cmax), time at which peak plasma concentration was observed (Tmax), terminal half-life (t1/2), and area under the concentration-time curve for zero to time t (AUC0-t) and zero to infinity (AUC0–∞). An analysis of variance (ANOVA) model on untransformed and dose-normalized data for AUC0-t, AUC0–∞, and Cmax was used to establish dose linearity and proportionality.
Results
The study was completed by 31 of 32 subjects. Median Tmax (12.0–16.0 hours) and mean t1/2 (10.6–11.0 hours) were found to be independent of dose. Regression analyses of Cmax, AUC0–48, and AUC0–∞ by dose indicated that the relationship was linear (slope, P ≤ 0.05) and that the intercept did not differ significantly from zero (P > 0.05). Similar analyses with dose-normalized parameters also indicated that the slope did not differ significantly from zero (P > 0.05).
Conclusion
The pharmacokinetics of OROS® hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses.
Trial Registration
Clinical Trials.gov NCT00398957
doi:10.1186/1472-6904-7-3
PMCID: PMC1808051  PMID: 17270058
5.  Effect of OROS® controlled-release delivery on the pharmacokinetics and pharmacodynamics of oxybutynin chloride 
Aims
Dry mouth is a common side-effect seen with immediate-release oxybutynin (IR-Oxy). Ditropan XL® [(Oxy-XL), a controlled-release formulation of oxybutynin chloride, is a once-daily oral dosage form that incorporates the OROS® technology. Dry mouth as the pharmacodynamic measure was compared between Oxy-XL and IR-Oxy administration. The steady state stereospecific pharmacokinetics were also established for the two formulations and the kinetic-dynamic relationship of oxybutynin was examined.
Methods
This was a randomized, repeated-dose, double-blind, two-treatment, two-period, crossover study. After a baseline assessment day, volunteers were randomly assigned to one of two treatment sequences and received 4 days of each treatment with a washout period of 7 days between treatments. The treatments were: 1) Oxy-XL 10 mg in the morning and placebo 8 h later, and 2) IR-Oxy 5 mg in the morning and again 8 h later. Volunteers assessed dry mouth severity subjectively using a 100 mm visual analogue scale, VAS (Baseline, treatment days 1 and 4) and objectively by collecting saliva (Baseline and treatment day 4) before dosing and every hour after the morning dose for ∼16 h. Several blood samples were collected during each treatment, with frequent sampling on day 4 to analyse for plasma R- and S-oxybutynin and R- and S-desethyloxybutynin concentrations.
Results
Relatively constant plasma concentrations of oxybutynin and its metabolite were seen over 24 h following Oxy-XL administration with the degree of fluctuation being much lower (P = 0.001; 66% to 81% reduction for the various analytes) than IR-Oxy. Compared with IR-Oxy, Oxy-XL yielded higher (131% and 158% for the R- and S-isomer, respectively) oxybutynin and lower (62% and 78% for the R- and S-isomer, respectively) desethyloxybutynin bioavailability, suggesting reduced first-pass metabolism. Saliva output (area under the effect curve) was significantly higher [P = 0.001; 37% (95% confidence interval: 24, 51%)] with Oxy-XL than with IR-Oxy and, accordingly, dry mouth severity (VAS) integrated over the day was significantly lower with Oxy-XL. The decrease in saliva output and the consequent increase in dry mouth severity correlated with the metabolite R-desethyloxybutynin concentration, and no apparent relationship was observed with the R-oxybutynin concentration. This suggests that the metabolite may contribute to the dry mouth. Therefore, the reduction in metabolite exposure with Oxy-XL may be a possible explanation for the observed decrease in dry mouth severity with OXY-XL compared with IR-Oxy.
Conclusions
Oxy-XL maintains relatively constant plasma drug and metabolite concentrations and minimizes first-pass metabolism of oxybutynin. The metabolite appears to contribute to dry mouth associated with oxybutynin, and following Oxy-XL metabolite exposure is reduced compared with IR-Oxy. Consequently less dry mouth was observed with Oxy-XL as compared with IR-Oxy.
doi:10.1046/j.0306-5251.2001.01463.x
PMCID: PMC2014596  PMID: 11678784
anticholinergic; controlled-release; Ditropan XL®; dry mouth; OROS® systems; oxybutynin; urinary incontinence
6.  Pharmacokinetic and pharmacodynamic characterization of OROS® and immediate-release amitriptyline 
Aims
To characterize the pharmacokinetics of amitriptyline and its metabolite nortriptyline following OROS® and IR treatments, and to correlate them with anticholinergic side-effects.
Methods
The pharmacokinetics and safety of amitriptyline following administration of an osmotic controlled release tablet (OROS® and an immediate release (IR) tablet were evaluated in 14 healthy subjects. In this randomized, open label, three-way crossover feasibility study, the subjects received a single 75 mg OROS® tablet, three 25 mg IR tablets administered every 8 h, or 3×25 mg IR tablets administered at nighttime. In each treatment arm serial blood samples were collected for a period of 84 h after dosing. The plasma samples were analysed by gas chromatography for amitriptyline and its metabolite nortriptyline. Anticholinergic effects such as saliva output, visual acuity, and subject-rated drowsiness and dry mouth were measured on a continuous scale during each treatment period.
Results
Following dosing with OROS® (amitriptyline hydrochloride), the mean maximal plasma amitriptyline concentration Cmax (15.3 ng ml−1) was lower and the mean tmax (25.7 h) was longer than that associated with the equivalent IR dose administered at nighttime (26.8 ng ml−1 and 6.3 h, respectively). The bioavailability of amitriptyline following OROS® dosing was 95% relative to IR every 8 h dosing, and 89% relative to IR nighttime dosing. The metabolite-to-drug ratios after the three treatment periods were similar, suggesting no change in metabolism between treatments. The relationships between plasma amitriptyline concentration and anticholinergic effects (e.g. reduced saliva weight, dry mouth, and drowsiness) were similar with all three treatments. Of the anticholinergic effects, only decreased saliva weight and dry mouth correlated well with plasma amitriptyline concentrations; drowsiness did not. There was no apparent correlation between anticholinergic effects and the plasma nortriptyline concentration.
Conclusions
The bioavailability of OROS® (amitriptyline hydrochloride) was similar to that of the IR treatments and the pharmacokinetics of amitriptyline after OROS® dosing may decrease the incidence of anticholinergic effects compared with that seen with nighttime dosing of the IR formulation. Therefore, this controlled-release formulation of amitriptyline may be appropriate for single daily administration.
doi:10.1046/j.1365-2125.1999.00973.x
PMCID: PMC2014871  PMID: 10383563
amitriptyline; anticholinergic effects; controlled-release; pharmacodynamics; pharmacokinetics
7.  Population Pharmacodynamics of IPX066: An Oral Extended-Release Capsule Formulation of Carbidopa–Levodopa, and Immediate-Release Carbidopa–Levodopa in Patients With Advanced Parkinson’s Disease 
Journal of Clinical Pharmacology  2013;53(5):523-531.
A pharmacodynamic model is presented to describe the motor effects (tapping rate, Unified Parkinson’s Disease Rating Scale [UPDRS] Part III, and investigator-rating of ON/OFF, including dyskinesia) of levodopa (LD) in patients with advanced idiopathic Parkinson’s disease (PD) treated with immediate-release (IR) carbidopa–levodopa (CD–LD) or an extended-release (ER) formulation of CD–LD (IPX066). Twenty-seven patients participated in this open-label, randomized, single-and multiple-dose, crossover study. The pharmacodynamic models included a biophase effect site with a sigmoid Emax transduction for tapping and UPDRS and an ordered categorical model for dyskinesia. The pharmacodynamics of LD was characterized by a conduction function with a half-life of 0.59 hours for tapping rate, and 0.4 hours for UPDRS Part III and dyskinesia. The LD concentration for half-maximal effect was 1530 ng/mL, 810 ng/mL, and 600 ng/mL for tapping rate, UPDRS Part III, and dyskinesia, respectively. The sigmoidicity of the transduction was 1.53, 2.5, and 2.1 for tapping rate, UPDRS Part III, and dyskinesia, respectively. External validation of the pharmacodynamic model using tapping rate indicated good performance of the model.
doi:10.1002/jcph.63
PMCID: PMC3798100  PMID: 23426902
IPX066; levodopa; Parkinson’s disease; pharmacodynamics

Results 1-7 (7)